bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients
Authors: Santini Daniele , Vincenzi Bruno , Galluzzo Sara , Battistoni Fabrizio , Rocci Laura , Venditti Olga , Schiavon Gaia , Angeletti Silvia , Uzzalli Federica , Caraglia Michele , Dicuonzo Giordano , Tonini Giuseppe 
Published: August 2007

Abstract
Purpose: On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies.
Experimental Design: Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion.
Results: The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion.
Conclusions: In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.
Inhibition of Hsp90: A Multitarget Approach to Radiosensitization
Authors: Camphausen Kevin , Tofilon Philip J. 
Published: August 2007

Abstract
Hsp90, the 90 kDa heat shock protein, is a highly expressed molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory proteins. Among Hsp90 clients are a number of proteins, which in a cell type–dependent manner, contribute to tumor cell radioresistance. Exposure of a variety of solid tumor cell lines to clinically relevant Hsp90 inhibitors results in the simultaneous loss of these radioresponse-associated proteins, which is accompanied by an increase in radiosensitivity. This radiosensitization has been linked to a compromise in the DNA damage response to radiation including the inhibition of cell cycle checkpoint activation and DNA double-strand break repair. With respect to potential clinical application, the expression of ErbB3 seems to predict tumor cells that are resistant to the effects of Hsp90 inhibition on radiosensitivity. Moreover, whereas an increase in tumor cell radiosensitivity was consistently reported, the radiosensitivity of normal fibroblasts was not affected by Hsp90 inhibition, suggesting the potential for tumor-selective radiosensitization. This review summarizes the preclinical data available on Hsp90 inhibition and cellular radiosensitivity. Results generated to date suggest that Hsp90 inhibition can provide a multitarget approach to tumor radiosensitization.
Augmented Antitumor Activity against B-Cell Lymphoma by a Combination of Monoclonal Antibodies Targeting TRAIL-R1 and CD20
Authors: Maddipatla Sreeram , Hernandez-Ilizaliturri Francisco J. , Knight Joy , Czuczman Myron S. 
Published: August 2007

Abstract
Purpose: Mapatumumab and lexatumumab are fully humanized, high-affinity immunoglobulin G1λ monoclonal antibodies (mAb) that target/activate the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2), respectively, triggering the extrinsic apoptotic pathway. Theoretically, synergistic antitumor activity should be observed by combining TRAIL-R mAbs with agents (e.g., rituximab) that activate the intrinsic apoptotic pathway.
Experimental Design: To this end, targeted antigen expression in a NHL-cell panel was evaluated by flow cytometry. NHL cells were exposed to mapatumumab or lexatumumab followed by rituximab, isotype, or RPMI. DNA synthesis was quantified by [3H]-thymidine incorporation assays. Induction of apoptosis was detected by flow-cytometric analysis. For antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CMC) studies, standardized 51Cr-release assays were done. We inoculated severe combined immunodeficiency (SCID) mouse with Raji cells i.v. The animals then were treated with various combinations of rituximab, mapatumumab, lexatumumab, and isotype alone or in combination.
Results: In vitro exposure to mapatumumab resulted in significant apoptosis (30-50%) and decreased DNA synthesis in sensitive lymphoma cells. Mapatumumab/rituximab combination resulted in a significant inhibition of cell proliferation (90% reduction) when compared with mapatumumab (60% reduction) or rituximab (5% reduction). In vivo, the median survival time of animals treated with mapatumumab and rituximab was longer (not reached) than those treated with rituximab monotherapy [33 days (95% confidence interval, 29-37), log-rank test, P = 0.05].
Conclusions: Mapatumumab induces apoptosis, cell growth arrest, ADCC, and CMC. The combination of mapatumumab plus rituximab is more effective in controlling lymphoma growth in vivo than either antibody. Rituximab and mapatumumab warrant further evaluation against B-cell lymphoma.
Peptide Epitopes from the Wilms' Tumor 1 Oncoprotein Stimulate CD4+ and CD8+ T Cells That Recognize and Kill Human Malignant Mesothelioma Tumor Cells
Authors: May Rena J. , Dao Tao , Pinilla-Ibarz Javier , Korontsvit Tatyana , Zakhaleva Victoriya , Zhang Rong H. , Maslak Peter , Scheinberg David A. 
Published: August 2007

