bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein Kinase C β Enhances Growth and Expression of Cyclin D1 in Human Breast Cancer Cells
Authors: Li Haiyang , Weinstein I. Bernard
Published: December 2006

Although alterations in the expressions of protein kinase C (PKC) have been implicated in breast carcinogenesis, the roles of specific isoforms in this process remain elusive. In the present study, we examined the specific roles of PKCβ1 and β2 in growth control in human breast cancer cell lines. The PKCβ-specific inhibitor LY379196 significantly inhibited growth of the breast cancer cell lines MCF-7, MDA-MB-231, and BT474, but not the normal mammary epithelial cell line MCF-10F. Treatment of MCF-7 cells with LY379196 caused an increase in the fraction of cells in the G1 phase of the cell cycle. To explore the roles of PKCβ1 and β2, we used cDNA expression vectors that encode wild-type and constitutively activated or dominant negative mutants of these two proteins. When compared with vector controls, derivatives of MCF-7 cells that stably overexpress wild-type PKCβ1 or PKCβ2 displayed a slight increase in growth rate; derivatives that stably express the constitutively active mutants of PKCβ1 or PKCβ2 displayed a marked increase in growth rate; and derivatives that stably express a dominant negative mutant of PKCβ1 or β2 displayed inhibition of growth. The derivatives of MCF-7 cells that stably express the constitutively activated mutants of PKCβ1 or β2 were more resistant to growth inhibition by LY379196 than the vector control MCF-7 cells. Immunoblot analysis indicated that MCF-7 cells that stably overexpress wild-type or constitutively activated mutants of PKCβ1 or β2 had higher cellular levels of cyclin D1 than vector control cells, whereas cells that express a dominant negative mutant had decreased levels of cyclin D1. The derivatives that stably express the constitutively activated mutants of PKCβ1 or β2 also displayed increased cyclin D1 promoter activity in transient transfection luciferase reporter assays, and this induction of activity requires activator protein 1. Constitutively activated PKCβ1 and β2 also enhanced the transcription of c-fos in transient transfection luciferase reporter assays. Thus, PKCβ1 and β2 may play important positive roles in the growth of at least a subset of human breast cancers. Therefore, inhibitors of these isoforms may be useful in breast cancer chemoprevention or therapy. (Cancer Res 2006; 66(23): 11399-408)
Preparing the “Soil”: The Premetastatic Niche
Authors: Kaplan Rosandra N. , Rafii Shahin , Lyden David
Published: December 2006

Current focus on cancer metastasis has centered on the intrinsic factors regulating the cell autonomous homing of the tumor cells to the metastatic site. Specific up-regulation of fibronectin and clustering of bone marrow–derived cellular infiltrates coexpressing matrix metalloproteinases in distant tissue sites before tumor cell arrival are proving to be indispensable for the initial stages of metastasis. These bone marrow–derived hematopoietic progenitors that express vascular endothelial growth factor receptor 1 mobilize in response to the unique array of growth factors produced by the primary tumor. Their arrival in distant sites represents early changes in the local microenvironment, termed the “premetastatic niche,” which dictate the pattern of metastatic spread. Focus on the early cellular and molecular events in cancer dissemination and selectivity will likely lead to new approaches to detect and prevent metastasis at its earliest inception. (Cancer Res 2006; 66(23): 11089-93)
Cellular FLICE-Inhibitory Protein Down-regulation Contributes to Celecoxib-Induced Apoptosis in Human Lung Cancer Cells
Authors: Liu Xiangguo , Yue Ping , Schönthal Axel H. , Khuri Fadlo R. , Sun Shi-Yong
Published: December 2006

The cyclooxygenase-2 (COX-2) inhibitor celecoxib is an approved drug in the clinic for colon cancer chemoprevention and has been tested for its chemopreventive and therapeutic efficacy in various clinical trials. Celecoxib induces apoptosis in a variety of human cancer cells including lung cancer cells. Our previous work has shown that celecoxib induces death receptor 5 expression, resulting in induction of apoptosis and enhancement of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in human lung cancer cells. In the current study, we further show that celecoxib down-regulated the expression of cellular FLICE-inhibitory protein (c-FLIP), a major negative regulator of the death receptor–mediated extrinsic apoptotic pathway, through a ubiquitin/proteasome–dependent mechanism independent of COX-2 in human lung cancer cells. Overexpression of c-FLIP, particularly FLIPL, inhibited not only celecoxib-induced apoptosis but also apoptosis induced by the combination of celecoxib and TRAIL. These results thus indicate that c-FLIP down-regulation also contributes to celecoxib-induced apoptosis and enhancement of TRAIL-induced apoptosis, which complements our previous finding that the extrinsic apoptotic pathway plays a critical role in celecoxib-induced apoptosis in human lung cancer cells. Collectively, we conclude that celecoxib induces apoptosis in human lung cancer cells through activation of the extrinsic apoptotic pathway, primarily by induction of death receptor 5 and down-regulation of c-FLIP. (Cancer Res 2006; 66(23): 11115-9)
Tumor Necrosis Factor-α Increases Reactive Oxygen Species by Inducing Spermine Oxidase in Human Lung Epithelial Cells: A Potential Mechanism for Inflammation-Induced Carcinogenesis
Authors: Babbar Naveen , Casero Robert A.
Published: December 2006

Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor-α (TNF-α) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-α exposure results in increased production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in human lung bronchial epithelial cells. The source of the ROS in TNF-α–treated cells was determined by both pharmacologic and small interfering RNA (siRNA) strategies to be spermine oxidase (SMO/PAOh1). SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H2O2. Inhibition of TNF-α–induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, interleukin-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H2O2 by SMO/PAOh1. Further, these results suggest a common mechanism by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers. (Cancer Res 2006; 66(23): 11125-30)
A Phase I Study of Pemetrexed (ALIMTA) and Cyclophosphamide in Patients with Locally Advanced or Metastatic Breast Cancer
Authors: Dittrich Christian , Petruzelka Lubos , Vodvarka Pavel , Gneist Margit , Janku Filip , Kysela Tamara , Melemed Allen , Latz Jane , Simms Lorinda , Krejcy Kurt
Published: December 2006

Purpose: Determine the maximum tolerated dose (MTD) of pemetrexed and cyclophosphamide combination therapy for patients with locally advanced or metastatic breast cancer.

Experimental Design: Patients with locally advanced or metastatic breast cancer and WHO performance status 0 to 2 were eligible. Pemetrexed (range, 400-2,400 mg/m2) was administered on day 1 of a 21-day schedule followed by cyclophosphamide (range, 400-800 mg/m2). Folic acid and vitamin B12 supplementation began 1 to 2 weeks before the first pemetrexed dose.

Results: Fifty-seven pretreated patients were enrolled and received 342 cycles (median, 4 cycles; range, 1-26) through 14 dose levels. The MTD of pemetrexed was 2,400 mg/m2 (combined with cyclophosphamide, 600 mg/m2) with dose-limiting toxicities of grade 4 neutropenia with grade 4 infection and grade 3 diarrhea. Other grade 3 or 4 toxicities included (febrile) neutropenia, thrombocytopenia, anemia, elevated alanine aminotransferase/aspartate aminotransferase, and diarrhea. Pharmacokinetic analysis indicated that pemetrexed clearance and central volume of distribution were 40% lower than single-agent reference data, yielding a 68% increase in total systemic exposure and a 56% increase in maximal plasma concentration. Among the 50 patients evaluable for efficacy, 13 (26%) patients had a partial response and 17 (34%) patients had stable disease.

Conclusions: Pemetrexed was generally well tolerated. The observed toxicities were consistent with the known toxicity profiles of pemetrexed and cyclophosphamide. Considering the MTD and the toxicity and efficacy results in this and prior studies, a low (600 mg/m2) and a high (1,800 mg/m2) dose of pemetrexed with cyclophosphamide (600 mg/m2) will be evaluated in the consecutive prospective randomized phase II study.
Tumor Angiogenesis Is Associated with Plasma Levels of Stromal-Derived Factor-1α in Patients with Multiple Myeloma
Authors: Martin Sally K. , Dewar Andrea L. , Farrugia Amanda N. , Horvath Noemi , Gronthos Stan , To L. Bik , Zannettino Andrew C.W.
Published: December 2006

Purpose: Multiple myeloma is an incurable hematologic malignancy characterized by increased bone marrow angiogenesis and extensive lytic bone disease. We have previously shown that elevated levels of stromal-derived factor-1α (SDF-1α) in peripheral blood plasma are associated with osteolysis in multiple myeloma patients. We have now examined whether SDF-1α levels also correlate with angiogenesis.

Experimental Design: We examined the contribution of multiple myeloma plasma cell–derived SDF-1α in the stimulation of in vitro angiogenesis using a tube formation assay. We also collected trephine and peripheral blood plasma samples from patients with multiple myeloma to analyze microvessel density and SDF-1α levels, respectively.

Results: We show that multiple myeloma plasma cell line–derived conditioned medium containing SDF-1α stimulates in vitro angiogenesis. In addition, in a large cohort of patients with multiple myeloma and its precursor condition monoclonal gammopathy of undetermined significance, we confirm previous findings that plasma cell burden correlates with both angiogenesis and plasma levels of SDF-1α. We now extend these observations and show the novel finding that peripheral blood plasma levels of SDF-1α positively correlate with the degree of bone marrow angiogenesis in multiple myeloma and monoclonal gammopathy of undetermined significance patients.

Conclusions: High levels of SDF-1α produced by multiple myeloma plasma cells promote osteolysis and bone marrow angiogenesis. Therefore, we propose that inhibition of SDF-1α may be an effective mechanism by which angiogenesis and osteolysis can be reduced in multiple myeloma patients.
Chromosome 20q13.2 Gain May Predict Intravesical Recurrence after Nephroureterectomy in Upper Urinary Tract Urothelial Tumors
Authors: Akao Jumpei , Matsuyama Hideyasu , Yamamoto Yoshiaki , Sasaki Kohsuke , Naito Katsusuke
Published: December 2006

Purpose: Amplification or gain of copy number of chromosome 20q13.2 has been implicated as a causal factor for chromosome instability. We investigated the impact of chromosomal instability and its causative molecular markers, 20q13.2 gain and centrosome amplification, on patient outcome in upper urinary tract transitional cell carcinoma (UUT-TCC).

