bluuebunny/crossref_metadata_2025_split huggingface dataset:
Notch1 Expression Predicts an Unfavorable Prognosis and Serves as a Therapeutic Target of Patients with Neuroblastoma
Authors: Chang Hsiu-Hao , Lee Hsinyu , Hu Ming-Kuan , Tsao Po-Nien , Juan Hsueh-Fen , Huang Min-Chuan , Shih Yu-Yin , Wang Bo-Jeng , Jeng Yung-Ming , Chang Christina Ling , Huang Shiu-Feng , Tsay Yeou-Guang , Hsieh Fon-Jou , Lin Kai-Hsin , Hsu Wen-Ming , Liao Yung-Feng 
Published: August 2010

AbstractPurpose: Notch signaling has been implicated to play a critical role in the tumorigenesis of neuroblastoma (NB) and can modulate calreticulin (CRT) expression that strongly correlates with tumor differentiation and favorable prognosis of NB. We thus sought to determine how Notch regulates CRT expression and affects NB tumor behavior.Experimental Design: The Notch-dependent regulation of CRT expression in cultured NB cells was analyzed by confocal microscopy and Western blotting. Notch1 protein expression in 85 NB tumors was examined by immunohistochemistry and correlated with the clinicopathologic/biological characters of NB patients. The progression of NB tumors in response to attenuated Notch signaling was examined by using a xenograft mouse model.Results: We showed that CRT is essential for the neuronal differentiation of NB cells elicited by inhibition of Notch signaling. This effect was mediated by a c-Jun-NH2-kinase–dependent pathway. Furthermore, NB tumors with elevated Notch1 protein expression were strongly correlated with advanced tumor stages, MYCN amplification, an undifferentiated histology, as well as a low CRT expression level. Most importantly, the opposing effect between Notch1 and CRT could reciprocally affect the survival of NB patients. The administration of a γ-secretase inhibitor into a xenograft mouse model of NB significantly suppressed the tumor progression.Conclusions: Our findings provide the first evidence that a c-Jun-NH2-kinase-CRT–dependent pathway is essential for the neuronal differentiation elicited by Notch signaling blockade and that Notch1 and CRT can synergistically predict the clinical outcomes of NB patients. The present data suggest that Notch signaling could be a therapeutic target for NB. Clin Cancer Res; 16(17); 4411–20. ©2010 AACR.
Inconsistent Labeling of Food Effect for Oral Agents across Therapeutic Areas: Differences between Oncology and Non-Oncology Products
Authors: Kang Soonmo Peter , Ratain Mark J. 
Published: August 2010

Abstract
Purpose: Several recent oral oncology drugs were labeled for administration in fasted states despite the fact that food increases their bioavailability. Because this was inconsistent with the principles of oral drug delivery, we hypothesized that there were inconsistencies across therapeutic areas.
Experimental Design: Oral agents approved by the U.S. Food and Drug Administration from January 2000 to May 2009 were included in our study. Comparison of the food labeling patterns between oncology and non-oncology drugs was made using Fisher's exact test.
Results: Of the 99 drugs evaluated, 34 showed significant food effects on bioavailability. When food markedly enhanced bioavailability, eight out of nine non-oncology drugs were labeled “fed” to take advantage of the food-drug interaction, whereas all oncology drugs (n = 3) were labeled to be administered in “fasted” states (Fisher's exact test, P = 0.01).
Conclusions: Drug labeling patterns with respect to food-drug interactions observed with oncology drugs are in contradiction with fundamental pharmacologic principles, as exemplified in the labeling of non-oncology drugs. Clin Cancer Res; 16(17); 4446–51. ©2010 AACR.
The Relationship between Prostate-Specific Antigen and Prostate Cancer Risk: The Prostate Biopsy Collaborative Group
Authors: Vickers Andrew J. , Cronin Angel M. , Roobol Monique J. , Hugosson Jonas , Jones J. Stephen , Kattan Michael W. , Klein Eric , Hamdy Freddie , Neal David , Donovan Jenny , Parekh Dipen J. , Ankerst Donna , Bartsch George , Klocker Helmut , Horninger Wolfgang , Benchikh Amine , Salama Gilles , Villers Arnauld , Freedland Steve J. , Moreira Daniel M. , Schröder Fritz H. , Lilja Hans 
Published: August 2010

