bluuebunny/crossref_metadata_2025 huggingface dataset:
The Impact of Entrepreneurial Leadership on EU High Politics: A Case Study of Jacques Delors and the Creation of EMU
Authors: Van Assche Tobias
Published: July 2005

This article argues that entrepreneurial leadership (Young, 1991) of European Commission president Jacques Delors was a necessary factor in the creation of an Economic and Monetary Union (EMU). More specifically, it examines Delors’s role during the creation and duration of the Delors Committee in which a group of member state central bank governors and experts met to examine how an EMU could be accomplished. The Delors Report led to a change in the German position and a weakening of the British position. This article contributes to the growing literature on leadership in international bargaining, as well as the role of the Commission in European integration.
Crisis and Charisma in the California Recall Election
Authors: Bligh Michelle C. , Kohles Jeffrey C. , Pillai Rajnandini
Published: July 2005

The 2003 California recall election represented a unique opportunity to study leadership in the context of what has been described in the popular media as an economic and political crisis. Participants (N= 311) reported their perceptions of the current situation in California and their tendency to attribute outcomes to leaders rather than situational factors (the Romance of Leadership Scale, or RLS). They subsequently watched video clips of the incumbent, the incumbent party challenger and the outside challenger, and rated their delivery style, charisma and expected effectiveness in office. Results indicate that both challengers were rated as more charismatic than the incumbent, and crisis perceptions were related to expected effectiveness ratings for all three candidates. In addition, higher charismatic delivery was associated with higher ratings of charisma and effectiveness. Finally, the RLS was significantly related to ratings of the outside challenger’s charisma, and interacted with crisis perceptions to predict charisma ratings of both the incumbent party challenger and the outside challenger. Implications for the relationship between crisis and charisma, the importance of charismatic delivery style, and situational influences on the RLS are discussed.
Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model
Authors: Menu Eline , Jernberg-Wiklund Helena , Stromberg Thomas , De Raeve Hendrik , Girnita Leonard , Larsson Olle , Axelson Magnus , Asosingh Kewal , Nilsson Kenneth , Van Camp Ben , Vanderkerken Karin
Published: July 2005

Insulin-like growth factor 1 (IGF-1) plays a pleiotropic role in multiple myeloma (MM), that is, in survival, proliferation, chemotaxis, and angiogenesis. Strategies targeting the IGF-1 receptor (IGF-1R) may therefore be important to develop efficient anti-MM agents. In this work we investigated the effect of an IGF-1R tyrosine kinase (IGF-1RTK) inhibitor (picropodophyllin or PPP) in the 5T33MM mouse model. In vitro data showed that PPP reduced IGF-1R autophosphorylation and downstream ERK activation, leading to inhibition of IGF-1–stimulated proliferation and vascular endothelial growth factor (VEGF) secretion of MM cells. In an in vivo study, PPP reduced the bone marrow tumor burden and serum paraprotein in 5T33MM mice by 77% and 90%, respectively, compared to vehicle-treated animals. Angiogenesis was assessed by quantifying the microvessel density on CD31-stained paraffin sections and this was reduced by 60% in the PPP-treated group. In a separate survival experiment, Kaplan-Meier analysis demonstrated a significant increase in survival in PPP-treated 5T33MM animals compared to the vehicle controls (28 versus 18 days). These data suggest that the IGF-1RTK inhibitor PPP possesses a marked antitumor activity and strongly points to the possibility of using IGF-1R inhibitors in the treatment of MM.
The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D–target-cell interactions
Authors: Sconocchia Giuseppe , Lau Michelle , Provenzano Maurizio , Rezvani Katayoun , Wongsena Wachanan , Fujiwara Hiroshi , Hensel Nancy , Melenhorst Jos , Li Jonming , Ferrone Soldano , Barrett A. John
Published: July 2005

To study natural killer (NK) cell–mediated antileukemic activity in chronic myelogenous leukemia (CML), we investigated the ability of HLA-matched and mismatched CD56+ cells to inhibit granulocyte macrophage–colony-forming unit (CFU-GM) formation by leukemic CD34+ cells. In 14 HLA-identical donor-recipient pairs, donor CD56+ cells inhibited CML CFU-GM comparably to effectors from 14 HLA-mismatched unrelated individuals (mean inhibition 42% ± 9% vs 39.5% ± 7% at a 10:1 effector-to-target (E/T) ratio), suggesting that killer inhibitory receptor (KIR) incompatibility was not essential for an antileukemic effect. Both CD56+CD3- (natural killer [NK]) and CD56+CD3+(NK-T) cells inhibited CFU-GM growth of CML but not normal CD34+ cells. A mechanism for this leukemia-specific cytotoxicity was suggested by the abnormal overexpression of major histocompatibility class I chain–related gene A or gene B (MICA/B) on CML CD34 cells and their ability to bind the NK activation ligand NKG2D. However, in vivo, CML cells may avoid NK-cell–mediated immune destruction by immune escape, shedding MICA into the plasma, thereby down-regulating NKG2D on CML CD56+ cells.
CD94 1A transcripts characterize lymphoblastic lymphoma/leukemia of immature natural killer cell origin with distinct clinical features
Authors: Lin Chung-Wu , Liu Ting-Yun , Chen Shee-Uan , Wang Kun-Teng , Medeiros L. Jeffrey , Hsu Su-Ming
Published: July 2005

