bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Inhibition of Movement
Authors: Coxon James P. , Stinear Cathy M. , Byblow Winston D.
Published: January 2007

In studies of volitional inhibition, successful task performance usually requires the prevention of all movement. In reality, movements are selectively prevented in the presence of global motor output. The aim of this study was to investigate the ability to prevent one movement while concurrently executing another, referred to as selective inhibition. In two experiments, participants released switches with either their index and middle fingers (unimanual) or their left and right index fingers (bimanual) to stop two moving indicators at a fixed target (Go trials). Stop trials occurred when either one or both indicators automatically stopped before reaching the target, signaling that prevention of the prepared movement was required. Stop All and selective Stop trials were randomly interspersed among more frequently occurring Go trials. We found that selective inhibition is harder to perform than nonselective inhibition, for both unimanual and bimanual task contexts. During selective inhibition trials, lift time of the responding digit was delayed in both experiments by ≤100 ms, demonstrating the generality of the result. A nonselective neural inhibitory pathway may temporarily “brake” the required response, followed by selective excitation of the to-be-moved digit's cortical representation. After selective inhibition trials, there were persistent asynchronies between finger lift times of subsequent Go trials. The persistent effects reflect the behavioral consequences of nonspecific neural inhibition combined with selective neural disinhibition.
Shaping the Effects of Transcranial Direct Current Stimulation of the Human Motor Cortex
Authors: Nitsche M. A. , Doemkes S. , Karaköse T. , Antal A. , Liebetanz D. , Lang N. , Tergau F. , Paulus W.
Published: January 2007

Transcranial DC stimulation (tDCS) induces stimulation polarity-dependent neuroplastic excitability shifts in the human brain. Because it accomplishes long-lasting effects and its application is simple, it is used increasingly. However, one drawback is its low focality, caused by 1) the large stimulation electrode and 2) the functionally effective reference electrode, which is also situated on the scalp. We aimed to increase the focality of tDCS, which might improve the interpretation of the functional effects of stimulation because it will restrict its effects to more clearly defined cortical areas. Moreover, it will avoid unwanted reversed effects of tDCS under the reference electrode, which is of special importance in clinical settings, when a homogeneous shift of cortical excitability is needed. Because current density (current strength/electrode size) determines the efficacy of tDCS, increased focality should be accomplished by 1) reducing stimulation electrode size, but keeping current density constant; or 2) increasing reference electrode size under constant current strength. We tested these hypotheses for motor cortex tDCS. The results show that reducing the size of the motor cortex DC-stimulation electrode focalized the respective tDCS-induced excitability changes. Increasing the size of the frontopolar reference electrode rendered stimulation over this cortex functionally inefficient, but did not compromise the tDCS-generated motor cortical excitability shifts. Thus tDCS-generated modulations of cortical excitability can be focused by reducing the size of the stimulation electrode and by increasing the size of the reference electrode. For future applications of tDCS, such paradigms may help to achieve more selective tDCS effects.
Multiple Gene Expression Classifiers from Different Array Platforms Predict Poor Prognosis of Colorectal Cancer
Authors: Lin Yu-Hsin , Friederichs Jan , Black Michael A. , Mages Jörg , Rosenberg Robert , Guilford Parry J. , Phillips Vicky , Thompson-Fawcett Mark , Kasabov Nikola , Toro Tumi , Merrie Arend E. , van Rij Andre , Yoon Han-Seung , McCall John L. , Siewert Jörg Rüdiger , Holzmann Bernhard , Reeve Anthony E.
Published: January 2007

Purpose: This study aimed to develop gene classifiers to predict colorectal cancer recurrence. We investigated whether gene classifiers derived from two tumor series using different array platforms could be independently validated by application to the alternate series of patients.

Experimental Design: Colorectal tumors from New Zealand (n = 149) and Germany (n = 55) patients had a minimum follow-up of 5 years. RNA was profiled using oligonucleotide printed microarrays (New Zealand samples) and Affymetrix arrays (German samples). Classifiers based on clinical data, gene expression data, and a combination of the two were produced and used to predict recurrence. The use of gene expression information was found to improve the predictive ability in both data sets. The New Zealand and German gene classifiers were cross-validated on the German and New Zealand data sets, respectively, to validate their predictive power. Survival analyses were done to evaluate the ability of the classifiers to predict patient survival.

Results: The prediction rates for the New Zealand and German gene-based classifiers were 77% and 84%, respectively. Despite significant differences in study design and technologies used, both classifiers retained prognostic power when applied to the alternate series of patients. Survival analyses showed that both classifiers gave a better stratification of patients than the traditional clinical staging. One classifier contained genes associated with cancer progression, whereas the other had a large immune response gene cluster concordant with the role of a host immune response in modulating colorectal cancer outcome.

Conclusions: The successful reciprocal validation of gene-based classifiers on different patient cohorts and technology platforms supports the power of microarray technology for individualized outcome prediction of colorectal cancer patients. Furthermore, many of the genes identified have known biological functions congruent with the predicted outcomes.
An Integrated Clinical-Genomics Approach Identifies a Candidate Multi-Analyte Blood Test for Serous Ovarian Carcinoma
Authors: Meinhold-Heerlein Ivo , Bauerschlag Dirk , Zhou Yingyao , Sapinoso Lisa M. , Ching Keith , Frierson Henry , Bräutigam Karen , Sehouli Jalid , Stickeler Elmar , Könsgen Dominique , Hilpert Felix , von Kaisenberg Constantin S. , Pfisterer Jacobus , Bauknecht Thomas , Jonat Walter , Arnold Norbert , Hampton Garret M.
Published: January 2007

Purpose: Cancer of the ovary confers the worst prognosis among women with gynecologic malignancies, underscoring the need to develop new biomarkers for detection of early disease, particularly those that can be readily monitored in the blood.