Abstract
Purpose: The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.
Experimental Design: We used data from five European and three U.S. cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally weighted scatterplot smoothing.
Results: The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased the risk of cancer (odds ratio for &gt;6- versus 6-core biopsy, 1.35; 95% confidence interval, 1.18-1.54; P &lt; 0.0005); recent screening led to a smaller increase in risk per unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the European cohorts (2.14; 95% confidence interval, 1.99-2.30; P &lt; 0.0005).
Conclusions: Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated. Clin Cancer Res; 16(17); 4374–81. ©2010 AACR.
Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients
Authors: Jacobs Joannes F.M. , Punt Cornelis J.A. , Lesterhuis W. Joost , Sutmuller Roger P.M. , Brouwer H. Mary-lène H. , Scharenborg Nicole M. , Klasen Ina S. , Hilbrands Luuk B. , Figdor Carl G. , de Vries I. Jolanda M. , Adema Gosse J. 
Published: August 2010

AbstractPurpose: The success of cancer immunotherapy depends on the balance between effector T cells and suppressive immune regulatory mechanisms within the tumor microenvironment. In this study we investigated whether transient monoclonal antibody–mediated depletion of CD25high regulatory T cells (Treg) is capable of enhancing the immunostimulatory efficacy of dendritic cell vaccines.Experimental Design: Thirty HLA-A2.1+ metastatic melanoma patients were vaccinated with mature dendritic cells pulsed with tumor peptide and keyhole limpet hemocyanin (KLH). Half of the patients were pretreated with daclizumab, a humanized antibody against the interleukin-2 (IL-2) receptor α-chain (CD25), either four or eight days before dendritic cell vaccinations. Clinical and immunologic parameters were determined.Results: Daclizumab efficiently depleted all CD25high immune cells, including CD4+FoxP3+CD25high cells, from the peripheral blood within four days of administration. Thirty days after administration, daclizumab was cleared from the circulation and all CD25+ cells reappeared. The presence of daclizumab during dendritic cell vaccinations prevented the induction of specific antibodies in vivo but not the presence of antigen-specific T cells. Daclizumab, however, did prevent these CD25+ T cells from acquiring effector functions. Consequently, significantly less patients pretreated with daclizumab developed functional, vaccine-specific effector T cells and antibodies compared with controls. Daclizumab pretreatment had no significant effect on progression-free survival compared with the control group.Conclusions: Although daclizumab depleted the CD4+FoxP3+CD25high Tregs from the peripheral circulation, it did not enhance the efficacy of the dendritic cell vaccine. Residual daclizumab functionally suppressed de novo induced CD25+ effector cells during dendritic cell vaccinations. Our results indicate that for immunotherapeutic benefit of transient Treg depletion, timing and dosing as well as Treg specificity are extremely important. Clin Cancer Res; 16(20); 5067–78. ©2010 AACR.
Cyclin-Dependent Kinase 4–Mediated Phosphorylation Inhibits Smad3 Activity in Cyclin D–Overexpressing Breast Cancer Cells
Authors: Zelivianski Stanislav , Cooley Anne , Kall Ron , Jeruss Jacqueline S. 
Published: August 2010