AbstractPurpose: Wilms' tumor 1 protein (WT1), a transcription factor overexpressed in malignant mesothelioma, leukemias, and other solid tumors, is an ideal target for immunotherapy. WT1 class I peptide epitopes that were identified and shown to stimulate CD8+ T cells are being tested as vaccine candidates in several clinical trials. The induction and maintenance of a robust memory CD8+ cytotoxic T-cell response requires CD4+ T-cell help.Experimental Design: Three HLA class II peptide epitopes of WT1 with high predictive affinities to multiple HLA-DRB1 molecules were identified using the SYFPEITHI algorithm. Due to the highly polymorphic nature of the HLA class II alleles, such reactivity is critical in the development of a broadly useful therapeutic. One of the WT1 CD4+ peptide epitopes, 122-140, comprises a previously identified CD8+ peptide epitope (126-134). By mutating residue 126 from an arginine to a tyrosine, we embedded a synthetic immunogenic analogue CD8+ epitope (126-134) inside the longer peptide (122-140). This analogue was previously designed to improve immunogenicity and induce a potent CD8+ response.Results: WT1 peptides 328-349 and 423-441 are able to stimulate a peptide-specific CD4+ response that can recognize WT1+ tumor cells in multiple HLA-DRB1 settings as determined by IFN-γ enzyme-linked immunospot assays. The mutated WT1 peptide epitope 122-140 is able to induce CD4+ and cytotoxic CD8+ WT1-specific T-cell responses that can recognize the native WT1 epitopes on the surface of human WT1+ cancer cells. Cross-priming experiments showed that antigen-presenting cells pulsed with either mesothelioma or leukemia tumor lysates can process and present each of the CD4+ peptides identified.Conclusions: These studies provide the rationale for using the WT1 CD4+ peptides in conjunction with CD8+ peptide epitopes to vaccinate patients with WT1-expressing cancers.
Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non–Small Cell Lung Cancer
Authors: Johnson Bruce E. , Jackman David , Jänne Pasi A. 
Published: August 2007

AbstractBackground and Rationale: Only 10% of patients with relapsed non–small cell lung cancer (NSCLC) treated with chemotherapy or erlotinib have a partial response to treatment, and nearly all eventually recur and die from their NSCLC. Agents that can block other pathways in addition to the epidermal growth factor receptor signals may improve the therapeutic efficacy of erlotinib. Everolimus (RAD001) is an inhibitor of the mammalian target of rapamycin, which is downstream of initial epidermal growth factor receptor signaling. A trial combining erlotinib with everolimus has been undertaken for patients with relapsed NSCLC.Materials and Methods: Subjects with previously treated NSCLC are treated with increasing doses of daily erlotinib and everolimus given either daily or once weekly. The study's objectives in phase I are to assess the feasibility of combining daily erlotinib and either daily or weekly everolimus, to assess toxicity, and to determine the appropriate dose for subsequent trials.Results: The protocol calls for patients to be treated with escalating daily or weekly everolimus in combination with erlotinib given at doses of 100 mg daily to escalate to 150 mg daily. The dose escalation with both daily and weekly everolimus and erlotinib is ongoing.Conclusions: Everolimus has an appropriate rationale for therapeutic use in combination with erlotinib for patients with NSCLC. This manuscript will review the preclinical rationale for undertaking a study of erlotinib combined with everolimus for patients with relapsed NSCLC.
Climate Response Using a Three-Dimensional Operator Based on the Fluctuation–Dissipation Theorem
Authors: Gritsun Andrey , Branstator Grant 
Published: August 2007

Abstract
The fluctuation–dissipation theorem (FDT) states that for systems with certain properties it is possible to generate a linear operator that gives the response of the system to weak external forcing simply by using covariances and lag-covariances of fluctuations of the undisturbed system. This paper points out that the theorem can be shown to hold for systems with properties very close to the properties of the earth’s atmosphere.
As a test of the theorem’s applicability to the atmosphere, a three-dimensional operator for steady responses to external forcing is constructed for data from an atmospheric general circulation model (AGCM). The response of this operator is then compared to the response of the AGCM for various heating functions. In most cases, the FDT-based operator gives three-dimensional responses that are very similar in structure and amplitude to the corresponding GCM responses. The operator is also able to give accurate estimates for the inverse problem in which one derives the forcing that will produce a given response in the AGCM. In the few cases where the operator is not accurate, it appears that the fact that the operator was constructed in a reduced space is at least partly responsible.
As an example of the potential utility of a response operator with the accuracy found here, the FDT-based operator is applied to a problem that is difficult to solve with an AGCM. It is used to generate an influence function that shows how well heating at each point on the globe excites the AGCM’s Northern Hemisphere annular mode (NAM). Most of the regions highlighted by this influence function, including the Arctic and tropical Indian Ocean, are verified by AGCM solutions as being effective locations for stimulating the NAM.
Relating Overreflection and Wave Geometry to the Counterpropagating Rossby Wave Perspective: Toward a Deeper Mechanistic Understanding of Shear Instability
Authors: Harnik N. , Heifetz E. 
Published: August 2007

