bluuebunny/crossref_metadata_2025_split huggingface dataset:
RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
Authors: Su Yingjun , Vilgelm Anna E. , Kelley Mark C. , Hawkins Oriana E. , Liu Yan , Boyd Kelli L. , Kantrow Sara , Splittgerber Ryan C. , Short Sarah P. , Sobolik Tammy , Zaja-Milatovic Snjezana , Dahlman Kimberly Brown , Amiri Katayoun I. , Jiang Aixiang , Lu Pengcheng , Shyr Yu , Stuart Darrin D. , Levy Shawn , Sosman Jeffrey A. , Richmond Ann 
Published: February 2012

Abstract
Purpose: The purpose of this preclinical study was to determine the effectiveness of RAF265, a multikinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response.
Experimental Design: Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17 of 34) were evaluated for response to RAF265 (40 mg/kg, every day) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, mitogen-activated protein/extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) phosphorylation, proliferation, and apoptosis markers was evaluated.
Results: Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAFV600E/K), whereas eight of 17 (47%) tumors were BRAF wild type (BRAFWT). Tumor implants from 7 of 17 patients (41%) responded to RAF265 treatment with more than 50% reduction in tumor growth. Five of the 7 (71%) responders were BRAFWT, of which 1 carried c-KITL576P and another N-RASQ61R mutation, while only 2 (29%) of the responding tumors were BRAFV600E/K. Gene expression microarray data from nonimplanted tumors revealed that responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. Although response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11.
Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A subpopulation of human melanoma tumors responds to RAF265 and can be characterized by gene mutation and gene expression profiles. Clin Cancer Res; 18(8); 2184–98. ©2012 AACR.
Tumor Epidermal Growth Factor Receptor and EGFR PY1068 Are Independent Prognostic Indicators for Head and Neck Squamous Cell Carcinoma
Authors: Wheeler Sarah , Siwak Doris R. , Chai Raymond , LaValle Courtney , Seethala Raja R. , Wang Lin , Cieply Kathleen , Sherer Carol , Joy Corwin , Mills Gordon B. , Argiris Athanassios , Siegfried Jill M. , Grandis Jennifer R. , Egloff Ann Marie 
Published: February 2012

Abstract
Purpose: To assess the prognostic value of epidermal growth factor receptor (EGFR) molecular characteristics of head and neck squamous cell carcinoma (HNSCC).
Patients and Methods: HNSCC tumors from patients prospectively enrolled in either an Early Detection Research Network (EDRN) study and treated with surgery without an EGFR-targeted agent (N = 154) or enrolled in a chemoradiation trial involving the EGFR-targeted antibody cetuximab (N = 39) were evaluated for EGFR gene amplification by FISH and EGFR protein by immunohistochemical staining. Fresh-frozen tumors (EDRN) were also evaluated for EGFR protein and site-specific phosphorylation at Y992 and Y1068 using reverse-phase protein array (n = 67). Tumor (n = 50) EGFR and EGFRvIII mRNA levels were quantified using real-time PCR.
Results: EGFR expression by immunohistochemistry (IHC) was significantly higher in the EDRN tumors with EGFR gene amplification (P &lt; 0.001), and a similar trend was noted in the cetuximab-treated cohort. In the EDRN and cetuximab-treated cohorts elevated EGFR by IHC was associated with reduced survival (P = 0.019 and P = 0.06, respectively). Elevated expression of total EGFR and EGFR PY1068 were independently significantly associated with reduced progression-free survival in the EDRN cohort [HR = 2.75; 95% confidence interval (CI) = 1.26–6.00 and HR = 3.29; 95% CI = 1.34–8.14, respectively].
Conclusions: In two independent HNSCC cohorts treated with or without cetuximab, tumor EGFR levels were indicative of survival. Tumor EGFR PY1068 levels provided prognostic information independent of total EGFR. Clin Cancer Res; 18(8); 2278–89. ©2012 AACR.
ON 01910.Na Is Selectively Cytotoxic for Chronic Lymphocytic Leukemia Cells through a Dual Mechanism of Action Involving PI3K/AKT Inhibition and Induction of Oxidative Stress
Authors: Chapman Colby M. , Sun Xiameng , Roschewski Mark , Aue Georg , Farooqui Mohamed , Stennett Lawrence , Gibellini Federica , Arthur Diane , Pérez-Galán Patricia , Wiestner Adrian 
Published: February 2012

