bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defucosylated Anti–CC Chemokine Receptor 4 Monoclonal Antibody Combined with Immunomodulatory Cytokines: A Novel Immunotherapy for Aggressive/Refractory Mycosis Fungoides and Sézary Syndrome
Authors: Yano Hiroki , Ishida Takashi , Inagaki Atsushi , Ishii Toshihiko , Ding Jianmin , Kusumoto Shigeru , Komatsu Hirokazu , Iida Shinsuke , Inagaki Hiroshi , Ueda Ryuzo 
Published: November 2007

Abstract
Purpose: Sézary syndrome (SS) and Mycosis fungoides (MF) in the advanced stage have dismal prognoses. Because CC chemokine receptor 4 (CCR4) has an important role in the skin-homing capacity of MF/SS cells, we postulated that anti-CCR4 monoclonal antibody (mAb) could represent a novel therapeutic agent against aggressive/refractory MF/SS.
Experimental Design: The defucosylated next-generation therapeutic mAb KM2760 induces enhanced antibody-dependent cellular cytotoxicity (ADCC). Here, we assessed the therapeutic potential of this antibody against aggressive MF/SS tumor cells in vitro and in animal models in vivo.
Results: KM2760 induced robust ADCC by peripheral blood mononuclear cell (PBMC) from healthy controls against a MF/SS cell line as well as against primary tumor cells from patients with aggressive MF/SS. KM2760 also showed significant antitumor activity in disseminated and nondisseminated MF/SS mouse models. In addition, ∼30% of autologous MF/SS tumor cells were killed in in vitro assays of KM2760-induced ADCC mediated by patients' PBMC after only 4 h, despite the low numbers of natural killer cells present in these PBMCs. It is also shown that ADCC induced by defucosylated therapeutic mAb can be greatly augmented by the immunomodulatory cytokines interleukin-12, IFN-α-2b, and IFN-γ.
Conclusions: The present study has encouraged us in the conducting of a phase I clinical trial of a completely defucosylated anti-CCR4 mAb in patients with CCR4-positive T-cell lymphomas, including aggressive MF/SS (ClinicalTrials.gov identifier: NCT00355472). In the near future, the efficacy not only of defucosylated anti-CCR4 mAb single-agent treatment but also of combination therapy with immunomodulatory cytokines will be clinically established to target aggressive/refractory MF/SS.
P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan
Authors: de Vries Nienke A. , Zhao Jin , Kroon Emily , Buckle Tessa , Beijnen Jos H. , van Tellingen Olaf 
Published: November 2007

AbstractPurpose: The brain is a pharmacologic sanctuary site, due to the presence of the blood-brain barrier (BBB). Whereas the effect of P-glycoprotein (P-gp) at the BBB is well established, the role of breast cancer resistance protein (BCRP) that is also expressed at the BBB is not.Experimental Design: We have studied the effect of BCRP by administering topotecan to wild-type (WT), single Mdr1a/b(−/−) and Bcrp1(−/−), and compound Mdr1a/b(−/−)Bcrp1(−/−) knockout mice. Drug levels in plasma and tissues were determined by high-performance liquid chromatography.Results: The area under the plasma and tissue concentration-time curve (AUC) of topotecan in brains of Mdr1a/b(−/−) and Bcrp1(−/−) mice was only 1.5-fold higher compared with WT mice, but in Mdr1a/b(−/−)Bcrp1(−/−) mice, where both transporters are absent, the AUC increased by 12-fold. The AUC in plasma was ∼0.75-, 2.4-, and 3.7-fold higher in Mdr1a/b(−/−), Bcrp1(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) mice, respectively, resulting in 2.0-fold (P &lt; 0.01), 0.65-fold (P, not significant), and 3.2-fold (P &lt; 0.01), respectively, higher brain-to-plasma AUC ratios. Results using Mrp4(−/−) mice showed that this transporter had no effect on the brain penetration of topotecan. The P-gp/BCRP inhibitor elacridar fully inhibited P-gp–mediated transport of topotecan, whereas inhibition of Bcrp1-mediated transport by elacridar was minimal.Conclusions: Our results using Mdr1a/b(−/−)Bcrp1(−/−) mice clearly show the effect of Bcrp1 at the BBB and also show how two drug transporters act in concert to limit the brain penetration of topotecan. We expect that this finding will also apply to other drugs that are substrates of both P-gp and BCRP. Consequently, to improve the brain penetration of such compounds for targeting intracranial malignancies in patients, it will be essential to use potent inhibitors of both drug transporters.
The Frequency and Suppressor Function of CD4+CD25highFoxp3+ T Cells in the Circulation of Patients with Squamous Cell Carcinoma of the Head and Neck
Authors: Strauss Laura , Bergmann Christoph , Gooding William , Johnson Jonas T. , Whiteside Theresa L. 
Published: November 2007