Experimental Design: We developed an algorithm to identify secreted proteins encoded among ∼22,500 genes on commercial oligonucleotide arrays and applied it to gene expression profiles of 67 stage I to IV serous papillary carcinomas and 9 crudely enriched normal ovarian tissues, to identify putative diagnostic markers. ELISAs were used to validate increased levels of secreted proteins in patient sera encoded by genes with differentially high expression.

Results: We identified 275 genes predicted to encode secreted proteins with increased/decreased expression in ovarian cancers (<0.5- or >2-fold, P < 0.001). The serum levels of four of these proteins (matrix metalloproteinase-7, osteopontin, secretory leukoprotease inhibitor, and kallikrein 10) were significantly elevated in a series of 67 independent patients with serous ovarian carcinomas compared with 67 healthy controls (P < 0.001, Wilcoxon rank sum test). Optimized support vector machine classifiers with as few as two of these markers (osteopontin or kallikrein 10/matrix metalloproteinase-7) in combination with CA-125 yielded sensitivity and specificity values ranging from 96% to 98.7% and 99.7% to 100%, respectively, with the ability to discern early-stage disease from normal, healthy controls.

Conclusions: Our data suggest that this assay combination warrants further investigation as a multi-analyte diagnostic test for serous ovarian adenocarcinoma.
Gene Expression Signature and the Prediction of Ulcerative Colitis–Associated Colorectal Cancer by DNA Microarray
Authors: Watanabe Toshiaki , Kobunai Takashi , Toda Etsuko , Kanazawa Takamitsu , Kazama Yoshihiro , Tanaka Junichiro , Tanaka Toshiaki , Yamamoto Yoko , Hata Keisuke , Kojima Tetsu , Yokoyama Tadashi , Konishi Tsuyoshi , Okayama Yoshihiro , Sugimoto Yoshikazu , Oka Toshinori , Sasaki Shin , Ajioka Yohichi , Muto Tetsuichiro , Nagawa Hirokazu
Published: January 2007

Purpose: Ulcerative colitis (UC) is associated with a high risk of colorectal cancer. To identify genes that could predict the development of cancer in UC, we conducted a DNA microarray analysis using nonneoplastic rectal mucosa of UC patients.

Experimental Design: Gene expression in nonneoplastic mucosa of 53 UC patients were examined. Gene expression profiles were examined using human Genome U133 Plus 2.0 gene chip array (Affymetrix). Among 53 UC patients, 10 had UC-associated cancer (UC-Ca group) whereas 43 did not (UC-NonCa group).

Results: By comparing gene expression profiles of nonneoplastic rectal mucosae between the UC-Ca and UC-NonCa groups, we could identify 40 genes that were differentially expressed between two groups. The list of discriminating genes included low-density lipoprotein receptor–related protein (LRP5 and LRP6). Previous studies suggested that LRP5 and LRP6 expression promotes cancer cell proliferation and tumorigenesis and are considered as candidate oncogenes. In the present study, both LRP5 and LRP6 showed significantly higher expression in the UC-Ca group, which suggests the importance of these genes in the development of UC-associated colorectal cancers. With the 40 selected discriminating genes, we did class prediction of the development of colorectal neoplasms in UC patients. Using the k-nearest neighbor method and the support vector machine, we could predict the development of UC-associated neoplasms with an accuracy of 86.8% and 98.1%, respectively.

Conclusions: These findings have important implications for the early detection of malignant lesions in UC and may provide directions for future research into the molecular mechanisms of UC-associated cancer.
Human Glioma Cell Sensitivity to the Sequence-Specific Alkylating Agent Methyl-Lexitropsin
Authors: Bobola Michael S. , Varadarajan Sridhar , Smith Nolan W. , Goff Ryan D. , Kolstoe Douglas D. , Blank A. , Gold Barry , Silber John R.
Published: January 2007

Purpose: Defining the cytotoxicity of individual adducts in DNA is necessary for mechanistic understanding of human brain tumor resistance to therapeutic alkylating agents and for design of DNA repair-related antiresistance strategies. Our purpose is to characterize the sensitivity of human glioma cells to methyl-lexitropsin (Me-lex), a sequence-specific alkylator that produces 3-methyladenine (3-meA) as the predominant (>90%) DNA lesion.

Experimental Design: We quantitated the Me-lex cytotoxicity of 10 human glioma cell lines that differ in O6-methylguanine (O6-meG)-DNA methyltransferase (MGMT) and mismatch repair activity. We used antisense suppression of alkyladenine DNA glycosylase (AAG) and Ape1 to assess the contribution of 3-meA and abasic sites to lethality and measured abasic sites.