Abstract
Purpose: Chronic lymphocytic leukemia (CLL), a malignancy of mature B cells, is incurable with chemotherapy. Signals from the microenvironment support leukemic cell survival and proliferation and may confer chemotherapy resistance. ON 01910.Na (Rigosertib), a multikinase phosphoinositide 3-kinase (PI3K) inhibitor, is entering phase III trials for myelodysplastic syndrome. Our aim was to analyze the efficacy of ON 01910.Na against CLL cells in vitro and investigate the molecular effects of this drug on tumor biology.
Experimental Design: Cytotoxicity of ON 01910.Na against CLL cells from 34 patients was determined in vitro with flow cytometry of cells stained with Annexin V and CD19. Global gene expression profiling on Affymetrix microarrays, flow cytometry, Western blotting, and cocultures with stroma cells were used to delineate ON 01910.Na mechanism of action.
Results: ON 01910.Na induced apoptosis in CLL B cells without significant toxicity against T cells or normal B cells. ON 01910.Na was equally active against leukemic cells associated with a more aggressive disease course [immunoglobulin heavy-chain variable region unmutated, adverse cytogenetics] than against cells without these features. Gene expression profiling revealed two main mechanisms of action: PI3K/AKT inhibition and induction of ROS that resulted in an oxidative stress response through activating protein 1 (AP-1), c-jun-NH2-terminal kinase, and ATF3 culminating in the upregulation of NOXA. ROS scavengers and shRNA mediated knockdown of ATF3- and NOXA-protected cells from drug-induced apoptosis. ON 01910.Na also abrogated the prosurvival effect of follicular dendritic cells on CLL cells and reduced SDF-1–induced migration of leukemic cells.
Conclusions: These data support the clinical development of ON 01910.Na in CLL. Clin Cancer Res; 18(7); 1979–91. ©2012 AACR.
A Comprehensive Analysis of Human Gene Expression Profiles Identifies Stromal Immunoglobulin κ C as a Compatible Prognostic Marker in Human Solid Tumors
Authors: Schmidt Marcus , Hellwig Birte , Hammad Seddik , Othman Amnah , Lohr Miriam , Chen Zonglin , Boehm Daniel , Gebhard Susanne , Petry Ilka , Lebrecht Antje , Cadenas Cristina , Marchan Rosemarie , Stewart Joanna D. , Solbach Christine , Holmberg Lars , Edlund Karolina , Kultima Hanna Göransson , Rody Achim , Berglund Anders , Lambe Mats , Isaksson Anders , Botling Johan , Karn Thomas , Müller Volkmar , Gerhold-Ay Aslihan , Cotarelo Christina , Sebastian Martin , Kronenwett Ralf , Bojar Hans , Lehr Hans-Anton , Sahin Ugur , Koelbl Heinz , Gehrmann Mathias , Micke Patrick , Rahnenführer Jörg , Hengstler Jan G. 
Published: February 2012

AbstractPurpose: Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available.Experimental Design: On the basis of receiver operating characteristic analyses, robust markers were identified from a 60-gene B cell–derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non–small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy.Results: We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P &lt; 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression.Conclusion: Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining. Clin Cancer Res; 18(9); 2695–703. ©2012 AACR.
First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway
Authors: Manu Kanjoormana A. , Shanmugam Muthu K. , Ramachandran Lalitha , Li Feng , Fong Chee Wai , Kumar Alan Prem , Tan Patrick , Sethi Gautam 
Published: February 2012

