bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concerted Potent Humoral Immune Responses to Autoantigens Are Associated with Tumor Destruction and Favorable Clinical Outcomes without Autoimmunity
Authors: Sittler Taylor , Zhou Jun , Park Joosang , Yuen Noah K. , Sarantopoulos Stefanie , Mollick Joseph , Salgia Ravi , Giobbie-Hurder Anita , Dranoff Glenn , Hodi F. Stephen 
Published: June 2008

AbstractPurpose: The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy.Experimental Design: Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non–small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies.Results: Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients.Conclusions: This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.
Oncogenic and Angiogenic Growth Factors Accumulate during Routine Storage of Apheresis Platelet Concentrates
Authors: Kanter Julie , Khan Samina Y. , Kelher Marguerite , Gore Lia , Silliman Christopher C. 
Published: June 2008

Abstract
Purpose: Platelet concentrates are important for support of patients with malignancies requiring myelotoxic chemotherapy. During storage, 10% to 15% of platelets may become activated resulting in the release of α-granules, which contain growth factors. We hypothesize that, during storage, growth factors accumulate in the plasma, specifically platelet-derived growth factor, vascular endothelial growth factor (VEGF), transforming growth factor-β, and fibroblast growth factor-2, which may adversely affect cancer patients.
Experimental Design: The concentrations of growth factors were measured by ELISA from the plasma of apheresis platelets serially throughout storage (days 1, 3, 5, and 7) and compared with concentrations in fresh plasma from healthy blood donors. Washing was evaluated as a method of growth factor removal, and an in vitro model of platelet transfusion in a patient receiving Bevacizumab (Avastin) using immunoprecipitation was employed to determine if Bevacizumab would be bound by the VEGF in apheresis platelets.
Results: VEGF, platelet-derived growth factor, and transforming growth factor-β were increased on day 1 versus fresh plasma and throughout storage reaching a relative maximum at outdate (P &lt; 0.01, day 5 or 7). Fibroblast growth factor-2 concentrations were significantly increased on day 7 alone versus day 1 or to fresh plasma (P &lt; 0.01). Washing removed 41 ± 11% to 56 ± 2% of the growth factors. Bevacizumab effectively bound the VEGF from apheresis platelets, with significant amounts of VEGF remaining in the supernatant.
Conclusions: Significant amounts of growth factors are present in apheresis platelets due to the isolation procedures, and these concentrations increase over storage, which may be partially removed by washing. In addition, apheresis platelet transfusion could affect cancer treatment by binding monoclonal antibodies directed against growth factors of tumor origin.
Dasatinib Cellular Uptake and Efflux in Chronic Myeloid Leukemia Cells: Therapeutic Implications
Authors: Hiwase Devendra K. , Saunders Verity , Hewett Duncan , Frede Amity , Zrim Stephanie , Dang Phuong , Eadie Laura , To L. Bik , Melo Junia , Kumar Sharad , Hughes Timothy P. , White Deborah L. 
Published: June 2008

Abstract
Purpose: The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed.
Experimental Design: The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors.
Results: Unlike imatinib, there was no significant difference in the dasatinib IUR at 37°C and 4°C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50dasatinib values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P &lt; 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P &lt; 0.05) and reduced IC50dasatinib (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC50dasatinib.
Conclusion: Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.
T Regulatory Type 1 Cells in Squamous Cell Carcinoma of the Head and Neck: Mechanisms of Suppression and Expansion in Advanced Disease
Authors: Bergmann Christoph , Strauss Laura , Wang Yun , Szczepanski Miroslaw J. , Lang Stephan , Johnson Jonas T. , Whiteside Theresa L. 
Published: June 2008