Results: (a) The LD10 for Me-lex varied widely among the cell lines. (b) MGMT-proficient lines were more resistant than MGMT-deficient lines, an unexpected finding because Me-lex produces very little O6-meG. (c) Suppression of AAG increased Me-lex killing and reduced abasic site content. (d) Suppression of Ape1 increased Me-lex killing and increased abasic site content. (e) Ablation of MGMT had no effect on Me-lex cytotoxicity.

Conclusions: (a) Me-lex is cytotoxic in human glioma cells and AAG promotes resistance, indicating that 3-meA is a lethal lesion in these cells. (b) Abasic sites resulting from 3-meA repair are cytotoxic and Ape1 promotes resistance to these derivative lesions. (c) A factor(s) associated with MGMT expression, other than repair of O6-meG, contributes to Me-lex resistance. (d) Me-lex may have clinical utility in the adjuvant therapy of gliomas. (e) AAG and Ape1 inhibitors may be useful in targeting alkylating agent resistance.
Cyclophosphamide Enhances the Antitumor Efficacy of Adoptively Transferred Immune Cells through the Induction of Cytokine Expression, B-Cell and T-Cell Homeostatic Proliferation, and Specific Tumor Infiltration
Authors: Bracci Laura , Moschella Federica , Sestili Paola , La Sorsa Valentina , Valentini Mara , Canini Irene , Baccarini Sara , Maccari Sonia , Ramoni Carlo , Belardelli Filippo , Proietti Enrico
Published: January 2007

Purpose: Immunotherapy is a promising antitumor strategy, which can be successfully combined with current anticancer treatments, as suggested by recent studies showing the paradoxical chemotherapy-induced enhancement of the immune response. The purpose of the present work is to dissect the biological events induced by chemotherapy that cooperate with immunotherapy in the success of the combined treatment against cancer. In particular, we focused on the following: (a) cyclophosphamide-induced modulation of several cytokines, (b) homeostatic proliferation of adoptively transferred lymphocytes, and (c) homing of transferred lymphocytes to secondary lymphoid organs and tumor mass.

Experimental Design: Here, we used the adoptive transfer of tumor-immune cells after cyclophosphamide treatment of tumor-bearing mice as a model to elucidate the mechanisms by which cyclophosphamide can render the immune lymphocytes competent to induce tumor rejection.

Results: The transfer of antitumor immunity was found to be dependent on CD4+ T cells and on the cooperation of adoptively transferred cells with the host immune system. Of note, tumor-immune lymphocytes migrated specifically to the tumor only in mice pretreated with cyclophosphamide. Cyclophosphamide treatment also promoted homeostatic proliferation/activation of transferred B and T lymphocytes. Optimal therapeutic responses to the transfer of immune cells were associated with the cyclophosphamide-mediated induction of a “cytokine storm” [including granulocyte macrophage colony-stimulating factor, interleukin (IL)-1β, IL-7, IL-15, IL-2, IL-21, and IFN-γ], occurring during the “rebound phase” after drug-induced lymphodepletion.

Conclusions: The ensemble of these data provides a new rationale for combining immunotherapy and chemotherapy to induce an effective antitumor response in cancer patients.
Cumulative Incidence in Competing Risks Data and Competing Risks Regression Analysis
Authors: Kim Haesook T.
Published: January 2007

Competing risks occur commonly in medical research. For example, both treatment-related mortality and disease recurrence are important outcomes of interest and well-known competing risks in cancer research. In the analysis of competing risks data, methods of standard survival analysis such as the Kaplan-Meier method for estimation of cumulative incidence, the log-rank test for comparison of cumulative incidence curves, and the standard Cox model for the assessment of covariates lead to incorrect and biased results. In this article, we discuss competing risks data analysis which includes methods to calculate the cumulative incidence of an event of interest in the presence of competing risks, to compare cumulative incidence curves in the presence of competing risks, and to perform competing risks regression analysis. A hypothetical numeric example and real data are used to compare those three methods in the competing risks data analysis to their respective counterparts in the standard survival analysis. The source and magnitude of bias from the Kaplan-Meier estimate is also detailed.
Increased Expression of Insulin-like Growth Factor-II Messenger RNA–Binding Protein 1 Is Associated with Tumor Progression in Patients with Lung Cancer
Authors: Kato Tatsuya , Hayama Satoshi , Yamabuki Takumi , Ishikawa Nobuhisa , Miyamoto Masaki , Ito Tomoo , Tsuchiya Eiju , Kondo Satoshi , Nakamura Yusuke , Daigo Yataro
Published: January 2007

Purpose: To identify novel biomarkers and therapeutic targets for lung cancers, we screened for genes that were highly transactivated in a large proportion of non–small cell lung cancers (NSCLC) using a cDNA microarray representing 27,648 genes.

Experimental Design: A gene encoding insulin-like growth factor-II mRNA-binding protein 1 (IMP-1) was selected as a candidate (≥3-fold expression than in normal lung tissue in about 70% of NSCLCs). Tumor tissue microarray was applied to examine expression of IMP-1 protein in archival lung cancer samples from 267 patients and investigated its clinicopathologic significance. A role of IMP-1 in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of IMP-1 on mammalian cells was examined using Matrigel assays. mRNAs associated with IMP-1 in cancer cells were also isolated by RNA immunoprecipitation followed by cDNA microarray analysis.