AbstractPurpose: Because of poor prognosis and development of resistance against chemotherapeutic drugs, the existing treatment modalities for gastric cancer are ineffective. Hence, novel agents that are safe and effective are urgently needed. Whether γ-tocotrienol can sensitize gastric cancer to capecitabine in vitro and in a xenograft mouse model was investigated.Experimental Design: The effect of γ-tocotrienol on proliferation of gastric cancer cell lines was examined by mitochondrial dye uptake assay, apoptosis by esterase staining, NF-κB activation by DNA-binding assay, and gene expression by Western blotting. The effect of γ-tocotrienol on the growth and chemosensitization was also examined in subcutaneously implanted tumors in nude mice.Results: γ-Tocotrienol inhibited the proliferation of various gastric cancer cell lines, potentiated the apoptotic effects of capecitabine, inhibited the constitutive activation of NF-κB, and suppressed the NF-κB–regulated expression of COX-2, cyclin D1, Bcl-2, CXCR4, VEGF, and matrix metalloproteinase-9 (MMP-9). In a xenograft model of human gastric cancer in nude mice, we found that administration of γ-tocotrienol alone (1 mg/kg body weight, intraperitoneally 3 times/wk) significantly suppressed the growth of the tumor and this effect was further enhanced by capecitabine. Both the markers of proliferation index Ki-67 and for microvessel density CD31 were downregulated in tumor tissue by the combination of capecitabine and γ-tocotrienol. As compared with vehicle control, γ-tocotrienol also suppressed the NF-κB activation and the expression of cyclin D1, COX-2, intercellular adhesion molecule-1 (ICAM-1), MMP-9, survivin, Bcl-xL, and XIAP.Conclusions: Overall our results show that γ-tocotrienol can potentiate the effects of capecitabine through suppression of NF-κB–regulated markers of proliferation, invasion, angiogenesis, and metastasis. Clin Cancer Res; 18(8); 2220–9. ©2012 AACR.
The HSP90 Inhibitor XL888 Overcomes BRAF Inhibitor Resistance Mediated through Diverse Mechanisms
Authors: Paraiso Kim H.T. , Haarberg H. Eirik , Wood Elizabeth , Rebecca Vito W. , Chen Y. Ann , Xiang Yun , Ribas Antoni , Lo Roger S. , Weber Jeffrey S. , Sondak Vernon K. , John Jobin K. , Sarnaik Amod A. , Koomen John M. , Smalley Keiran S.M. 
Published: February 2012

AbstractPurpose: The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study shows the potential therapeutic use of the HSP90 inhibitor (XL888) in six different models of vemurafenib resistance.Experimental Design: The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was shown in vitro and in vivo. A novel mass spectrometry–based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts, and melanoma biopsies. Mechanistic studies were carried out to determine the mechanism of XL888-induced apoptosis.Results: XL888 potently inhibited cell growth, induced apoptosis, and prevented the growth of vemurafenib-resistant melanoma cell lines in 3-dimensional cell culture, long-term colony formation assays, and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFRβ, COT, IGFR1, CRAF, ARAF, S6, cyclin D1, and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM (Bcl-2 interacting mediator of cell death) expression, and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual mitogen-activated protein–extracellular signal–regulated kinase/phosphoinositide 3-kinase (MEK/PI3K) inhibition.Conclusions: HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy. Clin Cancer Res; 18(9); 2502–14. ©2012 AACR.
Implications of Plasma Protein Binding for Pharmacokinetics and Pharmacodynamics of the γ-Secretase Inhibitor RO4929097
Authors: Wu Jianmei , LoRusso Patricia M. , Matherly Larry H. , Li Jing 
Published: February 2012