Most lymphoblastic lymphomas (LBLs) are regarded as neoplasms of immature T cells because they express cytoplasmic CD3 and frequently carry T-cell receptor (TCR) gene rearrangements. Immature natural killer (NK) and T cells, however, have a common bipotent T/NK-cell precursor in the thymus, and NK cells also express cytoplasmic CD3. Thus, some LBLs could arise from immature NK cells. Mature NK cells express 2 CD94 transcripts: 1A, induced by interleukin 15 (IL-15), and 1B constitutively. Because immature NK cells require IL-15 for development, CD94 1A transcripts could be a marker of NK-LBL. To test this hypothesis, we used laser capture microdissection to isolate IL-15 receptor α+ lymphoid cells from the thymus and showed that these cells contained CD94 1A transcripts. We then assessed for CD94 transcripts in 21 cases of LBL that were cytoplasmic CD3+, nuclear terminal deoxynucleotidyl transferase positive (TdT+), and CD56-, consistent with either the T-cell or NK-cell lineage. We found that 7 LBLs expressed CD94 1A transcripts without TCR gene rearrangements, suggesting NK-cell lineage. Patients with NK-LBL were younger than patients with T-LBL (15 years versus 33 years; P = .11) and had a better 2-year survival (100% versus 27%; P < .01). These results improve the current classification of LBL and contribute to our understanding of NK-cell differentiation.
Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells
Authors: Thomas Maria , Geßner Andreas , Vornlocher Hans-Peter , Hadwiger Philipp , Greil Johann , Heidenreich Olaf
Published: July 2005

The chromosomal translocation t(4;11) marks infant acute lymphoblastic leukemia associated with a particularly dismal prognosis. The leukemogenic role of the corresponding fusion gene MLL-AF4 is not well understood. We show that transient inhibition of MLL-AF4 expression with small interfering RNAs impairs the proliferation and clonogenicity of the t(4; 11)–positive human leukemic cell lines SEM and RS4;11. Reduction of mixed-lineage leukemia (MLL)–ALL-1 fused gene from chromosome 4 (AF4) levels induces apoptosis associated with caspase-3 activation and diminished BCL-XL expression. Suppression of MLL-AF4 is paralleled by a decreased expression of the homeotic genes HOXA7, HOXA9, and MEIS1. MLL-AF4 depletion inhibits expression of the stem-cell marker CD133, indicating hematopoietic differentiation. Transfection of leukemic cells with MLL-AF4 siRNAs reduces leukemia-associated morbidity and mortality in SCID mice that received a xenotransplant, suggesting that MLL-AF4 depletion negatively affects leukemia-initiating cells. Our findings demonstrate that MLL-AF4 is important for leukemic clonogenicity and engraftment of this highly aggressive leukemia. Targeted inhibition of MLL-AF4 fusion gene expression may lead to an effective and highly specific treatment of this therapy-resistant leukemia.
Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation
Authors: Pavletic Steven Z. , Carter Shelly L. , Kernan Nancy A. , Henslee-Downey Jean , Mendizabal Adam M. , Papadopoulos Esperanza , Gingrich Roger , Casper James , Yanovich Saul , Weisdorf Daniel ,   for the members of the National Heart, Lung, and Blood Institute Unrelated Donor Marrow Transplantation Trial
Published: July 2005

Donor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.
Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination
Authors: Noda Satoshi , Aguirre Shirley A. , Bitmansour Andrew , Brown Janice M. , Sparer Timothy E. , Huang Jing , Mocarski Edward S.
Published: July 2005

Murine cytomegalovirus encodes a secreted, pro-inflammatory chemokine-like protein, MCK-2, that recruits leukocytes and facilitates viral dissemination. We have shown that MCK-2-enhanced recruitment of myelomonocytic leukocytes with an immature phenotype occurs early during infection and is associated with efficient viral dissemination. Expression of MCK-2 drives the mobilization of a population of leukocytes from bone marrow that express myeloid marker Mac-1 (CD11b), intermediate levels of Gr-1 (Ly6 G/C), platelet-endothelial-cell adhesion molecule-1 (PECAM-1, CD31), together with heterogeneous levels of stem-cell antigen-1 (Sca-1, Ly-6 A /E). Recombinant MCK-2 mediates recruitment of this population even in the absence of viral infection. Recruitment of this cell population and viral dissemination via the bloodstream to salivary glands proceeds normally in mice that lack CCR2 and MCP-1 (CCL2), suggesting that recruitment of macrophages is not a requisite component of pathogenesis. Thus, a systemic impact of MCK-2 enhances the normal host response and causes a marked increase in myelomonocytic recruitment with an immature phenotype to initial sites of infection. Mobilization influences levels of virus dissemination via the bloodstream to salivary glands and is dependent on a myelomonocytic cell type other than mature macrophages.
Women's quality of life is decreased by acute cystitis and antibiotic adverse effects associated with treatment
Authors: Ernst Erika J , Ernst Michael E , Hoehns James D , Bergus George R
Published: July 2005

Background

Although acute cystitis is a common infection in women, the impact of this infection and its treatment on women's quality of life (QOL) has not been previously described.