Experimental Design: The number of centrosomes was assessed by immunohistochemistry. Numerical aberrations of chromosomes 7, 9, and 17 that allowed the estimation of chromosomal instability and 20q13.2 gain were evaluated by fluorescence in situ hybridization in 96 frozen specimens from UUT-TCC and compared with clinicopathologic background and patient outcome.

Results: Chromosomal instability, 20q13.2 gain, and centrosome amplification were detected in 62 of 96 (64.6%), 61 of 96 (63.5%), and 45 of 90 (50.0%) tumors, respectively. 20q13.2 Gain was significantly associated with tumor stage (P = 0.042), chromosomal instability (P < 0.0001), and centrosome amplification (P < 0.0001). Kaplan-Meier analysis showed that 20q13.2 gain was strongly associated with intravesical recurrence-free survival in all patients (P = 0.0050), as well as in patients with grade 2 tumors (P = 0.0011, log-rank test). On multivariate analysis, 20q13.2 gain was found to be the sole independent prognostic factor predicting subsequent intravesical recurrence (hazard ratio, 1.65; 95% confidence interval, 1.03–2.90; P = 0.036).

Conclusions: 20q13.2 gain was strongly associated with a reduced time to intravesical recurrence in all patients. Our data suggest that 20q13.2 gain may be a predictive marker of intravesical recurrence in patients with UUT-TCC.
Correlation between High Vascular Endothelial Growth Factor-A Serum Levels and Treatment Outcome in Patients with Standard-Risk Acute Lymphoblastic Leukemia: A Report from Children's Oncology Group Study CCG-1962
Authors: Avramis Ioannis A. , Panosyan Eduard H. , Dorey Fred , Holcenberg John S. , Avramis Vassilios I.
Published: December 2006

Purpose: Many molecular pathways, including cell cycle control, angiogenesis, and drug resistance, mediate tumor growth and survival. Vascular endothelial growth factor-A (VEGF-A) serum levels <40 and >100 pg/mL have been associated with good and poor prognoses, respectively.

Experimental Design: The hypothesis was that serum VEGF-A levels in standard-risk acute lymphoblastic leukemia pediatric patients at induction are predictive of event-free survival (EFS). One hundred seventeen patients were entered in CCG-1962 study and randomized into the native and polyethylene glycolated asparaginase arms. VEGF-A levels were quantified by an ELISA assay.

Results: All patients had a decrease in VEGF-A levels by day 14 of induction, but they later dichotomized; EFS group levels remained low and event group levels increased. A correlation exists between high VEGF-A levels at entry to induction and time to event. Moreover, 6-year EFS patients have lower end of induction VEGF-A levels (28 ± 6 pg/mL) than event patients (>100 pg/mL; P < 0.01). Kaplan-Meier curves using various VEGF-A values were produced; with ≤30 at entry into induction (day 0) and ≤60 pg/mL at the end of induction (day 28), patients with low VEGF-A levels had superior EFS (P < 1e−4). Furthermore, patients who had an increase in VEGF-A during induction (ΔVEGF-positive, days 0-28) were more likely to have an event (P < 1e−4). Bifurcation by asparaginase treatment arm did not alter these results.

Conclusions: These observations strongly support that high VEGF-A levels in induction are an asparaginase treatment–independent predictive marker for EFS. Hence, an anti-VEGF-A therapy should be tested in acute lymphoblastic leukemia.
Late Toxicity Is Not Increased in BRCA1/BRCA2 Mutation Carriers Undergoing Breast Radiotherapy in the United Kingdom
Authors: Shanley Susan , McReynolds Kate , Ardern-Jones Audrey , Ahern Roger , Fernando Indrajit , Yarnold John , Evans Gareth , Eccles Diana , Hodgson Shirley , Ashley Sue , Ashcroft Linda , Tutt Andrew , Bancroft Elizabeth , Short Susan , Gui Gerald ,   The Breast Unit of the Royal Marsden NHS Foundation Trust, Barr Lester , Baildam Andrew , Howell Anthony , Royle Gavin , Pierce Lori , Easton Douglas , Eeles Rosalind
Published: December 2006

Purpose: To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom.

Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points.

Results: No increase in clinically significant late toxicity was seen in the mutation carriers.

Conclusions: These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.
Acute Chemotherapy–Related Toxicity Is Not Increased in BRCA1 and BRCA2 Mutation Carriers Treated for Breast Cancer in the United Kingdom
Authors: Shanley Susan , McReynolds Kate , Ardern-Jones Audrey , Ahern Roger , Fernando Indrajit , Yarnold John , Evans Gareth , Eccles Diana , Hodgson Shirley , Ashley Sue , Ashcroft Linda , Tutt Andrew , Bancroft Elizabeth , Short Susan , Smith Ian , Gui Gerald ,   The Breast Unit of the Royal Marsden NHS Foundation Trust, Barr Lester , Baildam Andrew , Howell Anthony , Royle Gavin , Pierce Lori , Easton Douglas , Eeles Rosalind
Published: December 2006

Purpose: To evaluate acute toxicity induced by chemotherapy for breast cancer in a retrospective study of 62 BRCA1/2 mutation carriers matched 1:1 with women who had treatment for sporadic disease in the United Kingdom between 1983 and 2003.

Experimental Design: All participants were interviewed by one of two researchers using standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent, but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers.