Abstract
The two major approaches to understanding plane parallel shear instability—the counterpropagating Rossby wave (CRW) and overreflection (OR) approaches—illuminate very different fundamental aspects. This work examines how such seemingly different views can explain the same phenomena and why these differences arise, with the overall goal of deepening our understanding of shear instability.
This is done by rationalizing the OR theory in terms of CRW thinking, using a generalization of the CRW approach to multiple infinitesimal potential vorticity (PV) kernels. First the mechanics of cross-shear wave propagation and the exponential decay in an evanescent region are qualitatively explained. Then the cross-shear behavior in different wave geometries (full, partial, and overreflection) is examined. It is found that overreflection is basically a mutual amplification between PV kernels, with the main kernels being at the two sides of the evanescent region, which forms on one side of the critical level. The nondimensional overreflection coefficient is obtained by assuming a balance between the mutual amplification on the two sides of the evanescent region, and the rate at which this amplification is carried away. The critical level is found to be the only point at which there is a mutual amplification between two adjacent kernels.
A further examination of the sources of energy growth yields a generalized view of the restoking of the Orr mechanism, thought to be central to OR: growth depends explicitly on the shear, as in the Orr mechanism, while mutual PV kernel interactions are responsible for holding the perturbation at a configuration that allows it to contribute to growth (a restoking).
A Midlatitude Cirrus Cloud Climatology from the Facility for Atmospheric Remote Sensing. Part V: Cloud Structural Properties
Authors: Sassen Kenneth , Wang Likun , Starr David O’C. , Comstock Jennifer M. , Quante Markus 
Published: August 2007

Abstract
In this fifth of a series of papers describing the extended-time high cloud observation program from the University of Utah Facility for Atmospheric Remote Sensing, the structural properties of cirrus clouds over Salt Lake City, Utah, are examined. Wavelet analysis is applied to a 10-yr record of cirrus cloud ruby (0.694 μm) lidar backscatter data as a function of cloud height in order to study the presence of periodic cloud structures, such as the signatures of Kelvin–Helmholtz instabilities, cirrus mammata, and uncinus cells (all with length scales of ∼1–10 km), as well as mesoscale cloud organizations generally believed to be induced by gravity waves. About 8.4% of the data display structures after passing a 95% confidence level test, but an 80% confidence level, which seems better able to resolve structures spread over long periods, yields 16.4%. The amount of identified cloud structures does not change significantly with length scale from 0.2 to 200 km, although the frequency of mesoscale cloud structures tends to increase as length scales increase. The middle-to-lower portion of cirrus clouds contains the most identified cloud structures, which seems related to the mesoscale organization of fall streaks from cloud-top-generating cells. The variability of cirrus cloud optical depth τ (defined by the standard deviation over mean τ) derived from a combined lidar and infrared radiometer (LIRAD) analysis is shown to be largely independent of τ. Because visual examination of the lidar displays also indicates that few cirrus layers can be considered horizontally homogeneous over our typical 3-h lidar data collection period, the authors conclude that the clouds in their sample are inherently inhomogeneous even though most cirrus structures are not revealed as periodic by wavelet analysis.
The Effects of a Mountain on the Propagation of a Preexisting Convective System for Blocked and Unblocked Flow Regimes
Authors: Reeves Heather Dawn , Lin Yuh-Lang 
Published: August 2007

Abstract
Observations and previous research of squall lines impinging on mountain ranges have revealed that the squall lines sometimes stall upstream of the mountains for several hours leading to copious accumulations of precipitation. It has been hypothesized that squall-line stagnation may be more prone to occur in flows where the Froude number (F = U/Nh, where U is the basic-state wind, N is the Brunt–Väisälä frequency, and h is the mountain height) is low. This hypothesis is tested herein through a series of idealized, two-dimensional experiments where a convective system was triggered upstream of a mesoscale mountain in conditionally unstable flow. For simulations with relatively low Froude numbers, stagnation of the preexisting convective system was not observed. In the simulations with high values of F, squall lines were noted to stagnate between 100 and 200 km upstream of the mountain. This result indicates that squall-line stagnation may be more favored for moderate to large values of F for conditionally unstable flow. The mechanisms leading to the formation of the stationary convective system upstream of the mountain in the unblocked flows were explored and it was found that evaporative cooling played a pivotal role in the stagnation of the squall line.
Katabatic Winds on Ice Sheets: A Refinement of the Prandtl Model
Authors: Zammett R. J. , Fowler A. C. 
Published: August 2007

Abstract
Katabatic winds on ice sheets and glaciers are buoyancy-driven flows, much like turbidity currents in the ocean. These winds are driven by radiative cooling of the ice surface and are not resolved by the typical horizontal and vertical discretization of general circulation models; therefore, a parameterization of their magnitude is desirable. In this paper, it is shown that the simplest such parameterization, based on the classical Prandtl model of slope winds, is physically inadmissible, and an improved model, which removes this irregularity, is presented. It is also shown that the improved model allows favorable comparison with both observations and regional numerical models.
Dynamics of the Shallow Meridional Circulation around Intertropical Convergence Zones
Authors: Nolan David S. , Zhang Chidong , Chen Shu-hua 
Published: August 2007