AbstractPurpose: Regulatory T cells play a major role in tumor escape from immunosurveillance. T regulatory cells type 1 (Tr1), a subset of regulatory T cells present in the tumor and peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC), mediate immune suppression and might contribute to tumor progression.Experimental Design: CD4+CD25−T cells were isolated from peripheral blood mononuclear cells (PBMC) or tumor-infiltrating lymphocytes (TIL) of 26 HNSCC patients and 10 normal controls. The Tr1 cell phenotype was determined before and after culture in the presence of interleukin (IL)-2, IL-10, and IL-15, each at 10 to 20 IU/mL. Suppression was measured in carboxyfluorescein diacetate succinimidyl ester–based proliferation assays with or without neutralizing anti-IL-10 or anti–transforming growth factor-β1 (TGF-β1) monoclonal antibodies in Transwell systems. ELISA was used to define the Tr1 cytokine profile.Results: Tr1 cells originate from CD4+CD25− precursors present in TIL and PBMC of HNSCC patients. Cytokine-driven ex vivo expansion of Tr1 precursors yielded CD4+CD25−Foxp3lowCD132+IL-10+TGF-β1+ populations that mediated higher suppression than Tr1 cells of normal controls (P &lt; 0.0001). Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-β1 secretion. Expression of these cytokines was higher in TIL-derived than PBMC-derived Tr1 cells (P &lt; 0.0001). The Tr1 cell frequency and suppressor function were significantly higher in patients presenting with advanced than early disease stages and in patients “cured” by oncologic therapies than in those with active disease.Conclusions: In HNSCC, Tr1 cell generation is promoted at the tumor site. Tr1 cells use TGF-β and IL-10 to mediate suppression. They expand during disease progression and also following cancer therapy in patients with no evident disease.
Effect of Interleukin-10 Gene Polymorphisms on Clinical Outcome of Patients with Aggressive Non-Hodgkin's Lymphoma: An Exploratory Study
Authors: Kube Dieter , Hua Thanh-Duc , von Bonin Frederike , Schoof Nils , Zeynalova Samira , Klöss Marita , Gocht Daniela , Potthoff Bernd , Tzvetkov Mladen , Brockmöller Jürgen , Löffler Markus , Pfreundschuh Michael , Trümper Lorenz 
Published: June 2008

Abstract
Purpose: Current chemotherapy can achieve high response rates in aggressive non-Hodgkin's lymphoma (NHL), but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis whether interleukin-10 (IL-10) polymorphisms predict clinical outcome, leukocytopenia, or infectivity during therapy. IL-10 was chosen because immune alterations are a major risk factor for NHL, and IL-10 is a cytokine involved in inflammatory processes associated with clinical outcome.
Experimental Design: Five hundred patients with aggressive NHL treated with CHOP/CHOEP were analyzed for IL-10 gene polymorphisms, including distal loci -7400InDel, -6752AT (rs6676671), and -6208CG (rs10494879) in comparison with proximal loci -3538AT (rs1800890), -1087AG (rs1800896), and -597AC (rs1800872) according to the incidence and outcome of the lymphoma.
Results: No differences in allele frequencies or haplotypes were found comparing a cohort of patients with aggressive NHL/diffuse large B-cell lymphoma with a healthy control group. Patients with aggressive NHL characterized by IL-10-7400DelDel had shorter overall survival periods compared with the other genotypes (P = 0.004). The 3-year rate is 43.4% for IL-10-7400DelDel and 73.4% for IL-10-7400InIn and IL-10-7400InDel together. A significant increased risk for event-free survival is found for carriers of the genotype IL-10-6752TT-6208CC-3538AA (P = 0.047). Multivariate analysis of IL-10-7400 gene variation in relation to overall survival adjusted to international prognostic index revealed a relative risk of 1.9 for carriers of IL-10-7400DelDel (P = 0.037). No associations were found analyzing diffuse large B-cell lymphoma patients separately.
Conclusion: Our results indicate that IL-10 gene variations could be associated to the clinical course of aggressive NHL, which points out the importance of host factors and respective genetic elements for treatment response.
Snail Up-regulates Proinflammatory Mediators and Inhibits Differentiation in Oral Keratinocytes
Authors: Lyons J. Guy , Patel Vyomesh , Roue Naomi C. , Fok Sandra Y. , Soon Lilian L. , Halliday Gary M. , Gutkind J. Silvio 
Published: June 2008

Abstract
The transcriptional repressor Snail2 is overexpressed in head and neck squamous cell carcinomas (HNSCC) relative to nonmalignant head and neck mucosal epithelium, and in locally recurrent relative to nonrecurrent HNSCCs. We investigated the mechanisms by which Snails might contribute to the pathogenesis of HNSCCs using cell biological and molecular analyses. Oral keratinocytes that expressed Snails acquired an enhanced ability to attract monocytes and to invade a dense interstitial collagen matrix. They were also found to up-regulate production of proinflammatory cytokines and cyclooxygenase-2 (COX2), which have previously been shown to correlate with malignancy. Induction of nuclear factor-κB transcriptional activity by Snails was weak and not sufficient to account for the elevated levels of COX2, interleukin (IL)-6, IL8, or CXCL1. In addition, expression of Snails in oral keratinocytes impaired desquamation in vitro and strongly repressed expression of both ELF3 and matriptase-1, which play important roles in the terminal differentiation of keratinocytes. Reexpression of matriptase-1 in Snail-expressing cells partially rescued desquamation. This implicates Snails as contributing to malignancy both at the early stages, by impeding terminal differentiation, and at later stages, when invasion and inflammation are important. [Cancer Res 2008;68(12):4525–30]
Heterogeneous Ribonucleoprotein K and Thymidine Phosphorylase Are Independent Prognostic and Therapeutic Markers for Nasopharyngeal Carcinoma
Authors: Chen Lih-Chyang , Hsueh Chuen , Tsang Ngan-Ming , Liang Ying , Chang Kai-Ping , Hao Sheng-Po , Yu Jau-Song , Chang Yu-Sun 
Published: June 2008