Objectives: To evaluate QOL in women treated for acute cystitis, and describe the relationship between QOL, clinical outcome and adverse events of each of the interventions used in the study.

Methods

Design. Randomized, open-label, multicenter, treatment study.

Setting. Two family medicine outpatient clinics in Iowa.

Patients. One-hundred-fifty-seven women with clinical signs and symptoms of acute uncomplicated cystitis.

Intervention. Fifty-two patients received trimethoprim/sulfamethoxazole 1 double-strength tablet twice daily for 3 days, 54 patients received ciprofloxacin 250 mg twice daily for 3 days and 51 patients received nitrofurantoin 100 mg twice daily for 7 days.

Measurements. QOL was assessed at the time of enrollment and at 3, 7, 14 and 28 days after the initial visit. QOL was measured using a modified Quality of Well-Being scale, a validated, multi-attribute health scale. Clinical outcome was assessed by telephone interview on days 3, 7, 14 and 28 using a standardized questionnaire to assess resolution of symptoms, compliance with the prescribed regimen, and occurrence of adverse events.

Results

Patients experiencing a clinical cure had significantly better QOL at days 3 (p = 0.03), 7 (p < 0.001), and 14 (p = 0.02) compared to patients who failed treatment. While there was no difference in QOL by treatment assignment, patients experiencing an adverse event had lower QOL throughout the study period. Patients treated with ciprofloxacin appeared to experience adverse events at a higher rate (62%) compared to those treated with TMP/SMX (45%) and nitrofurantoin (49%), however the difference was not statistically significant (p = 0.2).

Conclusion

Patients experiencing cystitis have an increase in their QOL with treatment. Those experiencing clinical cure have greater improvement in QOL compared to patients fail therapy. While QOL is improved by treatment, those reporting adverse events have lower overall QOL compared to those who do not experience adverse events. This study is important in that it suggests that both cystitis and antibiotic treatment can affect QOL in a measurable way.
Differential expression of function-related antigens on blood monocytes in children with hemolytic uremic syndrome
Authors: Fernández Gabriela C , Ramos María V , Gómez Sonia A , Dran Graciela I , Exeni Ramón , Alduncín Marta , Grimoldi Irene , Vallejo Graciela , Elías-Costa Christian , Isturiz Martín A , Palermo Marina S
Published: July 2005

Monocytes (Mo) mediate central functions in inflammation and immunity. Different subpopulations of Mo with distinct phenotype and functional properties have been described. Here, we investigate the phenotype and function of peripheral Mo from children with hemolytic uremic syndrome (HUS). For this purpose, blood samples from patients in the acute period of HUS (HUS AP) were obtained on admission before dialysis and/or transfusion. The Mo phenotypic characterization was performed on whole blood by flow cytometry, and markers associated to biological functions were selected: CD14 accounting for lipopolysaccharide (LPS) responsiveness, CD11b for adhesion, Fc receptor for immunoglobulin G type I (FcγRI)/CD64 for phagocytosis and cytotoxicity, and human leukocyte antigen (HLA)-DR for antigen presentation. Some of these functions were also determined. Moreover, the percentage of CD14+ CD16+ Mo was evaluated. We found that the entire HUS AP Mo population exhibited reduced CD14, CD64, and CD11b expression and decreased LPS-induced tumor necrosis factor production and Fcγ-dependent cytotoxicity. HUS AP showed an increased percentage of CD14+ CD16+ Mo with higher CD16 and lower CD14 levels compared with the same subset from healthy children. Moreover, the CD14++ CD16– Mo subpopulation of HUS AP had a decreased HLA-DR expression, which correlated with severity. In conclusion, the Mo population from HUS AP patients presents phenotypic and functional alterations. The contribution to the pathogenesis and the possible scenarios that led to these changes are discussed.
A theoretical and experimental comparison of three-dimensional seismic reflection and offset vertical seismic profiling (VSP)
Authors: Rich Jamie P. , Witten Alan J.
Published: July 2005

Diffraction tomography imaging has been applied to data acquired with two different measurement geometries at a buried waste disposal site. The experimental scale is quite small, having a horizontal extent on the order of 10 m and considering features at depths (most importantly, a layer of buried waste) of less than 10 m. Both a 3D reflection and a pseudo-3D offset vertical seismic profiling (VSP) geometry were used. The use of these two different geometries allows for a comparison of the results and limitations of each method. Images derived from both techniques must be interpreted with a knowledge of the theoretical resolution and limitations imposed by each measurement geometry and imaging algorithm. The reflection algorithm leads to images that contain hollow objects, a consequence of the reflection geometry and linearized theory; this algorithm is unable to image the sides of objects because of a lack of information at oblique reflection angles. Offset VSP experiences a blurring of objects along a line between the source and receiver because information is integrated over transmission raypaths. The two techniques provide images which are consistent with each other and the expectations based on theoretical considerations.
Modeling and velocity analysis with a wavefront-construction algorithm for anisotropic media
Authors: Gibson Richard L. , Durussel Vincent , Lee Kyoung-Jin
Published: July 2005