Results: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02).

Conclusions: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.
Expression of Erythropoietin and Erythropoietin Receptor in Cervical Cancer and Relationship to Survival, Hypoxia, and Apoptosis
Authors: Leo Cornelia , Horn Lars-Christian , Rauscher Cora , Hentschel Bettina , Liebmann Andre , Hildebrandt Guido , Höckel Michael
Published: December 2006

Purpose: Physiologically, hypoxia induces the expression of erythropoietin (Epo) in adult kidney cells. Epo, in turn, acts on the Epo receptor (EpoR) in RBC precursors to stimulate growth and prevent apoptosis. Because hypoxia plays a major role in the malignant progression of tumors and Epo and its receptors have also been detected in malignant tumors, we investigated the expression of Epo and EpoR and their relationship with hypoxia, proliferation, apoptosis, and clinicopathologic variables in cervical cancer.

Experimental Design: Intratumoral oxygen measurement and needle biopsies of the tumors were done in 48 patients with cervical cancer. The obtained tissue was analyzed by immunohistochemistry with antibodies against Epo, EpoR, and Ki-67 as well as by terminal deoxynucleotidyl transferase–mediated deoxyuracil triphosphate nick-end labeling assays.

Results: Epo and EpoR were expressed in 88% and 92% of samples, respectively. Cervical cancers with higher Epo expression showed a significantly reduced overall survival (3 years, 50.0% versus 80.6%; P = 0.0084). Epo and EpoR expression correlated significantly with apoptosis (r = 0.49, P = 0.001 and r = 0.36, P = 0.021). Furthermore, EpoR expression correlated significantly with tumor size (r = 0.32, P = 0.032) and was significantly associated with the presence of lymphovascular space involvement (P = 0.037). However, we observed no correlation between Epo or EpoR expression and intratumoral hypoxia, although in well-oxygenated tumors, EpoR localized significantly more often to the invasion front (P = 0.047).

Conclusions: This study analyzes Epo/EpoR expression and their relationship with intratumoral pO2 levels as well as with survival in patients with cervical cancer. The data suggest a critical role of the endogenous Epo/EpoR system in cervical cancer.
A Novel Anticancer Effect of Thalidomide: Inhibition of Intercellular Adhesion Molecule-1–Mediated Cell Invasion and Metastasis through Suppression of Nuclear Factor-κB
Authors: Lin Yi-Chu , Shun Chia-Tung , Wu Ming-Shiang , Chen Ching-Chow
Published: December 2006

Purpose: Thalidomide has been reported to have antiangiogenic and antimetastatic effects. Intercellular adhesion molecule-1 (ICAM-1) was shown to be involved in monocyte adherence to epithelial cells and cancer cell invasion. In this study, we further investigated the role of ICAM-1 in tumorigenesis, including tumor formation and metastasis. ICAM-1 as a molecular target for cancer and the anticancer effect of thalidomide were investigated.

Experimental Design: Expression of ICAM-1 protein in human lung cancer specimens was assessed by immunohistochemistry. ICAM-1 overexpressing A549 cells (A549/ICAM-1) were established to investigate the direct effect of ICAM-1 on in vitro cell invasion and in vivo tumor metastasis. Transient transfection and luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation were done to assess the activity and binding of nuclear factor-κB to the ICAM-1 promoter. A xenograft model in nude mice was conducted to evaluate the anticancer effect of thalidomide.

Results: High expression of ICAM-1 in human lung cancer specimens was correlated with a greater risk of advanced cancers (stages III and IV). A549/ICAM-1 cells were shown to induce in vitro cell invasion and in vivo tumor metastasis. Anti-ICAM-1 antibody and thalidomide had inhibitory effect on these events. Thalidomide also suppressed tumor necrosis factor-α–induced ICAM-1 expression through inhibition of nuclear factor-κB binding to the ICAM-1 promoter. The in vivo xenograft model showed the effectiveness of thalidomide on tumor formation.

Conclusion: These studies provide a framework for targeting ICAM-1 as a biologically based therapy for cancer, and thalidomide might be effective in human lung cancer.
Aurora Kinases: New Targets for Cancer Therapy
Authors: Carvajal Richard D. , Tse Archie , Schwartz Gary K.
Published: December 2006

The Aurora kinase family is a collection of highly related serine/threonine kinases that functions as a key regulator of mitosis. In mammalian cells, Aurora has evolved into three related kinases known as Aurora-A, Aurora-B, and Aurora-C. These kinases are overexpressed in a number of human cancers, and transfection studies have established Aurora-A as a bone fide oncogene. Because Aurora overexpression is associated with malignancy, these kinases have been targeted for cancer therapy. This article reviews the multiple functions of Aurora kinase in the regulation of mitosis and the mitotic checkpoint, the role of abnormal Aurora kinase activity in the development of cancer, the putative mechanisms of Aurora kinase inhibition and its antitumor effects, the development of the first generation of Aurora kinase inhibitors, and prospects for the future of Aurora kinase inhibition in the treatment of cancer.
A Phase 2 Study of Rituximab in Combination with Recombinant Interleukin-2 for Rituximab-Refractory Indolent Non-Hodgkin's Lymphoma
Authors: Khan Khuda D. , Emmanouilides Christos , Benson Don M. , Hurst Deborah , Garcia Pablo , Michelson Glenn , Milan Sandra , Ferketich Amy K. , Piro Lawrence , Leonard John P. , Porcu Pierluigi , Eisenbeis Charles F. , Banks Amy L. , Chen Lei , Byrd John C. , Caligiuri Michael A.
Published: December 2006