Abstract
Purpose: Heterogeneous ribonucleoprotein K (hnRNP K) regulates thymidine phosphorylase (TP) mRNA stability. The aim of the present study was to analyze hnRNP K and TP expression in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic and therapeutic potential of these two markers.
Experimental Design: We analyzed hnRNP K and TP expression immunohistochemically in 121 clinically proven NPC cases. Statistical analyses were applied to correlate cytoplasmic hnRNP K with elevated TP expression and determine the prognostic significance of these parameters. The therapeutic implication of elevated TP expression was determined by measuring sensitivity of NPC cells to the TP-targeting drug, 5-fluoro-5′-deoxyuridine (5′-DFUR).
Results: There was a high correlation between cytoplasmic hnRNP K and high TP (P &lt; 0.001). Both cytoplasmic hnRNP K and high TP were associated with poor overall survival (OS; P = 0.007 and P &lt; 0.001, respectively) and distant metastasis-free survival (P = 0.003 and 0.001, respectively) of NPC patients. A multivariate analysis confirmed that both cytoplasmic hnRNP K and high TP are independent prognostic predictors for OS (P = 0.020 and 0.010, respectively). NPC cells expressing high TP were more sensitive to treatment with the TP-targeting drug, 5′-DFUR.
Conclusions: Cytoplasmic hnRNP K and high TP are associated with shorter OS and distant metastasis-free survival in NPC patients. In vitro experiments suggest that NPC tumors with high TP expression may be sensitive to 5′-DFUR treatment. Cytoplasmic hnRNP K and high TP may be potential prognostic and therapeutic markers for NPC, but additional validation studies are warranted.
The Ethics of Phase 0 Oncology Trials
Authors: Abdoler Emily , Taylor Holly , Wendler David 
Published: June 2008

AbstractRecent guidance from the Food and Drug Administration supports the conduct of a new type of exploratory clinical trial, commonly called phase 0 clinical trials. Proponents argue that phase 0 clinical trials have the potential to expedite the development of new oncology drugs while exposing fewer research subjects to the risks of experimental treatments. At the same time, phase 0 oncology trials raise important ethical concerns that have received little attention. In particular, there is a question of whether it is ethical to enroll individuals in research that offers them no potential for clinical benefit. Further concern focuses on the inclusion of terminally ill and consequently vulnerable cancer patients in these trials. To evaluate these concerns, this article considers relevant empirical data from phase 1 oncology trials and develops several recommendations regarding the conduct of phase 0 clinical trials in oncology.
The Emergence of Multiple Robust Zonal Jets from Freely Evolving, Three-Dimensional Stratified Geostrophic Turbulence with Applications to Jupiter
Authors: Sayanagi Kunio M. , Showman Adam P. , Dowling Timothy E. 
Published: June 2008

Abstract
Three-dimensional numerical simulations of freely evolving stratified geostrophic turbulence on the β plane are presented as a simplified model of zonal jet formation on Jupiter. This study samples the parameter space that covers the low, middle, and high latitudes of Jupiter by varying the central latitude of the β plane. The results show that robust zonal jets can emerge from initial small-scale random turbulence through the upscale redistribution of the kinetic energy in the spectral space. The resulting flow’s sensitivities to the flow’s deformation radius LD and the two-dimensional Rhines length Lβ = U/β (U is the characteristic turbulence velocity and β is the meridional gradient of the planetary vorticity) are tested, revealing that whether the outcome of the upscale energy transfer becomes dominated by jets or vortices depends on the relative values of LD and Lβ. The values of Lβ and LD are varied by tuning the β-plane parameters, and it is found that the flow transitions from a jet-dominated regime in Lβ ≲ LD to a vortical flow in Lβ ≳ LD. A height-to-width ratio equal to f /N, the Coriolis parameter divided by the Brunt–Väisälä frequency, has previously been established for stable vortices, and this paper shows that this aspect ratio also applies to the zonal jets that emerge in these simulations.
Tropical Atlantic Variability Modes (1979–2002). Part I: Time-Evolving SST Modes Related to West African Rainfall
Authors: Polo Irene , Rodríguez-Fonseca Belén , Losada Teresa , García-Serrano Javier 
Published: June 2008