Results: Positive immunostaining of IMP-1 was correlated with male (P = 0.0001), tumor size (P = 0.0003), non-adenocarcinoma histology (P < 0.0001), smoking history (P = 0.0005), non–well-differentiated tumor grade (P = 0.0001), and poor prognosis (P = 0.0053). Suppression of IMP-1 expression with small interfering RNA effectively suppressed growth of NSCLC cells. In addition, we identified that exogenous expression of IMP-1 increased the migratory activity of mammalian cells. IMP-1 was able to bind to mRNAs encoding a variety of proteins involved in signal transduction, cell cycle progression, cell adhesion and cytoskeleton, and various types of enzymatic activities.

Conclusions: These results suggest that IMP-1 expression is likely to play important roles in lung cancer development and progression, and that IMP-1 is a prognostic biomarker and a promising therapeutic target for lung cancer.
Antigenic Profiling of Glioma Cells to Generate Allogeneic Vaccines or Dendritic Cell–Based Therapeutics
Authors: Zhang Jian Gang , Eguchi Junichi , Kruse Carol A. , Gomez German G. , Fakhrai Habib , Schroter Stephanie , Ma Wenxue , Hoa Neil , Minev Boris , Delgado Christina , Wepsic H. Terry , Okada Hideho , Jadus Martin R.
Published: January 2007

Purpose: Allogeneic glioma cell lines that are partially matched to the patient at class I human leukocyte antigen (HLA) loci and that display tumor-associated antigens (TAA) or antigenic precursors [tumor antigen precursor proteins (TAPP)] could be used for generating whole tumor cell vaccines or, alternatively, for extraction of TAA peptides to make autologous dendritic cell vaccines.

Experimental Design: Twenty human glioma cell lines were characterized by molecular phenotyping and by flow cytometry for HLA class I antigen expression. Twelve of the 20 cell lines, as well as analyses of freshly resected glioma tissues, were further characterized for protein and/or mRNA expression of 16 tumor antigen precursor proteins or TAA.

Results: These 20 human glioma cell lines potentially cover 77%, 85%, and 78% of the U.S. Caucasian population at HLA-A, HLA-B, and HLA-C alleles, respectively. All cells exhibited multiple TAA expressions. Most glioma cells expressed antigen isolated from immunoselected melanoma-2 (Aim-2), B-cyclin, EphA2, GP100, β1,6-N-acetylglucosaminyltransferase V (GnT-V), IL13Rα2, Her2/neu, hTert, Mage, Mart-1, Sart-1, and survivin. Real-time PCR technology showed that glioblastoma specimens expressed most of the TAA as well. Tumor-infiltrating lymphocytes and CD8+ CTL killed T2 cells when loaded with specific HLA-A2+ restricted TAA, or gliomas that were both HLA-A2+ and also positive for specific TAA (Mart-1, GP100, Her2/neu, and tyrosinase) but not those cells negative for HLA-A2 and/or lacking the specific epitope.

Conclusions: These data provide proof-in-principle for the use of allogeneic, partially HLA patient–matched glioma cells for vaccine generation or for peptide pulsing with allogeneic glioma cell extracts of autologous patient dendritic cells to induce endogenous CTL in brain tumor patients.
Genetic Deletions in Sputum as Diagnostic Markers for Early Detection of Stage I Non–Small Cell Lung Cancer
Authors: Li Ruiyun , Todd Nevins W. , Qiu Qi , Fan Tao , Zhao Richard Y. , Rodgers William H. , Fang Hong-Bin , Katz Ruth L. , Stass Sanford A. , Jiang Feng
Published: January 2007

Purpose: Analysis of molecular genetic markers in biological fluids has been proposed as a powerful tool for cancer diagnosis. We have characterized in detail the genetic signatures in primary non–small cell lung cancer, which provided potential diagnostic biomarkers for lung cancer. The aim of this study was to determine whether the genetic changes can be used as markers in sputum specimen for the early detection of lung cancer.

Experimental Design: Genetic aberrations in the genes HYAL2, FHIT, and SFTPC were evaluated in paired tumors and sputum samples from 38 patients with stage I non–small cell lung cancer and in sputum samples from 36 cancer-free smokers and 28 healthy nonsmokers by using fluorescence in situ hybridization.

Results: HYAL2 and FHIT were deleted in 84% and 79% tumors and in 45% and 40% paired sputum, respectively. SFTPC was deleted exclusively in tumor tissues (71%). There was concordance of HYAL2 or FHIT deletions in matched sputum and tumor tissues from lung cancer patients (r = 0.82, P = 0.04; r = 0.84, P = 0.03), suggesting that the genetic changes in sputum might indicate the presence of the same genetic aberrations in lung tumors. Furthermore, abnormal cells were found in 76% sputum by detecting combined HYAL2 and FHIT deletions whereas in 47% sputum by cytology, of the cancer cases, implying that detecting the combination of HYAL2 and FHIT deletions had higher sensitivity than that of sputum cytology for lung cancer diagnosis. In addition, HYAL2 and FHIT deletions in sputum were associated with smoking history of cancer patients and smokers (both P < 0.05).