Abstract
Purpose: Understanding of plasma protein binding will provide mechanistic insights into drug interactions or unusual pharmacokinetic properties. This study investigated RO4929097 binding in plasma and its implications for the pharmacokinetics and pharmacodynamics of this compound.
Experimental Design: RO4929097 binding to plasma proteins was determined using a validated equilibrium dialysis method. Pharmacokinetics of total and unbound RO4929097 was evaluated in eight patients with breast cancer receiving RO4929097 alone and in combination with the Hedgehog inhibitor GDC-0449. The impact of protein binding on RO4929097 pharmacodynamics was assessed using an in vitro Notch cellular assay.
Results: RO4929097 was extensively bound in human plasma, with the total binding constant of 1.0 × 106 and 1.8 × 104 L/mol for α1-acid glycoprotein (AAG) and albumin, respectively. GDC-0449 competitively inhibited RO4929097 binding to AAG. In patients, RO4929097 fraction unbound (Fu) exhibited large intra- and interindividual variability; GDC-0449 increased RO4929097 Fu by an average of 3.7-fold. Concomitant GDC-0449 significantly decreased total (but not unbound) RO4929097 exposure. RO4929097 Fu was strongly correlated with the total drug exposure. Binding to AAG abrogated RO4929097 in vitro Notch-inhibitory activity.
Conclusions: RO4929097 is highly bound in human plasma with high affinity to AAG. Changes in plasma protein binding caused by concomitant drug (e.g., GDC-0449) or disease states (e.g., ↑AAG level in cancer) can alter total (but not unbound) RO4929097 exposure. Unbound RO4929097 is pharmacologically active. Monitoring of unbound RO4929097 plasma concentration is recommended to avoid misleading conclusions on the basis of the total drug levels. Clin Cancer Res; 18(7); 2066–79. ©2012 AACR.
Responsiveness of Intrinsic Subtypes to Adjuvant Anthracycline Substitution in the NCIC.CTG MA.5 Randomized Trial
Authors: Cheang Maggie C.U. , Voduc K. David , Tu Dongsheng , Jiang Shan , Leung Samuel , Chia Stephen K. , Shepherd Lois E. , Levine Mark N. , Pritchard Kathleen I. , Davies Sherri , Stijleman Inge J. , Davis Carole , Ebbert Mark T.W. , Parker Joel S. , Ellis Matthew J. , Bernard Philip S. , Perou Charles M. , Nielsen Torsten O. 
Published: February 2012

Abstract
Purpose: Recent studies suggest that intrinsic breast cancer subtypes may differ in their responsiveness to specific chemotherapy regimens. We examined this hypothesis on NCIC.CTG MA.5, a clinical trial randomizing premenopausal women with node-positive breast cancer to adjuvant CMF (cyclophosphamide-methotrexate-fluorouracil) versus CEF (cyclophosphamide-epirubicin-fluorouracil) chemotherapy.
Experimental Design: Intrinsic subtype was determined for 476 tumors using the quantitative reverse transcriptase PCR PAM50 gene expression test. Luminal A, luminal B, HER2-enriched (HER2-E), and basal-like subtypes were correlated with relapse-free survival (RFS) and overall survival (OS), estimated using Kaplan–Meier plots and log-rank testing. Multivariable Cox regression analyses determined significance of interaction between treatment and intrinsic subtypes.
Results: Intrinsic subtypes were associated with RFS (P = 0.0005) and OS (P &lt; 0.0001) on the combined cohort. The HER2-E showed the greatest benefit from CEF versus CMF, with absolute 5-year RFS and OS differences exceeding 20%, whereas there was a less than 2% difference for non–HER2-E tumors (interaction test P = 0.03 for RFS and 0.03 for OS). Within clinically defined Her2+ tumors, 79% (72 of 91) were classified as the HER2-E subtype by gene expression and this subset was strongly associated with better response to CEF versus CMF (62% vs. 22%, P = 0.0006). There was no significant difference in benefit between CEF and CMF in basal-like tumors [n = 94; HR, 1.1; 95% confidence interval (CI), 0.6–2.1 for RFS and HR, 1.3; 95% CI, 0.7–2.5 for OS].
Conclusion: HER2-E strongly predicted anthracycline sensitivity. The chemotherapy-sensitive basal-like tumors showed no added benefit for CEF over CMF, suggesting that nonanthracycline regimens may be adequate in this subtype although further investigation is required. Clin Cancer Res; 18(8); 2402–12. ©2012 AACR.
Effect of Aerosol on Circulations and Precipitation in Deep Convective Clouds
Authors: Lee Seoung Soo 
Published: February 2012