Wavefront construction methods allow for efficient simulation of seismic wave propagation in anisotropic media using ray theory. This approach models an individual wavefront as a mesh that is adaptively refined as the wave travels through an earth model. The algorithm, implemented here for quasi-compressional waves, provides an effective tool for modeling and analyzing a large vertical seismic-profile data set from the Gulf of Mexico. Seismic velocities in this region generally increase linearly with depth, but simulations show that an isotropic vertical-gradient model cannot accurately reproduce traveltimes of first arrivals. However, a simple velocity-analysis inversion based on the wavefront-construction method allows a straightforward estimation of improved isotropic and transversely isotropic models that significantly reduce the misfit between computed traveltimes and the observations. The goal of this analysis is to produce a simple model suitable for use as a starting point for migrations and for assessing the importance of anisotropy in the field site. In fact, the final anisotropic model is much more consistent with background geologic information than the best isotropic model, which also has a larger rms traveltime error. The results strongly support the presence of measurable anisotropy.
Inverting airborne electromagnetic (AEM) data with Zohdy's method
Authors: Sattel Daniel
Published: July 2005

Zohdy's method for the inversion of dc-resistivity data has been adapted to the inversion of airborne electromagnetic (AEM) data. AEM responses are first transformed into apparent-conductivity depth profiles, followed by an iterative adjustment of layer thicknesses and interval conductivities. The start model, including the number of layers, is determined from the data. This approach optimizes model flexibility without the need for parameter regularization. Results from Zohdy's inversion applied to TEMPEST, GEOTEM, and [Formula: see text] data acquired in a range of conductivity scenarios including the Bull Creek prospect in Queensland, Australia; the Boteti area, Botswana; and the Reid-Mahaffy test site in Ontario, Canada, show well-delineated target zones. A comparison with Occam's inversion shows good agreement between the conductivity-depth models recovered by the two methods, with Zohdy's inversion being 25 to 80 times faster.
Inversion of traveltime data under a statistical model for seismic velocities and layer interfaces
Authors: Bosch Miguel , Barton Penny , Singh Satish C. , Trinks Immo
Published: July 2005

We invert large-aperture seismic reflection and refraction data from a geologically complex area on the northeast Atlantic margin to jointly estimate seismic velocities and depths of major interfaces. Our approach combines this geophysical data information with prior information on seismic compressional velocities and the structural interpretation of seismic sections. We constrain expected seismic velocities in the prior model using information from well logs from a nearby area. The layered structure and prior positions of the interfaces follow information from the seismic section obtained by processing the short offsets. Instead of using a conventional regularization technique to smooth the interface-velocity model, we describe the spatial correlation of interfaces and velocities with a geostatistical model, using a multivariate Gaussian probability density function. We impose a covariance function on the velocity field in each layer and on each interface in the model to control the smoothness of the solution. The inversion is performed by minimizing an objective function with two terms, one term measuring traveltime residuals and the other measuring the fit to the statistical model. We calculate the posterior uncertainties and evaluate the relative influence of data and the prior model on estimated interface depths and seismic velocities. The method results in the estimation of velocity and interface geometry beneath a basaltic sill system down to 7 km depth. This method aims to enhance the interpretation process by combining multidisciplinary information in a quantitative model-based approach.
Antileakage Fourier transform for seismic data regularization
Authors: Xu Sheng , Zhang Yu , Pham Don , Lambaré Gilles
Published: July 2005

Seismic data regularization, which spatially transforms irregularly sampled acquired data to regularly sampled data, is a long-standing problem in seismic data processing. Data regularization can be implemented using Fourier theory by using a method that estimates the spatial frequency content on an irregularly sampled grid. The data can then be reconstructed on any desired grid. Difficulties arise from the nonorthogonality of the global Fourier basis functions on an irregular grid, which results in the problem of “spectral leakage”: energy from one Fourier coefficient leaks onto others. We investigate the nonorthogonality of the Fourier basis on an irregularly sampled grid and propose a technique called “antileakage Fourier transform” to overcome the spectral leakage. In the antileakage Fourier transform, we first solve for the most energetic Fourier coefficient, assuming that it causes the most severe leakage. To attenuate all aliases and the leakage of this component onto other Fourier coefficients, the data component corresponding to this most energetic Fourier coefficient is subtracted from the original input on the irregular grid. We then use this new input to solve for the next Fourier coefficient, repeating the procedure until all Fourier coefficients are estimated. This procedure is equivalent to “reorthogonalizing” the global Fourier basis on an irregularly sampled grid. We demonstrate the robustness and effectiveness of this technique with successful applications to both synthetic and real data examples.
Fermat's interferometric principle for target-oriented traveltime tomography
Authors: Schuster Gerard T.
Published: July 2005