Purpose: The incidence of non-Hodgkin's lymphoma (NHL), the fifth most common malignancy in the United States, has increased over 70% in the last 30 years. Fifty percent to 75% of patients with low-grade or follicular NHL respond to rituximab therapy. However, responses are generally of limited duration, and complete responses are rare. Preclinical work suggests that human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) enhances rituximab efficacy. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of action of rituximab. rIL-2 induces expansion and activation of Fc receptor (FcR)–bearing cells, thereby enhancing ADCC. Therefore, a large, multicenter phase 2 trial to assess the effects of rIL-2 on rituximab therapy in patients with rituxumab-refractory low-grade NHL was conducted.

Experimental Design: The combination of rituximab and rIL-2 was studied in 57 patients with rituximab-refractory low-grade NHL (i.e., patients must have received a single-agent course of rituximab and showed no tumor response, or had a response lasting <6 months). I.V. rituximab was given at 375 mg/m2 (weeks 1-4). S.C. rIL-2 was given thrice a week at 14 MIU (weeks 2-5) and at 10 MIU (weeks 6-9).

Results: Rituximab plus rIL-2 combination therapy was safe and generally well tolerated, but responses were low. Fifty-seven patients were enrolled with 54 evaluable for response; however, only five responses (one complete and four partial) were observed. Correlative data indicate that rIL-2 expanded FcR-bearing cells and enhanced ADCC. However, other factors, such as FcγR polymorphisms in patients refractory to single-agent rituxumab and heterogeneous tumor biology, may have influenced the lack of clinical efficacy seen with this combination therapy.

Conclusions: rIL-2 expands FcR-bearing cellular subsets in vivo and enhances in vitro ADCC of rituxumab. However, these findings do not directly translate into meaningful clinical benefit for patients with rituxumab-refractory NHL.
A Study to Determine the Effects of Food and Multiple Dosing on the Pharmacokinetics of Vorinostat Given Orally to Patients with Advanced Cancer
Authors: Rubin Eric H. , Agrawal Nancy G.B. , Friedman Evan J. , Scott Pamela , Mazina Kathryn E. , Sun Linda , Du Lihong , Ricker Justin L. , Frankel Stanley R. , Gottesdiener Keith M. , Wagner John A. , Iwamoto Marian
Published: December 2006

Purpose: This phase I study, conducted in advanced-stage cancer patients, assessed the safety and tolerability of oral vorinostat (suberoylanilide hydroxamic acid), single-dose and multiple-dose pharmacokinetics of vorinostat, and the effect of a high-fat meal on vorinostat pharmacokinetics.

Experimental Design: Patients (n = 23) received single doses of 400 mg vorinostat on day 1 (fasted) and day 5 (fed) with 48 hours of pharmacokinetic sampling on both days. Patients received 400 mg vorinostat once daily on days 7 to 28. On day 28, vorinostat was given (fed) with pharmacokinetic sampling for 24 hours after dose.

Results: The apparent t1/2 of vorinostat was short (∼1.5 hours). A high-fat meal was associated with a small increase in the extent of absorption and a modest decrease in the rate of absorption. A short lag time was observed before detectable levels of vorinostat were observed in the fed state, and Tmax was delayed. Vorinostat concentrations were qualitatively similar following single-dose and multiple-dose administration; the accumulation ratio based on area under the curve was 1.21. The elimination of vorinostat occurred primarily through metabolism, with <1% of the given dose recovered intact in urine. The most common vorinostat-related adverse experiences were mild to moderate nausea, anorexia, fatigue, increased blood creatinine, and vomiting.

Conclusions: Vorinostat concentrations were qualitatively similar after single and multiple doses. A high-fat meal increased the extent and modestly decreased the rate of absorption of vorinostat; this effect is not anticipated to be clinically meaningful. Continued investigation of 400 mg vorinostat given once daily in phase II and III efficacy studies is warranted.
A Clinical Study on the Tolerability of a Liposomal Povidone-Iodine Nasal Spray: Implications for Further Development
Authors: Gluck U. , Martin U. , Bosse B. , Reimer K. , Mueller S.
Published: December 2006

Purpose of Study: This phase I study assessed tolerability and local effect of a liposome dispersion with povidone-iodine (polyvinylpyrrolidone-iodine, PVP-I) as nasal spray. Procedures: Three groups received liposomal dispersion with PVP-I (2.2, 4.4 and 0% as control) in single and repeated use (3 days, three times a day). A set of functional and cytological tests as well as safety assessments were performed. Results: No safety-relevant finding or serious adverse events were reported, no evidence for cyto- nor genotoxicity obtained. No clinically relevant changes in mucosa appearance, nor in olfactory sense, nor in ciliary activity (sensitive indicator of local tolerance) occurred and no complaints about nasal airflow obstruction were observed. All liposomal formulations had a positive effect on the nasal mucosa, challenged by allergy in some volunteers. Conclusions and Message: Application of liposomal PVP-I spray to the nasal mucosa does not result in any demonstrable limitation of the nasal function nor in detectable damage to the multilayer ciliated epithelium of the nose. Improvement of various parameters of nasal function under liposomal PVP-I suggest improved mucociliary clearance. Explanation could be humidification, improved surfactant (phospholipid) level and/or sufficient mucolytic activity of iodide due to local application of the constituents.
Comparison of Automatic and Continuous Positive Airway Pressure in a Night-by-Night Analysis: A Randomized, Crossover Study
Authors: Galetke Wolfgang , Anduleit Norbert , Richter Kerstin , Stieglitz Sven , Randerath Winfried J.
Published: December 2006