Abstract
This study examines the effect of a mesoscale perturbation of aerosol on a larger-scale cloud system driven by deep convective clouds. An aerosol-perturbed domain of size 120 km is prescribed in the middle of the larger-scale domain of size 1100 km. Aerosol perturbations in the mesoscale domain result in an intensification of convection in a mesoscale convective system (MCS). This leads to an intensification of the larger-scale circulations, which in turn leads to an intensification of the larger-scale subsidence. While the invigorated convection enhances precipitation in the MCS, the intensified larger-scale subsidence acts to increase the larger-scale stability and thus to suppress convection and precipitation in the larger-scale domain. The suppression of precipitation in the larger-scale domain outweighs the enhancement of precipitation in the mesoscale domain, leading to suppressed precipitation over the entire domain. The ramifications of aerosol perturbations therefore need to be considered on scales much larger than the scale of the perturbation.
Precipitation Climatology in an Ensemble of CORDEX-Africa Regional Climate Simulations
Authors: Nikulin Grigory , Jones Colin , Giorgi Filippo , Asrar Ghassem , Büchner Matthias , Cerezo-Mota Ruth , Christensen Ole Bøssing , Déqué Michel , Fernandez Jesus , Hänsler Andreas , van Meijgaard Erik , Samuelsson Patrick , Sylla Mouhamadou Bamba , Sushama Laxmi 
Published: February 2012

Abstract
An ensemble of regional climate simulations is analyzed to evaluate the ability of 10 regional climate models (RCMs) and their ensemble average to simulate precipitation over Africa. All RCMs use a similar domain and spatial resolution of ~50 km and are driven by the ECMWF Interim Re-Analysis (ERA-Interim) (1989–2008). They constitute the first set of simulations in the Coordinated Regional Downscaling Experiment in Africa (CORDEX-Africa) project. Simulated precipitation is evaluated at a range of time scales, including seasonal means, and annual and diurnal cycles, against a number of detailed observational datasets. All RCMs simulate the seasonal mean and annual cycle quite accurately, although individual models can exhibit significant biases in some subregions and seasons. The multimodel average generally outperforms any individual simulation, showing biases of similar magnitude to differences across a number of observational datasets. Moreover, many of the RCMs significantly improve the precipitation climate compared to that from their boundary condition dataset, that is, ERA-Interim. A common problem in the majority of the RCMs is that precipitation is triggered too early during the diurnal cycle, although a small subset of models does have a reasonable representation of the phase of the diurnal cycle. The systematic bias in the diurnal cycle is not improved when the ensemble mean is considered. Based on this performance analysis, it is assessed that the present set of RCMs can be used to provide useful information on climate projections over Africa.
A Global Intercomparison of Modeled and Observed Land–Atmosphere Coupling*
Authors: Ferguson Craig R. , Wood Eric F. , Vinukollu Raghuveer K. 
Published: February 2012

Abstract
Land–atmosphere coupling strength or the degree to which land surface anomalies influence boundary layer development—and in extreme cases, rainfall—is arguably the single most fundamental criterion for evaluating hydrological model performance. The Global Land–Atmosphere Coupling Experiment (GLACE) showed that strength of coupling and its representation can affect a model’s ability to simulate climate predictability at the seasonal time scale. And yet, the lack of sufficient observations of coupling at appropriate temporal and spatial scales has made achieving “true” coupling in models an elusive goal. This study uses Advanced Microwave Scanning Radiometer for Earth Observing System (AMSR-E) soil moisture (SM), multisensor remote sensing (RS) evaporative fraction (EF), and Atmospheric Infrared Sounder (AIRS) lifting condensation level (LCL) to evaluate the realism of coupling in the Global Land Data Assimilation System (GLDAS) suite of land surface models (LSMs), Princeton Global Forcing Variable Infiltration Capacity model (PGF–VIC), seven global reanalyses, and the North American Regional Reanalysis (NARR) over a 5-yr period (2003–07). First, RS and modeled estimates of SM, EF, and LCL are intercompared. Then, emphasis is placed on quantifying RS and modeled differences in convective-season daily correlations between SM–LCL, SM–EF, and EF–LCL for global, regional, and conditional samples. RS is found to yield a substantially weaker state of coupling than model products. However, the rank order of basins by coupling strength calculated from RS and models do roughly agree. Using a mixture of satellite and modeled variables, a map of hybrid coupling strength was produced, which supports the findings of GLACE that transitional zones tend to have the strongest coupling.