Conclusions: Tobacco-related HYAL2 and FHIT deletions in sputum may constitute diagnostic markers for early-stage lung cancer.
Update on the Application of Interleukin-2 in the Treatment of Renal Cell Carcinoma
Authors: McDermott David F.
Published: January 2007

High-dose bolus interleukin 2 (IL-2) was granted Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic renal cell carcinoma. Results from randomized phase 3 trials suggest that regimens involving lower doses of IL-2, either alone or in combination with IFN, produce fewer tumor regressions of less overall quality. Given the toxicity, expense, and limited efficacy of this treatment, recent studies have focused on identifying predictors of response (or resistance) to IL-2 therapy. This year, investigators launched a clinical trial designed to prospectively determine if patients who are more likely to respond to high-dose IL-2 can be identified before starting therapy. As the list of effective therapies for metastatic renal cell carcinoma grows, improvements in patient selection will be necessary to ensure that patients who might attain a durable remission with IL-2 will not miss this opportunity.
Reduced Mammographic Density with Use of a Gonadotropin-Releasing Hormone Agonist–Based Chemoprevention Regimen in BRCA1 Carriers
Authors: Weitzel Jeffrey N. , Buys Saundra S. , Sherman William H. , Daniels Anna Marie , Ursin Giske , Daniels John R. , MacDonald Deborah J. , Blazer Kathleen R. , Pike Malcolm C. , Spicer Darcy V.
Published: January 2007

Purpose: Women with a BRCA1 mutation (BRCA1mut) need risk reduction options beyond mastectomy and oophorectomy. We evaluated the efficacy, safety, and tolerability of hormonal chemoprevention with a gonadotropin-releasing hormone agonist (GnRHA) with low-dose add-back steroids in BRCA1mut carriers.

Experimental Design: The 12-month open label clinical trial used the GnRHA deslorelin, ultra-low-dose estradiol (E2), and replacement testosterone, administered via daily intranasal spray in premenopausal women with a BRCA1mut, and intermittent oral medroxyprogesterone acetate. The end points included mammographic percent density, bone mineral density, endometrial hyperplasia, symptom inventory, and quality of life (Medical Outcomes SF-36 survey).

Results: Six of eight BRCA1mut women (mean age, 30.3 years; range, 25-36 years) completed the study. Mammographic percent density was significantly reduced at 12 months (median absolute mammographic percent density decrease, 8.3%; P = 0.043), representing a 29.2% median reduction in mammographic percent density. Bone mineral density remained within reference limits for all participants; there were no cases of atypical endometrial hyperplasia and menses resumed within a median of 67 days (range, 35-110 days) after last drug treatment day. The treatment was well tolerated; hypoestrogenic side effects were minimal and transient; and there were no significant changes in quality of life.

Conclusions: The GnRHA deslorelin, with low-dose add-back steroids, was well tolerated and significantly decreased mammographic percent density in BRCA1mut carriers. This regimen may reduce breast cancer risk and improve the usefulness of mammographic surveillance by reducing density. This is the first demonstration, to our knowledge, of a direct reduction of mammographic densities in young BRCA1mut carriers.
Opportunities and Obstacles to Combination Targeted Therapy in Renal Cell Cancer
Authors: Sosman Jeffrey A. , Puzanov Igor , Atkins Michael B.
Published: January 2007

The treatment of advanced renal cell carcinoma (RCC) has undergone a major change with the development of potent angiogenesis inhibitors and targeted agents. Several multitargeted tyrosine kinase inhibitors, sorafenib and sunitinib, have already been approved for the treatment of advanced RCC. Temsirolimus (CCI-779), a mammalian target of rapamycin inhibitor, has shown a survival advantage over IFN in advanced, poor-prognosis RCC patients. Bevacizumab, an antibody targeting vascular endothelial growth factor (VEGF) A, has also shown promising clinical activity. Benefits attributable to these agents have been recognized by high objective response rates (sunitinib), significant increases in progression-free survival (sunitinib, sorafenib and bevacizumab), or improved overall survival (temsirolimus). These agents mediate much of their effect through inhibition of the hypoxia-inducible factor (HIF)-VEGF-VEGF receptor axis. Their inhibitory activity for the signaling of platelet-derived growth factor (PDGF) receptor β or kinases like c-Raf may contribute to the antitumor effects of the multitargeted kinase inhibitors. Nevertheless, all four single agents rarely, if ever, induce complete responses and, at present, all patients develop resistance and, ultimately, progress during therapy. A critical need exists to develop strategies that may increase the degree of the antitumor effects with the hope of inducing more complete responses impeding the onset of or elimination of refractory disease. Combinations of these and other targeted agents may overcome the resistance that develops with single-agent therapy and could be incorporated either as part of initial therapy or later when disease resistance develops. Approaches aimed at combining these agents can be based on the genetics and biology of clear cell RCC. von Hippel-Lindau loss leads to an increase in cellular levels of HIF (HIF-1α or HIF-2α) leading to increased expression of a number of hypoxia-regulated genes critical to cancer progression. Combinations of targeted agents may block several of these mediators (VEGF, epidermal growth factor receptor, and PDGF), so-called horizontal blockade. Blockade could also take place at two levels of the pathways (vertical blockade), either at HIF and VEGF or at VEGF and VEGF receptor signaling. Many of the above strategies are ongoing and will require careful phase 1 determination of toxicity and even more rigorous phase 2 analysis before moving onto phase 3 trials.
Intercomparison of Water Vapor Data Measured with Lidar during IHOP_2002. Part II: Airborne-to-Airborne Systems
Authors: Behrendt Andreas , Wulfmeyer Volker , Schaberl Thorsten , Bauer Hans-Stefan , Kiemle Christoph , Ehret Gerhard , Flamant Cyrille , Kooi Susan , Ismail Syed , Ferrare Richard , Browell Edward V. , Whiteman David N.
Published: January 2007