Background: Long-term compliance is suboptimal in the treatment of the obstructive sleep apnea syndrome (OSAS). Objectives: We compared the efficacy of and the adherence to automatic continuous positive airway pressure (APAP) and constant continuous positive airway pressure (CPAP) based on a night-by-night analysis. Methods: We performed a randomized, single-blind crossover study in 20 patients with moderate-to-severe OSAS. After diagnostic polysomnography and manual titration, patients were treated for 8 weeks with both constant CPAP and APAP in random order. Compliance and leakage were analyzed night by night using the software LOGSoft® of the Magellan® iPAP device. Results: The reduction in the apnea/hypopnea index (baseline 32.9 ± 19.1/h, CPAP 4.6 ± 2.9/h, APAP 5.6 ± 3.6/h; p < 0.001 compared to baseline) and the Epworth Sleepiness Scale (baseline 10.3 ± 5.7, CPAP 6.6 ± 4.8, APAP 4.9 ± 4.6; p < 0.001 compared to baseline) did not significantly differ between the treatment modes. Leakage time and compliance per night were not statistically different (leakage CPAP 31 ± 57 min, APAP 25 ± 49 min; compliance CPAP 383 ± 116 min, APAP 382 ± 107 min). There was no correlation between leakage and compliance. Thirteen patients (65%) preferred APAP at the end of the study. Conclusions: Treatment efficacy and adherence are similar with CPAP and APAP. There is a trend towards lower leakage with APAP therapy. Patients prefer the automatic mode to fixed pressure.
Physical Activity Intervention Studies
Authors: Marcus Bess H. , Williams David M. , Dubbert Patricia M. , Sallis James F. , King Abby C. , Yancey Antronette K. , Franklin Barry A. , Buchner David , Daniels Stephen R. , Claytor Randal P.
Published: December 2006

In this review, our first purpose is to provide an overview of existing physical activity intervention research, focusing on subpopulations and intervention modalities. Our reviews within each area are not exhaustive or quantitative, as each area has been reviewed in more depth in numerous other reports. Instead, our goal is to provide a single document that provides a qualitative overview of intervention research that emphasizes selected topics of particular importance for improving the population-wide impact of interventions. Therefore, in synthesizing this vast literature, we begin with existing reviews of physical activity research in each area and incorporate in our discussions recent reports of well-designed individual physical activity intervention studies that expand the existing research base and/or target new areas of research. Our second purpose is to offer new ideas and recommendations to improve the state of the science within each area and, where possible, to propose ideas to help bridge the gaps between these existing categories of research.
Emergence of Sex Differences in Prevalence of High Systolic Blood Pressure
Authors: Dasgupta Kaberi , O’Loughlin Jennifer , Chen Shunfu , Karp Igor , Paradis Gilles , Tremblay Johanne , Hamet Pavel , Pilote Louise
Published: December 2006

Background—

High systolic blood pressure (SBP) occurs more frequently both among men and boys than among women and girls. No longitudinal study has investigated whether the impact of SBP determinants differ according to sex in youth.

Methods and Results—

Between 1999 and 2005, an adolescent cohort (n=1267) completed a questionnaire survey and underwent biannual blood pressure and anthropometric assessment (grades 7, 9, and 11). Boys accounted for ≈50% of those with high SBP at grade 7 and 9 assessments but 67% of those with high SBP at the grade 11 assessment. As computed through a generalized estimating equations logistic regression model (sex, age, sex and age interaction term, overweight, physical activity, sedentary behavior, heart rate, household income, tobacco use, and 4 language categories), the likelihood of high SBP values among boys compared with girls was 1.29 (95% CI, 0.77 to 2.16) in grade 7, 1.98 (95% CI, 1.35 to 2.93) in grade 9, and 2.74 (95% CI, 1.52 to 4.94) in grade 11. Although there was a significant interaction between sex and age, interaction terms of sex with overweight, sedentary behavior, and physical activity were not statistically significant. Overweight (odds ratio [OR], 2.63; 95% CI, 1.76 to 3.92) and sedentary behavior (OR, 1.17 for increment of 5 hours weekly; 95% CI 1.04 to 1.33) demonstrated positive associations with high SBP values. Physical activity was inversely associated with the presence of high SBP (OR, 0.92 for increment of 5 activities in 7 days; 95% CI, 0.84 to 1.00).