AbstractThis work presents a description of the 1979–2002 tropical Atlantic (TA) SST variability modes coupled to the anomalous West African (WA) rainfall during the monsoon season. The time-evolving SST patterns, with an impact on WA rainfall variability, are analyzed using a new methodology based on maximum covariance analysis. The enhanced Climate Prediction Center (CPC) Merged Analysis of Precipitation (CMAP) dataset, which includes measures over the ocean, gives a complete picture of the interannual WA rainfall patterns for the Sahel dry period. The leading TA SST pattern, related to the Atlantic El Niño, is coupled to anomalous precipitation over the coast of the Gulf of Guinea, which corresponds to the second WA rainfall principal component. The thermodynamics and dynamics involved in the generation, development, and damping of this mode are studied and compared with previous works. The SST mode starts at the Angola/Benguela region and is caused by alongshore wind anomalies. It then propagates westward via Rossby waves and damps because of latent heat flux anomalies and Kelvin wave eastward propagation from an off-equatorial forcing. The second SST mode includes the Mediterranean and the Atlantic Ocean, showing how the Mediterranean SST anomalies are those that are directly associated with the Sahelian rainfall. The global signature of the TA SST patterns is analyzed, adding new insights about the Pacific–Atlantic link in relation to WA rainfall during this period. Also, this global picture suggests that the Mediterranean SST anomalies are a fingerprint of large-scale forcing.This work updates the results given by other authors, whose studies are based on different datasets dating back to the 1950s, including both the wet and the dry Sahel periods.
Buoyancy-Forced Downwelling in Boundary Currents
Authors: Spall Michael A. 
Published: June 2008

Abstract
The issue of downwelling resulting from surface buoyancy loss in boundary currents is addressed using a high-resolution, nonhydrostatic numerical model. It is shown that the net downwelling is determined by the change in the mixed layer density along the boundary. For configurations in which the density on the boundary increases in the direction of Kelvin wave propagation, there is a net downwelling within the domain. For cases in which the density decreases in the direction of Kelvin wave propagation, cooling results in a net upwelling within the domain. Symmetric instability within the mixed layer drives an overturning cell in the interior, but it does not contribute to the net vertical motion. The net downwelling is determined by the geostrophic flow toward the boundary and is carried downward in a very narrow boundary layer of width E1/3, where E is the Ekman number. For the calculations here, this boundary layer is O(100 m) wide. A simple model of the mixed layer temperature that balances horizontal advection with surface cooling is used to predict the net downwelling and its dependence on external parameters. This model shows that the net sinking rate within the domain depends not only on the amount of heat loss at the surface but also on the Coriolis parameter, the mixed layer depth (or underlying stratification), and the horizontal velocity. These results indicate that if one is to correctly represent the buoyancy-forced downwelling in general circulation models, then it is crucial to accurately represent the velocity and mixed layer depth very close to the boundary. These results also imply that processes that lead to weak mixing within a few kilometers of the boundary, such as ice formation or freshwater runoff, can severely limit the downwelling forced by surface cooling, even if there is strong heat loss and convection farther offshore.
Correlations between Analyses and Forecasts of Banded Heavy Snow Ingredients and Observed Snowfall
Authors: Evans Michael , Jurewicz Michael L. 
Published: June 2008

Abstract
North American Mesoscale (NAM) model forecasts of the occurrence, magnitude, depth, and persistence of ingredients previously shown to be useful in the diagnosis of banded and/or heavy snowfall potential are examined for a broad range of 25 snow events, with event total snowfall ranging from 10 cm (4 in.) to over 75 cm (30 in.). The ingredients examined are frontogenetical forcing, weak moist symmetric stability, saturation, and microphysical characteristics favorable for the production of dendritic snow crystals. It is shown that these ingredients, previously identified as being critical indicators for heavy and/or banded snowfall in major storms, are often found in smaller snowfall events. It is also shown that the magnitude, depth, and persistence of these ingredients, or combinations of these ingredients, appear to be good predictors of event total snowfall potential. In addition, a relationship is demonstrated between temporal trends associated with one of the ingredients (saturated, geostrophic equivalent potential vorticity) and event total snowfall.
Correlations between forecast values of these ingredients and observed snowfall are shown to decrease substantially as forecast lead time increases beyond 12 h. It is hypothesized that model forecast positioning and timing errors are primarily responsible for the lower correlations associated with longer-lead forecasts. This finding implies that the best forecasts beyond 12 h may be produced by examining the diagnostics of heavy snow ingredients from a single, high-resolution model to determine snowfall potential, then using ensemble forecasting approaches to determine the most probable location and timing of any heavy snow.