The dataset of the International H2O Project (IHOP_2002) gives the first opportunity for direct intercomparisons of airborne water vapor lidar systems and allows very important conclusions to be drawn for future field campaigns. Three airborne differential absorption lidar (DIAL) systems were operated simultaneously during some IHOP_2002 missions: the DIAL of Deutsches Zentrum für Luft- und Raumfahrt (DLR), the Lidar Atmospheric Sensing Experiment (LASE) of the National Aeronautics and Space Administration (NASA) Langley Research Center, and the Lidar Embarque pour l’etude des Aerosols et des Nuages de l’interaction Dynamique Rayonnement et du cycle de l’Eau (LEANDRE II) of the Centre National de la Recherche Scientifique (CNRS). Data of one formation flight with DLR DIAL and LEANDRE II were investigated, which consists of 54 independent profiles of the two instruments measured with 10-s temporal average. For the height range of 1.14–1.64 km above sea level, a bias of (−0.41 ± 0.16) g kg−1 or −7.9% ± 3.1% was found for DLR DIAL compared to LEANDRE II (LEANDRE II drier) as well as root-mean-square (RMS) deviations of (0.87 ± 0.18) g kg−1 or 16.9% ± 3.5%. With these results, relative bias values of −9.3%, −1.5%, +2.7%, and +8.1% result for LEANDRE II, DLR DIAL, the scanning Raman lidar (SRL), and LASE, respectively, using the mutual bias values determined in Part I for the latter three sensors. From the three possible profile-to-profile intercomparisons between DLR DIAL and LASE, one case cannot provide information on the system performances due to very large inhomogeneity of the atmospheric water vapor field, while one of the two remaining two cases showed a difference of −4.6% in the height range of 1.4–3.0 km and the other of −25% in 1.3–3.8 km (in both cases DLR DIAL was drier than LASE). The airborne-to-airborne comparisons showed that if airborne water vapor lidars are to be validated down to an accuracy of better than 5% in the lower troposphere, the atmospheric variability of water vapor has to be taken into account down to scales of less than a kilometer unless a sufficiently large number of intercomparison cases is available to derive statistically solid biases and RMS deviations. In conclusion, the overall biases between the water vapor data of all three airborne lidar systems operated during IHOP_2002 are smaller than 10% in the present stage of data evaluation, which confirms the previous estimates of the instrumental accuracies for all the systems.
Application of a Differential Fuel-Cell Analyzer for Measuring Atmospheric Oxygen Variations
Authors: Stephens Britton B. , Bakwin Peter S. , Tans Pieter P. , Teclaw Ron M. , Baumann Daniel D.
Published: January 2007

A commercially available differential fuel-cell analyzer has been adapted to make field-based ppm-level measurements of atmospheric O2 variations. With the implementation of rapid calibrations and active pressure and flow control, the analysis system described here has a 1σ precision of ±2.5 per meg (≈0.5 ppm) for a 2-min measurement. Allowing for system stabilization after switching inlet lines, a 6-min measurement with a precision of ±1.4 per meg (≈0.3 ppm) every 20 min is obtained. The elimination of biases in any atmospheric O2 measurement depends critically on careful gas-handling procedures, and after screening for known sources of bias a comparability of ±10 per meg (≈2 ppm) with the present setup is estimated. In comparison to existing techniques, the relatively small size, low cost, fast response, motion insensitivity, and ease of implementation of the fuel-cell analyzer make it particularly useful for a wide range of unattended field applications. This system has been used to measure atmospheric O2 concentrations at the WLEF tall-tower research site in northern Wisconsin semicontinuously from June 2000 to December 2003. These measurements represent the first extended O2 record in and above a forest ecosystem, and are being used to investigate global carbon budgeting, plant physiology, continental boundary layer mixing and synoptic transport, and potential means of industrial emission verification. In this paper, the measurement technique is described in detail and several weeks of data are presented to illustrate its performance.
A Simulation-Based Optimization Approach for Investment Decisions
Authors: Dittman David A. , Hesford James W.
Published: January 2007

In this article, the authors demonstrate how to use optimization combined with Monte Carlo simulation to model an investment decision by means of a case study of a hotel considering the converting a portion of its inventory to allergy-friendly rooms (by applying a proprietary method). Using survey data on consumer demand and hotel occupancy data, the model considers the random nature of occupancy to determine the optimal number of rooms to convert and the corresponding price to charge. In setting up the model, the authors demonstrate the limitations of traditional approaches using average occupancy data.
A Timely Product Innovation
Authors: Brault Brian
Published: January 2007

Allergy-friendly rooms carry a compelling marketing story, combined with a solid return on investment, provided a hotel’s management follows the complete program.
Table-Games Revenue Management
Authors: Peister Clayton
Published: January 2007