AbstractObjective: Immune escape is a characteristic feature of head and neck squamous cell carcinoma (HNSCC). Regulatory T cells (Treg) might contribute to HNSCC progression by suppressing antitumor immunity, and their attributes in patients are of special interest.Methods: Multicolor flow cytometry was used to study the frequency and phenotype of Treg in peripheral blood lymphocytes of 35 patients with HNSCC and 15 normal controls (NC). CD4+CD25high T cells were purified by fluorescence-activated cell sorting and tested for regulatory function by coculture with carboxyfluorescein diacetate succinimidylester–labeled autologous CD4+CD25− responder cells.Results: The percentages of circulating CD4+CD25+ T cells were increased in HNSCC patients (5 ± 3%) versus NC (2 ± 1.5%). In patients, this cell subset largely contained CD4+CD25highFoxp3+ T cells and only few CD25low/interm cells. In addition, the frequency of Treg positive for CD62L, CTLA-4, Fas, FasL, and Foxp3 was greater in the circulation of patients than in NC (P &lt; 0.0001). In HNSCC patients, Treg mediated significantly higher suppression (78 ± 7%) compared with Treg in NC (12 ± 4%) with P &lt; 0.0001. Surprisingly, higher Treg frequency (P &lt; 0.0059) and levels of suppression (P &lt; 0.0001) were observed in patients with no evident disease (NED) than in untreated patients with active disease (AD).Conclusions: The frequency of T cells with suppressor phenotype and function (Treg) was significantly greater in HNSCC patients who were NED after oncologic therapy relative to those with AD. This finding suggests that oncologic therapy favors expansion of Treg.
Apicularen A Induces Cell Death through Fas Ligand Up-Regulation and Microtubule Disruption by Tubulin Down-Regulation in HM7 Human Colon Cancer Cells
Authors: Kim Jong-Seok , Lee Young-Chul , Nam Ho-Tak , Li Ge , Yun Eun-Jin , Song Kyoung-Sub , Seo Kang-Sik , Park Ji-Hoon , Ahn Jong-Woong , Zee OkPyo , Park Jong-Il , Yoon Wan-Hee , Lim Kyu , Hwang Byung-Doo 
Published: November 2007

AbstractPurpose: Apicularen A has been shown to cause growth inhibition and apoptosis in several cancer cell lines. However, the mechanisms of apicularen A–induced cell death and in vivo effects remain unclear. In this study, we investigated the molecular mechanisms of apicularen A–induced cell death in HM7 human colon cancer cells in vitro and anticancer activity in vivo.Experimental Design: We tested cytotoxicity with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, apoptosis with DNA fragmentation assay, mitochondrial membrane potential, and cell cycle with fluorescence-activated cell sorting. Caspase activation was done by fluorometry. Alterations of microtubule structure, tubulin protein, and mRNA level were assessed by immunofluorescence, Western blot, and reverse transcription-PCR. In vivo studies were assessed using nude mice tumor cell growth in xenograft model and liver colonization assay.Results: Apicularen A treatment of HM7 cells inhibited cell growth and this inhibition was partially rescued by z-VAD-fmk. Apicularen A caused accumulation of sub-G1-G0, DNA fragmentation, Fas ligand induction, and activation of caspase-8 and caspase-3, but mitochondrial membrane potential was not changed. Furthermore, β-tubulin protein and mRNA were decreased by apicularen A, but in vitro polymerization of tubulin was not affected. Concurrently, apicularen A–treated cell showed disruption of microtubule architecture. In in vivo studies, apicularen A reduced tumor volume by ∼72% at the end of a 15-day treatment. Moreover, apicularen A reduced liver colonization as much as 95.6% (50 μg/kg/d).Conclusion: Apicularen A induces cell death of HM7 cells through up-regulating Fas ligand and disruption of microtubule architecture with down-regulation of tubulin level. These findings indicate that apicularen A is a promising new microtubule-targeting compound.
Nerve-Sparing Therapy with Oncolytic Herpes Virus for Cancers with Neural Invasion
Authors: Gil Ziv , Rein Avigail , Brader Peter , Li Sen , Shah Jatin P. , Fong Yuman , Wong Richard J. 
Published: November 2007