An interferometric form of Fermat's principle is derived that allows for high-resolution estimation of the velocity distribution between deep interfaces. The data consist of reflection traveltimes from two deeply buried interfaces A and B recorded by sources and caused by receivers at the surface. Fermat's interferometric principle is then used to kinematically redatum the surface sources and receivers to interface A so that the associated reflection times correspond to localized transit times between the A and B interfaces. The velocity model above interface A does not need to be known, so the distorting effects of the overburden and statics are eliminated by this target-oriented approach. Interferometric target-oriented tomography promises to enhance the resolution of whole-earth and exploration tomograms.
Reliance on Hormone Receptor Assays of Surgical Specimens May Compromise Outcome in Patients With Breast Cancer
Authors: Mann G. Bruce , Fahey Vanessa D. , Feleppa Frank , Buchanan Malcolm R.
Published: July 2005

Purpose

To assess the concordance of breast cancer immunohistochemical receptor assays on core biopsy and surgical specimens.

Patients and Methods

We identified 100 patients whose core biopsy and definitive surgical specimens were processed in our hospital. New sections, with core and surgical specimens on the same slides, were stained for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC). Two pathologists assessed the sections independently. Raw scores and clinically significant groupings were compared.

Results

Concordance for ER, PR, overall hormone receptor (HR), and HER-2 status was seen in 86%, 83%, 90%, and 80% of patients, respectively. The core was positive, while the surgical specimen was negative in 13%, 11%, 9%, and 1% of patients, respectively. Using a log-linear model, differences in ER, PR, and HER-2 staining were all in the direction of stronger staining in the cores, and were statistically significant. Nine percent (95% CI, 4.2% to 16.4%) of women in this group would have had endocrine therapy inappropriately withheld if management decisions were based on surgical specimen results alone.

Conclusion

ER and PR assays on core biopsy specimens are more reliable than assays on surgical specimens. Receptor IHC should be performed on core biopsy specimens to avoid patients with HR positive cancers not receiving appropriate hormonal therapy and being overtreated with systemic chemotherapy. Biopsy should be considered in patients with “receptor negative” cancer and recurrent disease.
Persistence of Restrictions in Quality of Life From the First to the Third Year After Diagnosis in Women With Breast Cancer
Authors: Arndt Volker , Merx Henrike , Stegmaier Christa , Ziegler Hartwig , Brenner Hermann
Published: July 2005

Purpose

To assess whether detriments in quality of life (QOL) among women with breast cancer persist over years.

Patients and Methods

QOL was assessed in a population-based cohort of 314 women with breast cancer from Saarland (Germany) 1 and 3 years after diagnosis and compared internally and with reference data from the general population.

Results

Three years after diagnosis, deficits in QOL were still apparent for role, emotional, cognitive, and social functioning and for the symptoms of insomnia, fatigue, dyspnea, and financial difficulties. Differences between breast cancer patients and women from the general population were predominantly found in younger ages. Compared with the QOL scores measured 1 year after diagnosis, only minor functional changes were observed, but recurrence of breast cancer during the follow-up interval had a deleterious effect on QOL.

Conclusion

Deficits in role, emotional, cognitive, and social functioning persist over years in women with breast cancer and predominantly affect younger patients.
Meta-Analysis of Postoperative Adjuvant Chemotherapy With Tegafur-Uracil in Non–Small-Cell Lung Cancer
Authors: Hamada Chikuma , Tanaka Fumihiro , Ohta Mitsuo , Fujimura Shigefumi , Kodama Ken , Imaizumi Munehisa , Wada Hiromi
Published: July 2005

Purpose

Recent clinical trials have shown the efficacy of platinum-based adjuvant chemotherapy for completely resected non–small-cell lung cancer (NSCLC). In Japan, many clinical trials of adjuvant chemotherapy with tegafur-uracil (UFT) have been conducted, and some trials showed positive results while others showed negative results. Thus, we performed a meta-analysis to assess the efficacy of postoperative adjuvant chemotherapy with UFT in NSCLC.

Methods

Among nine trials of postoperative adjuvant UFT-containing chemotherapy, six trials comparing surgery alone with surgery plus UFT were identified. Of six trials, two were three-arm trials including cisplatin-based chemotherapy followed by UFT, and data from that arm were not included in the meta-analysis.

Results

Of 2,003 eligible patients, most (98.8%) had squamous cell carcinoma or adenocarcinoma, and most had stage I disease; the tumor classification was T1 in 1,308 (65.3%), T2 in 674 (33.6%), and the nodal status was N0 in 1,923 (96.0%). The two treatment groups did not differ significantly in major prognostic factors. The median duration of follow-up was 6.44 years. The survival rates at 5 and 7 years were significantly higher in the surgery plus UFT group (81.5% and 76.5%, respectively) than in the surgery alone group (77.2% and 69.5%, respectively; P = .011 and .001, respectively). The overall pooled hazard ratio was 0.74, and its 95% CI was 0.61 to 0.88 (P = .001).