The application of survival analysis to create a revenue management scheme for a casino’s table games is illustrated. Although logic suggests that table games revenue can easily be increased by manipulating minimum wagers, the matter is complicated by the nature of games, which allow “partial sales” (i.e., any number of hands) but do not allow a bet of zero, and in which actual demand is censored (when people are waiting to play). Survival analysis accommodates the time-played parameter while recognizing an inherent issue with capacity constrained supply. Optimization is then achieved by using traditional revenue-management tools, as demonstrated using a simulated data set.
Prevalence and impact of arthritis: Opportunities for prevention
Authors: Marks Ray , Allegrante John P
Published: January 2007

Background Due to its chronic nature and its associated impact on physical function and life quality, arthritis in its various forms imposes a significant burden on society. Objective To critically review and evaluate: (1) what has been documented about the burden of arthritis, (2) what is being done in treatment, and (3) what might be done at the primary, secondary and tertiary prevention levels to offset this burden. A further objective was to offer some evidence-based strategies for reducing the prevalence of arthritis and its disability-related complications, including screening, high-quality patient education and self-management programmes, advocacy, and research. Method An in-depth literature review and systematic analysis of the related literature was conducted. Results Although steps have been taken both in the context of the American Arthritis Plan and the Healthy People 2010 arthritis objectives, more needs to be done to reduce the increasing burden of arthritis through prevention. One or more of the currently documented intervention strategies may assist in ameliorating, or possibly preventing, the extent of arthritis-related disability.
Drop-in services: Findings from an evaluation of the Healthy Living Centre programme in Scotland
Authors: Truman J , Rankin D , Backett-Milburn K , Platt S
Published: January 2007

Objective To explore the diverse roles of drop-in services in the HLC sector; to develop further the classification of drop-in services offered by earlier studies; and to provide an example of some the challenges faced by HLCs in their attempts to tackle poor health using area-based methods with vulnerable, hard-to-reach users.

Setting Scottish Healthy Living Centres.

Methods Six Healthy Living Centres were purposively selected to reflect some of the diversity within the Healthy Living Centre programme in Scotland. Semi-structured interviews were undertaken with 10–15 respondents in each of the case studies.

Results The term ‘drop-in’ was used to describe services which varied in respect of activities, aims, management and resources. This variation reflected the specific context and understanding of health in individual HLCs. Some addressed health lifestyles, reflecting an individualistic model of health based on risk factor assessment; others focused more broadly on the fundamental determinants of ill health, such as employment, education, poverty and social well being,reflecting a social model of health.

Conclusions Our findings support and expand earlier work in the area.We have produced a revised typology of drop-in services, identifying ‘user-defined’ in addition to the previously developed categories of ‘consumer run’ and ‘consumer involved’ services.
Predicting default from smoking cessation treatment following enrolment
Authors: Challenger Alison , Coleman Tim , Lewis Sarah
Published: January 2007

Objective To determine which factors predict default from subsequent treatment sessions after initial enrolment and attendance at a large, English smoking cessation service.

Design Cross-sectional survey using data obtained at smokers' initial enrolment attendance to compare the characteristics of those who subsequently default with those who do not.

Participants and setting 2516 smokers who attended at least one appointment with a smoking cessation service serving the Nottingham City area, UK, in a two year period starting from 1 October 2001.

Results The 2516 smokers who consented for their data to be used in this analysis comprised 78.8 per cent of all smokers enrolled into the smoking cessation service during the study period. Of these, 73.9 per cent (1892) attended subsequent appointments, whilst 21.6 per cent defaulted (i.e. failed to re-attend for treatment after the initial appointment). Default from treatment was independently associated with younger age, heavier smoking, living alone or in a house with a smoker, and being less motivated to stop smoking, but was unrelated to smokers' routes of referral to the service.

Conclusions Further work is required to explain why described factors are associated with default from smoking cessation treatment in this service and to determine whether similar factors influence this in other services. Our results suggest that, to minimize default, smoking cessation services should, at initial enrolment consultations, employ strategies to increase smokers' motivation to stop, combat nicotine addiction and the influence of other smokers at home.
Language ability: A neglected dimension in the profiling of populations and health service users
Authors: Aspinall Peter J
Published: January 2007

Britain is becoming an increasingly diverse society in ethnic, cultural, and linguistic terms. Race equality as a matter of governance has gained momentum through legal developments and prioritization in policies. However, ethnic inequalities in health and healthcare are marked and persistent and language has been identifi ed as a key barrier to accessing services and effective communication. There is, for example, currently substantial under use of NHS Direct, England's telephonic health and information service, by non English-speaking callers. It is surprising, therefore, that there are no offi cial sources of comprehensive information for the UK population on main spoken languages and competency in English. While such questions are routinely asked in national population censuses in the USA and Old Commonwealth countries, in the UK these are conspicuously absent from the decennial censuses, most of the major Government social surveys, nearly all NHS core datasets, and ethnic monitoring in primary care. The NHS Resource Allocation Weighted Capitation Formula now uses data on language diffi culty 10-15 years out of date. The upcoming 2011 Census offers an important opportunity for NHS organizations to secure the comprehensive national and small area data required to establish the need for language support services, including bilingual support and interpreting and translation provision.
The influence of flush volume and branch drain cross-section on deformable solid transport in attenuating flows
Authors: McDougall J A , Wakelin R H M
Published: January 2007