Abstract
Purpose: The invasion of cancer cells along nerves is an ominous pathologic finding associated with poor outcomes for a variety of tumors, including pancreatic and head and neck carcinomas. Peripheral nerves may serve as a conduit for these cancers to track into the central nervous system. Cancer progression within nerves and surgical resection of infiltrated nerves result in a permanent loss of neural function, potentially causing cosmetic and functional morbidity. Herpes simplex viruses (HSV) have utility for gene transfer into nerves and as oncolytic agents. We studied the use of an attenuated HSV, NV1023, as treatment for cancers with neural invasion.
Experimental Design and Results: NV1023 injection into the sciatic nerves of nude mice had no toxic effect on nerve function, whereas similar doses of wild-type HSV-1 (F′ strain) caused complete nerve paralysis within 4 days and 100% mortality at day 6. NV1023 showed effective cytotoxicity in vitro on three neurotrophic human carcinoma cell lines, including pancreatic (MiaPaCa2), squamous cell (QLL2), and adenoid cystic (ACC3) carcinomas. A model of neural invasion was established by implanting human carcinoma cells in the sciatic nerves of nude mice. All control group mice developed left hind limb paralysis 5 to 7 weeks after tumor injection, whereas animals treated with NV1023 maintained intact nerve function and showed significant tumor regression (P &lt; 0.0001).
Conclusions: These results show that NV1023 oncolytic therapy may effectively treat cancers with neural invasion and preserve neural function. These findings hold significant clinical implications for patients with cancer neural invasion.
Antithrombin Reduces Ischemic Volume, Ameliorates Neurologic Deficits, and Prolongs Animal Survival in Both Transient and Permanent Focal Ischemia
Authors: Cuomo Ornella , Pignataro Giuseppe , Gala Rosaria , Scorziello Antonella , Gravino Elvira , Piazza Ornella , Tufano Rosalba , Di Renzo Gianfranco , Annunziato Lucio 
Published: November 2007

Background and Purpose—Antithrombin (AT), a glycoprotein belonging to the serpin family, blocks thrombin formation and activity at several steps. Thrombin, beside its relevant role in the coagulation cascade, exerts neurodetrimental effects through the activation of a family of protease-activated receptors, which can be implicated in stroke pathophysiology. The aims of the present study were to evaluate whether AT could reduce brain damage, ameliorate neurologic deficits, and prolong animal survival.Methods—Two different doses of AT (10 and 30 IU/kg IP) were administered 3 hours, 6 hours, or 3 and 6 hours after an ischemic insult to mice and rats subjected to either transient or permanent focal ischemia. Ischemic volume was evaluated 24 hours or 7 days after the ischemic insult. Neurologic deficits were also scored.Results—In mice, 10 or 30 IU/kg AT administered twice, at 3 and 6 hours after transient ischemia, and 30 IU/kg AT administered 3 hours only after transient ischemia substantially reduced total ischemic volume, significantly improved neurologic deficits evaluated 24 hours after the insult, and prolonged animal survival. In rats, the same doses given at the same time intervals significantly reduced ischemic volume, evaluated 24 hours after permanent ischemia.Conclusions—These results indicate that AT remarkably reduces infarct volume, ameliorates neurologic deficit scores, and prolongs animal survival in 2 rodent models of brain ischemia. Taken together, our data suggest that AT, delivered via systemic administration, an easily achievable route of administration and in a clinically useful time window, could represent a new therapeutic strategy to be validated for the clinical treatment of human stroke.
Hydrometeorological Analysis of the 29 August 2003 Flash Flood in the Eastern Italian Alps
Authors: Borga Marco , Boscolo Paolo , Zanon Francesco , Sangati Marco 
Published: November 2007