Conclusion

This meta-analysis showed that postoperative adjuvant chemotherapy with UFT was associated with improved 5- and 7-year survival in a Japanese patient population composed primarily of stage I adenocarcinoma patients.
Immune Reconstitution Inflammatory Syndrome Associated With Kaposi's Sarcoma
Authors: Bower M. , Nelson M. , Young A.M. , Thirlwell C. , Newsom-Davis T. , Mandalia S. , Dhillon T. , Holmes P. , Gazzard B.G. , Stebbing J.
Published: July 2005

Purpose

A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens.

Patients and Methods

From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively.

Results

After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS.

Conclusion

We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.
Setting Course Goals: Privileges and Responsibilities in a World of Ideas
Authors: Benjamin Ludy T.
Published: July 2005

Teachers and students come to their classes with quite different goals for the course. This article discusses the importance of knowing what student expectations are for a course and of giving students some shared role in the content and conduct of a course. Such investment on the part of students is important for a number of reasons, not the least of which is to encourage students to accept more responsibility for their learning.
Extra Credit as Incentive for Voluntary Research Participation
Authors: Padilla-Walker Laura M. , Thompson Ross A. , Zamboanga Byron. L. , Schmersal Larissa A.
Published: July 2005

This study examined whether offering extra credit for research participation was effective at meeting educational goals (e.g., enabling all students to learn about the research process) and providing a representative sample of college students for researchers. Results revealed that less than half (38%) of 193 undergraduate students in an introductory course participated in research. Those who did participate scored higher on measures of academic performance than those who did not participate. Offering extra credit for research participation might not meet educational goals and possibly limits the generalizability of research findings.
Using Student Journals to Stimulate Authentic Learning: Balancing Bloom's Cognitive and Affective Domains
Authors: Bolin Aaron U. , Khramtsova Irina , Saarnio David
Published: July 2005

Bloom (1956) pioneered the measurement of learning outcomes with a taxonomy of educational objectives, but educators often ignore affective learning objectives and focus on attaining cognitive objectives. This study examined student journals as a way to correct the overemphasis on cognitive objectives. Results suggested that course expectations and affective journal outcomes were important correlates of student evaluations of course outcomes even after controlling for the instructor, student gender, and student achievement. These findings have important implications for the use of student journals and for interventions aimed at increasing student evaluations of course outcomes.
Using Your Tests to Teach: Formative Summative Assessment
Authors: Wininger Steven R.
Published: July 2005

Two studies supported the efficacy of a structured method for providing students with feedback on exams and means of using the teaching potential of exams, collectively referred to as formative summative assessment (FSA). In the first study, students responded positively to the method. In the second study, students enrolled in 2 sections of educational psychology taught by the same instructor received either the FSA method or their exams to look over in class. Students retook the exam 1 week later. The FSA method resulted in an improvement of comprehension of 10%, significantly more than the control group, whose scores improved by only 2%. I also present other benefits of this method and suggestions for variations of the method as well as future research ideas.
PI3K activation by IGF-1 is essential for the regulation of membrane expansion at the nerve growth cone
Authors: Laurino Lisandro , Wang Xiaoxin X. , de la Houssaye Becky A. , Sosa Lucas , Dupraz Sebastian , Cáceres Alfredo , Pfenninger Karl H. , Quiroga Santiago
Published: July 2005

Exocytotic incorporation of plasmalemmal precursor vesicles (PPVs) into the cell surface is necessary for axonal outgrowth and is known to occur mainly at the nerve growth cone. We have demonstrated recently that plasmalemmal expansion is regulated at the growth cone by IGF-1, but not by BDNF, in a manner that is quasi independent of the neuron's perikaryon. To begin elucidating the signaling pathway by which exocytosis of the plasmalemmal precursor is regulated, we studied activation of the IRS/PI3K/Akt pathway in isolated growth cones and hippocampal neurons in culture stimulated with IGF-1 or BDNF. Our results show that IGF-1, but not BDNF, significantly and rapidly stimulates IRS/PI3K/Akt and membrane expansion. Inhibition of PI3K with Wortmannin or LY294002 blocked IGF-1-stimulated plasmalemmal expansion at the growth cones of cultured neurons. Finally, our results show that, upon stimulation with IGF-1, most active PI3K becomes associated with distal microtubules in the proximal or central domain of the growth cone. Taken together, our results suggest a critical role for IGF-1 and the IRS/PI3K/Akt pathway in the process of membrane assembly at the axonal growth cone.
MARCKS is a major PKC-dependent regulator of calmodulin targeting in smooth muscle
Authors: Gallant Cynthia , You Jae Young , Sasaki Yasuharu , Grabarek Zenon , Morgan Kathleen G.
Published: July 2005