Conclusions—

Boys are more likely than girls to develop high SBP as they approach adulthood. Even among overweight adolescents, reducing sedentary behavior and increasing physical activity may lower the risk of high SBP.
Unblinded Pilot Study of Autologous Transplantation of Bone Marrow Mononuclear Cells in Patients With Thromboangiitis Obliterans
Authors: Miyamoto Koji , Nishigami Kazuhiro , Nagaya Noritoshi , Akutsu Koichi , Chiku Masaaki , Kamei Masataka , Soma Toshihiro , Miyata Shigeki , Higashi Masahiro , Tanaka Ryoichi , Nakatani Takeshi , Nonogi Hiroshi , Takeshita Satoshi
Published: December 2006

Background—

The short-term clinical benefits of bone marrow mononuclear cell transplantation have been shown in patients with critical limb ischemia. The purpose of this study was to assess the long-term safety and efficacy of bone marrow mononuclear cell transplantation in patients with thromboangiitis obliterans.

Methods and Results—

Eleven limbs (3 with rest pain and 8 with an ischemic ulcer) of 8 patients were treated by bone marrow mononuclear cell transplantation. The patients were followed up for clinical events for a mean of 684±549 days (range 103 to 1466 days). At 4 weeks, improvement in pain was observed in all 11 limbs, with complete relief in 4 (36%). Pain scale (visual analog scale) score decreased from 5.1±0.7 to 1.5±1.3. An improvement in skin ulcers was observed in all 8 limbs with an ischemic ulcer, with complete healing in 7 (88%). During the follow-up, however, clinical events occurred in 4 of the 8 patients. The first patient suffered sudden death at 20 months after transplantation at 30 years of age. The second patient with an incomplete healing of a skin ulcer showed worsening of the lesion at 4 months. The third patient showed worsening of rest pain at 8 months. The last patient developed an arteriovenous shunt in the foot at 7 months, which spontaneously regressed by 1 year.

Conclusions—

In the present unblinded and uncontrolled pilot study, long-term adverse events, including death and unfavorable angiogenesis, were observed in half of the patients receiving bone marrow mononuclear cell transplantation. Given the current incomplete knowledge of the safety and efficacy of this strategy, careful long-term monitoring is required for future patients receiving this treatment.
Exploiting Proprioception to Improve Haptic Interaction in a Virtual Environment
Authors: Boeck Joan De , Raymaekers Chris , Coninx Karin
Published: December 2006

3D environments are designed to be intuitive and easy to use. However, when defining interaction in 3D virtual environments, suitable paradigms for accessing objects and user interface elements are often difficult to determine. Several solutions currently exist, all with their strengths and weaknesses, but due to the complexity of the human senses and technical and financial restrictions, none of them is ideal. In this paper, we describe a first step in our research investigating how 3D interaction can be improved by introducing a technique that uses proprioception together with realistic force feedback in order to more easily access objects and widgets in 3D space. In a user experiment, we also validate our newly proposed solution, and compare it to our earlier work.
Diplomacy with Fundamentalists: The United States and the Taliban
Authors: Kleiner Juergen
Published: December 2006

After the Taliban had become a permanent factor in Afghan politics at the beginning of 1995, the US administration started talking to them, mainly through the American Embassy in Islamabad. Declassified documents about the administration's dealings with the Taliban, which were obtained and published by the National Security Archive, give insight into the relationship between the two unlikely partners. The Americans discussed various issues with the Taliban, such as peace in Afghanistan, the fight against narcotics, human rights, the proposed Unocal gas pipeline from Turkmenistan through Afghanistan, and terrorism. The Taliban demanded recognition as Afghanistan's legitimate government and wanted access to additional revenue. American talks with the Taliban survived the deterioration of the relationship from original friendliness to opposition to the promotion of sanctions and finally to threats. Since the end of summer 1998, a solution to the issue of Osama Bin Laden has been the US administration's top issue. The Americans asked the Taliban with urgency to take Bin Laden into custody or to expel him. The US administration, however, did not offer the Taliban anything in return. Persuasion was not enough to achieve the desired result and the administration's strategy was self-defeating.
Movement Frames and African Women's Explanations for Opposing Female Genital Cutting
Authors: Boyle Elizabeth Heger , Carbone-López Kristin
Published: December 2006

This article addresses how people account for their beliefs and what social factors affect or determine those accounts. Considering the explanations women in five African countries give for their opposition to female genital cutting (FGC), we empirically examine the link between movement adherence and frame resonance. Although international anti-FGC activists employ medical and human rights frames to combat the practice, we find most of the women surveyed do not use these frames to account for their opposition to FGC. Rather, they tend to explain their opposition simply by stating female genital cutting is a ‘bad tradition.’ Based on descriptive statistics and the results of HGLM analyses, we conclude that 1) the importance of frame resonance for movement adherence varies across groups, 2) frame resonance is less important to ‘adherents’ whose supportive attitudes predate mobilization, 3) personal factors, such as being circumcised, exposure to western influence, and independence, increase the likelihood that adherents will link into international activist frames, and 4) the medical frame is more persuasive than the human rights frame for African anti-FGC adherents.
Neoliberalism, Institutional Change and the Welfare State: The Case of Britain and France
Authors: Kus Basak
Published: December 2006