Abstract
The 29 August 2003 storm on the upper Tagliamento River basin in the eastern Italian Alps is examined as a prototype for organized convective systems that dominate the upper tail of the precipitation frequency distribution and are likely responsible for the majority of flash flood peaks in this area. The availability of high-resolution rainfall estimates from radar observations and rain gauge networks, together with flood response observations derived from stream gauge data and post-event surveys, provides the opportunity to study the hydrometeorological and hydrological mechanisms associated with this extreme storm and the associated flood. The flood occurred at the end of a climatic anomaly of prolonged drought and warm conditions over Europe and the Mediterranean region. A characteristic of the event is its organization in well-defined banded structures, some of which persisted in the same locations for the duration of the event. The steadiness of these rainbands led to highly variable precipitation accumulations and, associated with orographic enhancement, played a central role in the space–time organization of the storm. Two dominant controls on extreme flood response are recognized and analyzed: steadiness of convective bands and dry antecedent soil moisture conditions.
Small-Scale Spatial Gradients in Climatological Precipitation on the Olympic Peninsula
Authors: Anders Alison M. , Roe Gerard H. , Durran Dale R. , Minder Justin R. 
Published: November 2007

Abstract
Persistent, 10-km-scale gradients in climatological precipitation tied to topography are documented with a finescale rain and snow gauge network in the Matheny Ridge area of the Olympic Mountains of Washington State. Precipitation totals are 50% higher on top of an ∼800-m-high ridge relative to valleys on either side, 10 km distant. Operational fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5) runs on a 4-km grid produce similar precipitation patterns with enhanced precipitation over high topography for 6 water years.
The performance of the MM5 is compared to the gauge data for 3 wet seasons and for 10 large precipitation events. The cumulative MM5 precipitation forecasts for all seasons and for the sum of all 10 large events compare well with the precipitation measured by the gauges, although some of the individual events are significantly over- or underforecast. This suggests that the MM5 is reproducing the precipitation climatology in the vicinity of the gauges, but that errors for individual events may arise due to inaccurate specification of the incident flow.
A computationally simple model of orographic precipitation is shown to reproduce the major features of the event precipitation pattern on the windward side of the range. This simple model can be coupled to landscape evolution models to examine the impact of long-term spatial variability in precipitation on the evolution of topography over thousands to millions of years.
Calibration of LaD Model in the Northeast United States Using Observed Annual Streamflow
Authors: Xia Y. 
Published: November 2007

Abstract
Calibration of land surface models improves simulations of surface water and energy fluxes and provides important information for water resources management. However, most calibration studies focus on local sites and/or small catchments because of computational limitations, lack of atmospheric forcing data, and lack of observed water and energy fluxes. Even though a well-established streamflow gauge network exists, its data are not well suited to the calibration of land surface models in cold regions because of large systematic precipitation biases. This study provides a newly developed method to adjust systematic precipitation biases arising from gauge undercatch (e.g., wind blowing, wetting loss, and evaporation loss). The new method estimates model parameter and precipitation errors simultaneously through the use of observed annual streamflow in the northeastern United States. The results show that this method improves streamflow simulations and gives a reasonable estimate for systematic precipitation bias. In addition, the impacts of model parameter errors on the calibration of the Land Dynamics (LaD) model and on the estimation of systematic precipitation biases are investigated in the northeastern United States.
Trends in Land Evapotranspiration over Canada for the Period 1960–2000 Based on In Situ Climate Observations and a Land Surface Model
Authors: Fernandes Richard , Korolevych Vladimir , Wang Shusen 
Published: November 2007