Abstract
Smad3, a component of the transforming growth factor β signaling cascade, contributes to G1 arrest in breast cancer cells. Cyclin D1/cyclin-dependent kinase 4 (CDK4) promotes G1-S–phase transition, and CDK phosphorylation of Smad3 has been associated with inhibition of Smad3 activity. We hypothesized that overexpression of cyclin D1 exerts tumorigenic effects in breast cancer cells through CDK4-mediated phosphorylation and inhibition of Smad3 and release of G1 arrest. Real-time quantitative reverse transcription-PCR and immunoblotting were used to evaluate expression of study proteins in cyclin D1–overexpressing breast cancer cells. Smad3 transcriptional activity and cell cycle control were examined in cells transfected with wild-type (WT) Smad3 or Smad3 with single or multiple CDK phosphorylation site mutations (M) in the presence or absence of the CDK4 inhibitor or cotransfection with cdk4 small interfering RNA (siRNA). Transfection of the Smad3 5M construct resulted in decreased c-myc and higher p15INK4B expression. Compared with WT Smad3, overexpression of the Smad3 T8, T178, 4M, or 5M mutant constructs resulted in higher Smad3 transcriptional activity. Compared with cells transfected with WT Smad3, Smad3 transcriptional activity was higher in cells overexpressing Smad3 mutant constructs and treated with the CDK4 inhibitor or transfected with cdk4 siRNA. Cells transfected with Smad3 T8 or T178 and treated with the CDK4 inhibitor showed an increase in the G1 cell population. Inhibition of CDK-mediated Smad3 phosphorylation released cyclin D1–regulated blockade of Smad3 transcriptional activity and recovered cell cycle arrest in breast cancer cells. Targeted inhibition of CDK4 activity may have a role in the treatment of cyclin D–overexpressing breast cancers. Mol Cancer Res; 8(10); 1375–87. ©2010 AACR.
Regional Control of Tumor Growth
Authors: Zaslavsky Alexander , Chen Catherine , Grillo Jenny , Baek Kwan-Hyuck , Holmgren Lars , Yoon Sam S. , Folkman Judah , Ryeom Sandra 
Published: August 2010

Abstract
Tumors implanted near the scapulae have been shown to grow four times faster than the same tumors implanted at the iliac crest. Although there were marked differences in the vascularization of tumors from these two different sites, the mechanism controlling regional angiogenesis was not identified. Here, we show site-specific growth of intraperitoneal tumor implants in the mouse abdomen. Our data indicate that the angiogenic response of the host differs significantly between the upper and lower sites in the mouse abdomen and reveal that the expansion of tumor mass is restricted to sites with low angiogenic responses, such as the bowel mesentery in the lower abdomen. We show that, in this model, this suppression of angiogenesis is due to an expression gradient of thrombospondin-1 (TSP-1), a potent endogenous angiogenesis inhibitor. Mice with a targeted deletion of TSP-1 no longer show regional restriction of tumor growth. The physiologic relevance of these findings may be seen in patients with peritoneal carcinomatosis, whereby tumors spread within the peritoneal cavity and show differential growth in the upper and lower abdomen. We hypothesize that the difference in tumor growth in these patients may be due to a gradient of TSP-1 expression in stroma. Finally, our studies suggest that upregulation of TSP-1 in tumor cells is one method to suppress the growth of tumors in the upper abdomen. Mol Cancer Res; 8(9); 1198–206. ©2010 AACR.
Imatinib Upregulates Compensatory Integrin Signaling in a Mouse Model of Gastrointestinal Stromal Tumor and Is More Effective When Combined with Dasatinib
Authors: Rossi Ferdinand , Yozgat Yasemin , de Stanchina Elisa , Veach Darren , Clarkson Bayard , Manova Katia , Giancotti Filippo G. , Antonescu Cristina R. , Besmer Peter 
Published: August 2010

Abstract
Activating mutations in the Kit receptor tyrosine kinase are associated with gastrointestinal stromal tumor (GIST). Imatinib inhibits Kit and is front-line therapy for GIST. However, imatinib most often elicits a partial response or stable disease, and most GIST patients who initially respond to imatinib eventually acquire resistance. Thus, improved treatment strategies for GIST are needed. We investigated the role of Src family kinases (SFK) in tumorigenesis in a mouse model of human GIST. The SFKs Src and Lyn were active in GIST, and surprisingly, imatinib treatment stimulated their phosphorylation/activation. We show that integrin signaling activates focal adhesion kinase and, consequently, SFKs in GIST and that imatinib enhances integrin signaling, implying a role for the extracellular matrix and integrin signaling in tumor maintenance and imatinib resistance. Dasatinib, an inhibitor of SFKs and Kit, inhibited SFK and focal adhesion kinase activation in GIST but also inhibited Kit and Kit-dependent downstream signaling pathways including phosphoinositide 3-kinase and mitogen-activated protein kinase, but not signal transducer and activator of transcription (STAT) signaling. Whereas dasatinib and imatinib alone both produced a minimal histopathologic response, combination therapy improved their efficacy, leading to increased necrosis in GIST. These results highlight the importance of SFK and STAT signaling in GIST and suggest that the clinical efficacy of imatinib may be limited by the stimulation of integrin signaling. Mol Cancer Res; 8(9); 1271–83. ©2010 AACR.
Autophagy Induction with RAD001 Enhances Chemosensitivity and Radiosensitivity through Met Inhibition in Papillary Thyroid Cancer
Authors: Lin Chi-Iou , Whang Edward E. , Donner David B. , Du Jinyan , Lorch Jochen , He Frank , Jiang Xiaofeng , Price Brendan D. , Moore Francis D. , Ruan Daniel T. 
Published: August 2010