Abstract
The generally accepted view of the meridional circulation in the tropical east Pacific is that of a single deep overturning cell driven by deep convective heating in the intertropical convergence zone (ITCZ), similar to the zonal mean Hadley circulation. However, recent observations of the atmosphere from the tropical eastern Pacific have called this view into question. In several independent datasets, significant meridional return flows out of the ITCZ region were observed, not only at high altitudes, but also at low altitudes, just above the atmospheric boundary layer. This paper presents a theory and idealized simulations to understand the causes and dynamics of this shallow meridional circulation (SMC).
Fundamentally, the SMC can be seen as a large-scale sea-breeze circulation driven by sea surface temperature gradients when deep convection is absent in the ITCZ region. A simple model of this circulation is presented. Using observed values, the sea-breeze model shows that the pressure gradient above the boundary can indeed reverse, leading to the pressure force that drives the shallow return flow out of the ITCZ.
The Weather Research and Forecast Model (WRF) is used to simulate an idealized Hadley circulation driven by moist convection in a tropical channel. The SMC is reproduced, with reasonable similarity to the circulation observed in the east Pacific. The simulations confirm that the SMC is driven by a reversal of the pressure gradient above the boundary layer, and that the return flow is strongest when deep convection is absent in the ITCZ, and weakest when deep convection is active. The model also shows that moisture transport out of the ITCZ region is far greater in the low-level shallow return flow than in the high-altitude return flow associated with the deep overturning, and that a budget for water transport in and out of the ITCZ region is grossly incomplete without it. Much of the moisture carried in the shallow return flow is recycled into the boundary layer, but does not appear to contribute to enhanced cloudiness in the subtropical stratocumulus poleward of the ITCZ.
Observed Characteristics of the MJO Relative to Maximum Rainfall
Authors: Benedict James J. , Randall David A. 
Published: August 2007

Abstract
This study examines various dynamical and thermodynamical processes that characterize the Madden–Julian oscillation (MJO). Episodes of deep convection related to the MJO based on rainfall data from the Tropical Rainfall Measuring Mission (TRMM) satellite and the Global Precipitation Climatology Project (GPCP) are identified. Although broad convective envelopes are located utilizing spectrally filtered precipitation, analyses of the features within the envelopes are carried out using unfiltered rainfall and 40-yr ECMWF Re-Analysis (ERA-40) fields. The events are composited and categorized based on geographic location and relative intensity.
The composited fields illustrate that, prior to the onset of deep convection, shallow cumulus and cumulus congestus clouds are actively involved in vertical convective transport of heat and moisture. Drying, first accomplished immediately following deep convection in the lower troposphere, is associated with an enhanced horizontal (westerly) advective component and may be related to mesoscale processes. Drying related to deep-layer subsidence is delayed until one to two weeks following intense rainfall. The importance of gradual lower-tropospheric heating and moistening and the vertical transport of energy and moisture are shown in a comparison of vigorous and weak MJO events. Additionally, a comparison of the composite fields to proposed wave instability theories suggests that certain theories are effective in explaining specific phases of the disturbance, but no single theory can yet explain all aspects of the MJO. The discharge–recharge and frictional moisture convergence mechanisms are most relevant for explaining many of the observed features of MJO evolution.
Influence of Doubled CO2 on Ozone via Changes in the Brewer–Dobson Circulation
Authors: Jiang Xun , Eichelberger Scott J. , Hartmann Dennis L. , Shia Runlie , Yung Yuk L. 
Published: August 2007

Abstract
In this short note, the effect of enhanced circulation due to doubling CO2 on ozone is investigated. The difference of Brewer–Dobson circulation (BDC) between the doubled CO2 and control run from an idealized atmospheric general circulation model is added to the BDC climatology derived from National Centers for Environmental Prediction—Department of Energy Reanalysis 2 (NCEP2) from 1979 to 2002. Then it is used to drive the California Institute of Technology/Jet Propulsion Laboratory (Caltech/JPL) two-dimensional chemistry and transport model. The results reveal that the total ozone increases by 7 and 3.5 Dobson units (DU) in the high latitudes of the Northern and Southern Hemispheres, respectively, and decreases by 4 DU in the Tropics as a result of the increase in BDC associated with doubled CO2. If the change of eddy mixing coefficients after doubling CO2 is also considered, the total ozone will increase by 6.5 and 3 DU in the high latitudes of the Northern and Southern Hemispheres after combining both effects from the change in BDC and eddy mixing coefficients.