The satisfactory removal of faecal and other waste by w.c. flushing and solid transport within a branch drain is a prerequisite of building drainage system design. The increasing importance of water conservation has led to renewed interest in the possibilities for reductions in overall building use through reduced w.c. flush volume operation. Current UK and international legislation has led to the 6 L flush being regarded as the upper acceptable limit, with consideration being given to further reductions to 4 L and below. Maintaining the operational integrity of the drainage system will require an understanding of both w.c. design and transport mechanisms to ensure solid clearance and the avoidance of solid deposition and the consequent disruption to the building user. It is necessary to regard the w.c. and the branch drain as a system. This paper analyses a major data set that includes a wide range of w.c. flush volumes as well as consideration of branch drain cross-sectional area and shape. Data for low flush volume operation with a parabolic cross-section branch drain is presented. Conclusions are drawn that indicate that low flush volume operation is feasible provided drain slope and cross-sectional area and shape are fully considered. The degree of slope enhancement required as flush volume is decreased is demonstrated.
Evaluation of the neutral criterion of indoor air quality for air-conditioned offices in subtropical climates
Authors: Mui K W , Wong L T
Published: January 2007

Occupant-generated carbon dioxide (CO2) is used as the tracer gas to determine ventilation rate. Although CO2 concentration may not provide a comprehensive indication of indoor air quality (IAQ), it can be a good indicator of the concentration of other human bioeffluents perceived as a nuisance and be used to identify the acceptability of IAQ in a space by its occupants. In this study, the acceptability of IAQ in air-conditioned offices was evaluated by the subjective responses of the office occupants with respect to indoor CO2 concentration. CO2 concentrations at 396 sample locations were measured and subjective responses at those locations were recorded by an electronic questionnaire. Specifically, an occupant’s indirect acceptability of the perceived IAQ indicated on a semantic differential evaluation scale was correlated to the occupant’s direct acceptability described by a dichotomous scale. The overall acceptability of IAQ from all occupants was then described by a logistic regression model and shown to correlate with indoor CO2 concentration.
Air pressure transient generation as a result of falling solids in building drainage stacks: definition, mechanisms and modelling
Authors: Gormley M
Published: January 2007

The consequences of air pressure transients in building drainage and vent systems (DVS) can be serious, as they compromise the integrity of the appliance trap seal - the last line of defence between the potentially hazardous foul air in the drainage and sewer network, and the habitable space within buildings. Pressure transients are caused by rapid changes in flow conditions in fluid systems. Much previous research has defined the nature and effect of air pressure transient generation and propagation on the air pressure regime within DVS. This paper confirms that falling solids have an effect on the pressure regime in a vertical stack; that transients are generated and that pressures are modified in a way hitherto undefined.
Determining the adventitious leakage of buildings at low pressure. Part 1: uncertainties
Authors: Cooper E W , Etheridge D W
Published: January 2007

Part 1 of this paper examines the uncertainties (errors) inherent in the determination of the low-pressure leakage of a building envelope. Current procedures use high-pressure data (typically 50 Pa) as a measure of the infiltration potential of an envelope. In reality, infiltration occurs at much lower pressures (typically 4 Pa). As a consequence, large uncertainties are inherent in the current procedures. It is shown that a technique for direct measurement of Q4 could reduce the uncertainty by a factor of three or more. One of the keys to such a measurement is to consecutively measure Dp with and without an imposed flow in a short time. In Part 2 of this paper, a technique is described that enables such measurements to be made.
Ownership Strategies and Survival of Foreign Subsidiaries: Impacts of Institutional Distance and Experience
Authors: Gaur Ajai S. , Lu Jane W.
Published: January 2007

This article integrates institutional theory and organizational learning perspective and proposes a contingency framework on the relationship between ownership strategies and subsidiary performance. Using a sample of Japanese subsidiaries worldwide, the article finds important main effects of ownership, institutional distance, and host country experience on subsidiary survival. Furthermore, the effect of ownership is contingent on institutional distance and host country experience. In institutionally distant countries, subsidiaries have better survival chances if foreign parents have more ownership. Host country experience has a negative impact on subsidiary survival, but the effect is weaker if foreign parents have larger ownership positions in the subsidiaries.
The Effects of Diversity Faultlines and Team Task Autonomy on Decision Quality and Social Integration
Authors: Rico Ramón , Molleman Eric , Sánchez-Manzanares Miriam , Van der Vegt Gerben S.
Published: January 2007

This study examines the effects of diversity faultlines stemming from educational background and conscientiousness on team decision quality and social integration and the moderating role of team task autonomy. Using a 2 × 2 (Weak/Strong Faultlines × Low/High Team Task Autonomy) factorial design, 52 four-person teams performed a decision-making task. Diverse weak-faultline teams performed better and reported higher levels of social integration than did strong-faultline teams. Team task autonomy moderated these effects, showing that the differences become significant only under high autonomy conditions. Implications for team diversity research and design and management of work teams are discussed.
“Temporary Worker, Permanent Loser?”A Model of the Stigmatization of Temporary Workers
Authors: Boyce Anthony S. , Ryan Ann Marie , Imus Anna L. , Morgeson Frederick P.
Published: January 2007

As organizations seek to increase flexibility and reduce costs, temporary work arrangements have increased. In this article, the authors argue that these workers can be the targets of devalued treatment. They develop a model of the individual and organizational antecedents and consequences of temporary worker stigmatization. Then, they articulate the implications of this model for research on workplace stigma and effective utilization of temporary workers.