Neoliberal turn in economic policy involved an attack on the welfare state in some countries but not in others. This article provides an institutionalist explanation of the causes of this variation through a comparative analysis of the transformation of British and French economic policy from the end of the Second World War through the end of the 1980s. The author shows that in both nations the transition to neoliberalism accompanied the economic crisis that took place in the 1970s. However, consistent with the differences in the way the two countries came to diagnose the nature of their respective crises; the policy manifestations of neoliberalism remained different in each. In Britain, where the crisis was diagnosed as one of Keynesianism, neoliberalism emerged as a radical antiKeynesian movement that sought to dismantle major Keynesian institutions and policies.In this context, the welfare state, a fundamental Keynesian institution, was identified as a part of the ‘problem,’ and became subject to the neoliberal ‘solution.’ On the other hand, in France, where the crisis was perceived to reside in the declining competitiveness of the dirigiste policies, the neoliberal reorganization of the economy focused on industrial policy. The welfare state was not associated with the problems of dirigisme, and remained largely resilient. Through this analysis, the author attempts to develop a general theory of the relationship between neoliberalism and national policies and provide insights into the process through which paradigmatic ideas such as neoliberalism translate into concrete policy preferences in different national contexts. Data for this study come from a combination of content analysis of major government documents concerning the economy and social policy, political party election manifestos, opinion papers, OECD statistics and secondary literature.
Defending the Republic: The García Atadell Brigade in Madrid, 1936
Authors: Ruiz Julius
Published: December 2006

During the Spanish Civil War of 1936–39, an estimated 50,000 executions took place in the Republican zone. Of these, around 9000 were killed in the Spanish capital. Explanations of Republican violence still tend to assume that it was the work of ‘uncontrollables’ and frequently cite Agapito García Atadell as an example. Atadell led a brigade of 48 men that spread terror in Madrid during the summer of 1936 before he attempted to escape for Cuba that October. However, he was captured in the Nationalist-held Canaries and executed in July 1937. This article considers whether Atadell was really an ‘uncontrollable’. It shows not only that Atadell was a significant figure in Madrid's Socialist movement before the Civil War but also that his brigade was the result of an initiative by the Socialist Party bureaucracy in early August 1936 to reinforce the police with loyal Republicans. This does not imply the existence of a Republican ‘programme of terror’. It suggests that the brigade operated autonomously in its pursuit of dangerous ‘internal enemies’. It also argues that the brigade was widely perceived to be efficiently defending the Republic against the ‘Fifth Column’ and that Atadell's departure did not harm the career prospects of many of his subordinates in the reorganized Republican police after 1936.
US ‘Atomic Capability’ and the British Forward Bases in the Early Cold War
Authors: Young Ken
Published: December 2006

During the Berlin crisis of 1948, US bombers were once again based in Britain, signalling to the Soviet government the American resolution to stand fast in defence of western Europe. Contemporary commentators and many historians readily assumed that the act of deployment represented the rattling of a nuclear sabre. But did the USA have the capability to deliver an atomic attack on the Soviet Union from English bases at that time? The answer is not obvious. A series of confusions obscures what the term ‘atomic capability’ really signified in the late 1940s and early 1950s. First, contrary views persist even in the recent literature as to whether the particular B-29s deployed to Britain in 1948 were capable of delivering an atomic attack on Russia. They were not, but were equipped, armed and prepared to fight a conventional air campaign. Second, nuclear capability is mistakenly seen as an attribute solely of the delivery vehicle rather than of the logistical capability of the bases themselves and their supply lines. Work on converting and equipping the East Anglian airbases for atomic operations, begun as early as 1946, had not been completed by the time of the Berlin crisis. Third, the date when US nuclear weapons were actually deployed to Britain is concealed by tactically convenient definitions of what constitutes a ‘weapon’. The article argues that USAF forces in England gained a nuclear capability only in 1949, and that the purpose of the deployment at the time of the Berlin blockade was not nuclear diplomacy but to secure the forward airbases required by contemporary US war plans.
The Concepts of ‘Religion’, ‘Political Religion’ and the Study of Nazism
Authors: Stowers Stanley
Published: December 2006

The concept of political religion as used in the study of National Socialism depends upon highly criticized expressive-symbolist theories of religion and an implied opposition to the religion of genuine Christianity. The idea of a counterfeit substitute for Christianity goes back to ancient Christian discourse about heresy. The article advocates rational-cognitivist approaches to religion and argues that these prove better for historical work on National Socialism, and that Steigmann-Galls Holy Reich is compatible with this way of theorizing religion.
Nazism and Christianity: Partners and Rivals? A Response to Richard Steigmann-Gall, The Holy Reich. Nazi Conceptions of Christianity, 1919–1945
Authors: Bergen Doris L.
Published: December 2006

This response accepts Richard Steigmann-Gall's argument that nazism and Christianity were less sharply opposed than popular and much scholarly opinion have assumed. Personal ties, institutional links and ideological common ground connected nazism and Christianity, and many members of the nazi elite considered themselves to be devoted Christians. Steigmann-Gall makes a significant contribution by focusing on such ‘Christian nazis’, in contrast to the ‘nazi Christians’ that others have examined. But he could do more to clinch his case. By defining religion solely in terms of belief, he ignores important aspects of nazi–Christian co-existence: for example, the fact that Church membership remained extremely high in Germany throughout the nazi era. His assumption of an especially close nazi–Protestant nexus obscures the significant cooperation of the Catholic Church. Meanwhile, by denying the existence of tensions between nazism and Christianity, he fails to consider the defensive posture of Church leaders, a stance that motivated much of their eager accommodation of National Socialism.