Calmodulin (CaM) is a ubiquitous transducer of intracellular Ca2+ signals and plays a key role in the regulation of the function of all cells. The interaction of CaM with a specific target is determined not only by the Ca2+-dependent affinity of calmodulin but also by the proximity to that target in the cellular environment. Although a few reports of stimulus-dependent nuclear targeting of CaM have appeared, the mechanisms by which CaM is targeted to non-nuclear sites are less clear. Here, we investigate the hypothesis that MARCKS is a regulator of the spatial distribution of CaM within the cytoplasm of differentiated smooth-muscle cells. In overlay assays with portal-vein homogenates, CaM binds predominantly to the MARCKS-containing band. MARCKS is abundant in portal-vein smooth muscle (∼16 μM) in comparison to total CaM (∼40 μM). Confocal images indicate that calmodulin and MARCKS co-distribute in unstimulated freshly dissociated smooth-muscle cells and are co-targeted simultaneously to the cell interior upon depolarization. Protein-kinase-C (PKC) activation triggers a translocation of CaM that precedes that of MARCKS and causes multisite, sequential MARCKS phosphorylation. MARCKS immunoprecipitates with CaM in a stimulus-dependent manner. A synthetic MARCKS effector domain (ED) peptide labelled with a photoaffinity probe cross-links CaM in smooth-muscle tissue in a stimulus-dependent manner. Both cross-linking and immunoprecipitation increase with increased Ca2+ concentration, but decrease with PKC activation. Introduction of a nonphosphorylatable MARCKS decoy peptide blocks the PKC-mediated targeting of CaM. These results indicate that MARCKS is a significant, PKC-releasable reservoir of CaM in differentiated smooth muscle and that it contributes to CaM signalling by modulating the intracellular distribution of CaM.
Actin remodeling requires ERM function to facilitate AQP2 apical targeting
Authors: Tamma Grazia , Klussmann Enno , Oehlke Johannes , Krause Eberhard , Rosenthal Walter , Svelto Maria , Valenti Giovanna
Published: July 2005

This study provides the first evidence that actin reorganization during AQP2 vesicular trafficking to the plasma membrane requires the functional involvement of ERM (ezrin/radixin/moesin) proteins cross-linking actin filaments with plasma membrane proteins. We report that forskolin stimulation was associated with a redistribution of moesin from intracellular sites to the cell cortex and with a concomitant enrichment of moesin in the particulate fraction in renal cells. Introduction of a peptide reproducing a short sequence of moesin within the binding site for F-actin induced all the key effects of forskolin stimulation, including a decrease in F-actin, translocation of endogenous moesin, and AQP2 translocation. A straightforward explanation for these effects is the ability of the peptide to uncouple moesin from its putative effector. This modifies the balance between the active and inactive forms of moesin. Extraction with Triton X-100, which preserves cytoskeletal associated proteins, showed that forskolin stimulation or peptide introduction reduced the amount of phophorylated moesin, a molecular modification known to stabilize moesin in an active state. Our data point to a dual role of moesin in AQP2 trafficking: it might modulate actin depolymerization and it participates in the reorganization of F-actin-containing cytoskeletal structures close to the fusion sites of the AQP2-bearing vesicles.
Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes
Authors: Zhu Donghui , Tan Kevin S. , Zhang Xiaolin , Sun Albert Y. , Sun Grace Y. , Lee James C.-M.
Published: July 2005

Excess hydrogen peroxide (H2O2) is produced in the pathogenesis of brain injuries and neurodegenerative diseases. H2O2 may damage cells through direct oxidation of lipids, proteins and DNA or it can act as a signaling molecule to trigger intracellular pathways leading to cell death. In this study, H2O2 caused plasma membranes of primary astrocytes to become more gel-like, while artificial membranes of vesicles composed of rat brain lipid extract became more liquid crystalline-like. Besides the effects on membrane phase properties, H2O2 promoted actin polymerization, induced the formation of cell-to-cell tunneling nanotube (TNT)-like connections among astrocytes and increased the colocalization of myosin Va with F-actin. Myosin Va was also observed in the H2O2-induced F-actin-enriched TNT-like connections. Western blot analysis suggests that H2O2 triggered the phosphorylation of the p38 mitogen-activated protein kinase (MAPK), and that SB203580, a specific inhibitor of p38 MAPK, suppressed the changes in membrane phase properties and cytoskeleton resulting from H2O2 treatment. These results suggest that H2O2 alters astrocyte membranes and the cytoskeleton through activation of the p38 MAPK pathway.
Development of an Ion-Pair Reverse-Phase Liquid Chromatographic/Tandem Mass Spectrometry Method for the Determination of an 18-Mer Phosphorothioate Oligonucleotide in Mouse Liver Tissue
Authors: Murphy Anthony T. , Brown-Augsburger Patricia , Yu Rosie Z. , Geary Richard S. , Thibodeaux Stefan , Ackermann Bradley L.
Published: July 2005