Abstract
Although autophagy is generally considered a prosurvival mechanism that preserves viability, there is evidence that it could drive an alternative programmed cell death pathway in cells with defects in apoptosis. Because the inhibition of autophagic activity promotes resistance to both chemotherapy and external beam radiation in papillary thyroid cancer (PTC), we determined if RAD001, a potent activator of autophagy, improves the efficacy of either therapy. We found that RAD001 increased the expression level of light chain 3-II, a marker for autophagy, as well as autophagosome formation in cell lines and in human PTC ex vivo. RAD001 sensitized PTC to doxorubicin and external beam radiation in a synergistic fashion, suggesting that combination therapy could improve therapeutic response at less toxic concentrations. The effects of RAD001 were abrogated by RNAi knockdown of the autophagy-related gene 5, suggesting that RAD001 acts, in part, by enhancing autophagy. Because the synergistic activity of RAD001 with doxorubicin and external radiation suggests distinct and complementary mechanisms of action, we characterized how autophagy modulates signaling pathways in PTC. To do so, we performed kinome profiling and discovered that autophagic activation resulted in Src phosphorylation and Met dephosphorylation. Src inhibition did not reverse the effects of RAD001, whereas Met inhibition reversed the effects of autophagy blockade on chemosensitivity. These results suggest that the anticancer effects of autophagic activation are mediated largely through Met. We conclude that RAD001 induces autophagy, which enhances the therapeutic response to cytotoxic chemotherapy and external beam radiation in PTC. Mol Cancer Res; 8(9); 1217–26. ©2010 AACR.
Erythropoietin in Patients With Acute ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Ott Ilka , Schulz Stefanie , Mehilli Julinda , Fichtner Stefanie , Hadamitzky Martin , Hoppe Katharina , Ibrahim Tareq , Martinoff Steffan , Massberg Steffen , Laugwitz Karl-Ludwig , Dirschinger Josef , Schwaiger Markus , Kastrati Adnan , Schömig Albert ,   for the REVIVAL-3 Study Investigators
Published: August 2010

Background—
Erythropoietin improves myocardial function in experimental models of myocardial infarction. The aim of the present study was to determine the value of erythropoietin in patients with acute ST-elevation myocardial infarction.

Methods and Results—

This randomized, double-blind study included 138 patients admitted with acute ST-elevation myocardial infarction and treated with primary percutaneous coronary intervention. Patients were randomly assigned to receive epoetin-β (3.33×104 U, n=68) or placebo (n=70) immediately and at 24 and 48 hours after percutaneous coronary intervention. The primary end point was left ventricular ejection fraction after 6 months measured by MRI. Other end points included infarct size at 5 days and 6 months. Clinical adverse events (death, recurrent myocardial infarction, stroke, and infarct-related artery revascularization) were investigated at 30 days and 6 months. Left ventricular ejection fraction at 6-month follow-up was 52.0±9.1% in the erythropoietin group compared with 51.8±9.3% in the placebo group (
P
=0.92). Five days after percutaneous coronary intervention, left ventricular ejection fraction was 49.4±8.0% in the erythropoietin group and 50.8±7.3% in the placebo group (
P
=0.32); infarct size was 26.8±20.9% and 28.3±24.4% (
P
=0.76) and decreased to 17.3±14.3% and 20.9±16.4% at 6-month follow-up (
P
=0.27). The cumulative 6-month incidence of death, recurrent myocardial infarction, stroke or target vessel revascularization was 13.2% in the erythropoietin group and 5.7% in the placebo group (hazard ratio, 2.36; 95% confidence interval, 0.73 to 7.66;
P
=0.15).