Abstract
An assessment of annual trends in actual evapotranspiration (AET) and associated meteorological inputs is performed at 101 locations across Canada with available long-term hourly surface climate observations to determine if AET in Canada is increasing in relation to observed increases in air temperature. AET was estimated for the dominant land cover class, with representative soil and leaf area index conditions, within a 50 km × 50 km window around each location for the period 1960–2000. The Ecological Assimilation of Land and Climate Observations (EALCO) land surface model, which simulates coupled carbon, energy, and water cycles, was applied to estimate AET on a half-hourly basis at each location using in situ meteorological measurements and ambient atmospheric CO2 concentrations. Increases in annual AET, of up to 0.73% yr−1, were identified at 81 locations, and decreases, of up to 0.25% yr−1, were found at the remaining 20 stations. Statistically significant increasing trends were detected in 35% of the locations with the majority corresponding to Atlantic and Pacific coastal regions. Increasing trends were generally related to increasing temperature and total downwelling surface radiation trends in eastern Canada and increasing temperature, surface radiation, and precipitation trends in western Canada. In sharp contrast to other studies based on simpler AET models, annual AET trends in the prairie climate zone were mixed in terms of increases and decreases with no locations showing statistically significant trends. Future studies focused on scaling AET model estimates to subbasins or basins are required both to account for this spatial variability in soil conditions and to permit water budget closure validation.
Multidecadal High-Resolution Hydrologic Modeling of the Arkansas–Red River Basin
Authors: Sharif Hatim O. , Crow W. , Miller N. L. , Wood E. F. 
Published: November 2007

Abstract
Land surface heterogeneity and its effects on surface processes have been a concern to hydrologists and climate scientists for the past several decades. The contrast between the fine spatial scales at which heterogeneity is significant (1 km and finer) and the coarser scales at which most climate simulations with land surface models are generated (hundreds of kilometers) remains a challenge, especially when incorporating land surface and subsurface lateral fluxes of mass. In this study, long-term observational land surface forcings and derived solar radiation were used to force high-resolution land surface model simulations over the Arkansas–Red River basin in the Southern Great Plains region of the United States. The most unique aspect of these simulations is the fine space (1 km2) and time (hourly) resolutions within the model relative to the total simulation period (51 yr) and domain size (575 000 km2). Runoff simulations were validated at the subbasin scale (600–10 000 km2) and were found to be in good agreement with observed discharge from several unregulated subbasins within the system. A hydroclimatological approach was used to assess simulated annual evapotranspiration for all subbasins. Simulated evapotranspiration values at the subbasin scale agree well with predictions from a simple one-parameter empirical model developed in this study according to Budyko’s concept of “geographical zonality.” The empirical model was further extended to predict runoff and evapotranspiration sensitivity to precipitation variability, and good agreement with computed statistics was also found. Both the empirical model and simulation results demonstrate that precipitation variability was amplified in the simulated runoff. The finescale at which the study is performed allows analysis of various aspects of the hydrologic cycle in the system including general trends in precipitation, runoff, and evapotranspiration, their spatial distribution, and the relationship between precipitation anomalies and runoff and soil water storage anomalies at the subbasin scale.
A Comparison of the Noah and OSU Land Surface Models in the ECPC Seasonal Forecast Model
Authors: De Haan Laurel L. , Kanamitsu Masao , Lu Cheng-Hsuan , Roads John O. 
Published: November 2007

Abstract
The Noah land surface model (LSM) has recently been implemented into the Experimental Climate Prediction Center’s (ECPC’s) global Seasonal Forecast Model (SFM). Its performance is compared to the older ECPC SFM with the Oregon State University (OSU) LSM using two sets of 10-member 50-yr Atmospheric Model Intercomparison Project (AMIP) runs. The climatological biases of several fields tend to increase with the Noah LSM. The differences in near-surface temperature bias are traced to changes in the energy budget. In addition to climatology, the variability and skill (anomaly correlation with observations) of the two ensembles are considered. Unlike the climatology, the near-surface temperature skill of the ECPC SFM generally improves with the Noah LSM. Other climatological fields, such as precipitation, show little change in skill.
While the global results are mixed, there are however significant regional improvements over Africa both in terms of climatological bias and skill. In the central African Congo River basin, the Noah LSM removed a warm-dry bias and improved upon the near-surface temperature skill of the OSU LSM. In the African Sahel, the Noah LSM greatly enhanced the climatology, variability, and skill of the ECPC SFM as well as improving the location of the African easterly jet.