A quantitative method for the determination of a partially modified, 2′-ribose alkoxy 18-mer phosphorothioate oligonucleotide in liver tissue has been developed. A liquid:liquid extraction, ion-pair reverse phase chromatographic separation and tandem mass spectrometry were used to achieve a quantitation range of 125 to 10,000 ng g−1 mouse liver tissue. A total cycle time of 5 min was obtained while maintaining separation of three potential impurities. Separations were performed using a Discovery RP-Amide C16, 100 × 2 mm column packed with 5 μm particles. The separation was facilitated by the use of triethylamine (TEA) and hexafluoroisopropanol (HFIP) as ion-pair agents. The method has subsequently been used for the determination of other phosphorothioate oligonucleotides in support of discovery research.
Shotgun Sequencing Small Oligonucleotides by Nozzle-Skimmer Dissociation and Electrospray Ionization Mass Spectrometry
Authors: Meng Zhaojing , Limbach Patrick A.
Published: July 2005

Nozzle-skimmer dissociation in combination with de novo sequencing was investigated as an approach for increasing the throughput of oligonucleotide analysis attainable by electrospray ionization mass spectrometry. An experimental method allowing for the sequential generation of precursor and fragment ion data during direct infusion of samples was developed. These data can then be used with readily available de novo sequencing software to characterize small oligonucleotides. When this approach was applied to mixtures of oligonucleotides, it was found that de novo sequencing becomes limited due to spectral congestion and overlapping oligonucleotide m/z dissociation product values. Self-packed C18 microspray emitters were investigated as a means of reducing spectral complexity. It was found that such emitters allow for the analysis of oligonucleotide mixtures with minimal component overlap, and these emitters provide additional benefits of pre-concentrating and desalting the sample. These developments can provide a route for the more rapid characterization of ribonucleic acid endonuclease digestion mixtures.
Tandem Mass Spectrometry Characteristics of Polyester Anions and Cations Formed by Electrospray Ionization
Authors: Arnould Mark A. , Vargas Rafael , Buehner Rita W. , Wesdemiotis Chrys
Published: July 2005

Electrospray ionization of polyesters composed of isophthalic acid and neopentyl glycol produces carboxylate anions in negative mode and mainly sodium ion adducts in positive mode. A tandem mass spectrometry (MS/MS) study of these ions in a quadrupole ion trap shows that the collisionally-activated dissociation pathways of the anions are simpler than those of the corresponding cations. Charge-remote fragmentations predominate in both cases, but the spectra obtained in negative mode are devoid of the complicating cation exchange observed in positive mode. MS/MS of the Na+ adducts gives rise to a greater number of fragments but not necessarily more structural information. In either positive or negative mode, polyester oligomers with different end groups fragment by similar mechanisms. The observed fragments are consistent with rearrangements initiated by the end groups. Single-stage ESI mass spectra are also more complex in positive mode because of extensive H/Na substitutions; this is also true for matrix-assisted laser desorption ionization mass spectra. Hence, formation and analysis of anions might be the method of choice for determining block length, end group structure and copolymer sequence, provided the polyester contains at least one carboxylic acid end group that is ionizable to anions.
Function of subscapularis after surgical treatment for recurrent instability of the shoulder using a bone-block procedure
Authors: Maynou C. , Cassagnaud X. , Mestdagh H.
Published: July 2005

We compared the long-term function of subscapularis after the Latarjet procedure using two surgical approaches. We treated 102 patients (106 shoulders) with a mean age of 26.8 years (15 to 51) with involuntary unidirectional recurrent instability. The operation was carried out through an L-shaped incision with trans-section of the upper two-thirds of the muscle in 69 cases and with a subscapularis split in 37. All clinical results were assessed by the Rowe and the Duplay scores and the function of subscapularis by evaluating the distance and strength at the lift-off position. Bilateral CT was performed in 77 patients for assessment of fatty degeneration. The mean follow-up was 7.5 years (2 to 15) and 18% of cases were lost to follow-up. The mean Duplay score was 82 of 100 for the L-shaped incision group and 90 of 100 for those with a subscapularis split (p = 0.02). The mean fatty degeneration score was 1.18 after an L-shaped incision compared with 0.12 after subscapularis split (p = 0.001). The subscapularis split approach is therefore recommended.
The effects of hyaluronic acid on articular chondrocytes
Authors: Akmal M. , Singh A. , Anand A. , Kesani A. , Aslam N. , Goodship A. , Bentley G.
Published: July 2005

The purpose of this study was to examine the effects of hyaluronic acid supplementation on chondrocyte metabolism in vitro. The clinical benefits of intra-articular hyaluronic acid injections are thought to occur through improved joint lubrication. Recent findings have shown that exogenous hyaluronic acid is incorporated into articular cartilage where it may have a direct biological effect on chondrocytes through CD44 receptors.

Bovine articular chondrocytes were isolated and seeded into alginate constructs. These were cultured in medium containing hyaluronic acid at varying concentrations. Samples were assayed for biochemical and histological changes.

There was a dose-dependent response to the exposure of hyaluronic acid to bovine articular chondrocytes in vitro. Low concentrations of hyaluronic acid (0.1 mg/mL and 1 mg/mL) significantly increase DNA, sulphated glycosaminoglycan and hydroxyproline synthesis. Immunohistology confirmed the maintenance of cell phenotype with increased matrix deposition of chondroitin-6-sulphate and collagen type II. These findings confirm a stimulatory effect of hyaluronic acid on chondrocyte metabolism.