Conclusions—
In patients with acute ST-elevation myocardial infarction treated with primary percutaneous coronary intervention, erythropoietin treatment did not improve left ventricular ejection fraction or reduce infarct size but may increase clinical adverse events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00390832.
The Platelet Activity After Clopidogrel Termination (PACT) Study
Authors: Frelinger Andrew L. , Barnard Marc R. , Fox Marsha L. , Michelson Alan D. 
Published: August 2010

Background—
“Rebound” platelet hyperreactivity after discontinuation of clopidogrel has been proposed to lead to increased thrombotic risk, including late stent thrombosis. However the hypothesis that discontinuation of clopidogrel results in platelet hyperreactivity has never been rigorously tested. We therefore performed a randomized, double-blind, placebo-controlled, crossover study: the Platelet Activity after Clopidogrel Termination (PACT) study.

Methods and Results—
Platelet reactivity in 15 healthy subjects was measured at baseline, during clopidogrel 75 mg or placebo daily for 14 days, and on days 1, 4, 8, 11, 15, and 45 after discontinuation of clopidogrel or placebo. Platelet reactivity was assessed by (1) platelet surface activated GPIIb-IIIa and surface P-selectin (by whole blood flow cytometry) in response to ADP 0.5, 1, and 20 μmol/L; thrombin receptor activating peptide (TRAP) 1 and 20 μmol/L; and collagen/epinephrine 5 μg/mL/5 μmol/L, (2) light transmission aggregation with ADP 2.5, 5, and 20 μmol/L; TRAP 2 and 20 μmol/L; and collagen 6 μg/mL, (3) whole blood impedance aggregation with ADP 1.6 and 6.5 μmol/L; TRAP 4 and 32 μmol/L; and collagen 3.2 μg/mL, and (4) plasma soluble CD40 ligand (by ELISA). Immature platelet fraction was measured in the Sysmex XE-2100. At no time point after discontinuation of clopidogrel was platelet reactivity, as determined by any assay end point, or the immature platelet fraction significantly greater than after discontinuation of placebo.

Conclusions—
This randomized, double-blind, placebo-controlled, crossover study demonstrates that discontinuation of clopidogrel does not result in “rebound” platelet hyperreactivity, as determined by multiple time points, assays, agonists, and agonist concentrations.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00619073.
Physical Activity Preferences and Type 2 Diabetes
Authors: Forbes Cynthia C. , Plotnikoff Ronald C. , Courneya Kerry S. , Boulé Normand G. 
Published: August 2010

Purpose The purpose of this study was to examine physical activity counseling and program preferences in a sample of adults with type 2 diabetes. Specifically, the objectives were to determine physical activity preferences (objective 1), and whether there were any significant differences between age and/or sex groups for these preferences (objective 1a). A subsidiary objective was to explore potential associations of key social-cognitive constructs (ie, self-efficacy and social support) with physical activity preferences (objective 2). Methods This exploratory study consisted of a quantitative, secondary analysis of survey data from a national sample of adults with type 2 diabetes (N = 244). A qualitative follow-up employing telephone interviews was conducted with 14 individuals. Results Consistent with hypotheses, walking was the most preferred physical activity behavior and there was a preference for engaging in physical activity with others. There were significant (P values < .05) differences in counseling and program preferences between demographic (age and sex), and physical activity cognitive scores. For example, a significantly (P < .05) higher physical activity intensity preference was found in men and younger participants. Conclusions Tailoring interventions and physical activity programs to the specific preferences of individuals is an important component for health professionals and researchers in facilitating this behavior.
Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis
Authors: Jafari Naghmeh , Broer Linda , Hoppenbrouwers Ilse A , van Duijn Cornelia M , Hintzen Rogier Q 
Published: August 2010

Background: Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism. Objectives: Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis. Methods: Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501. Results: HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10 -5). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 ( p = 0.003) for HLA-A. Conclusions: HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.