bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atypical retinoids ST1926 and CD437 are S-phase-specific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity
Authors: Valli Claudia , Paroni Gabriela , Di Francesco Angela Maria , Riccardi Riccardo , Tavecchio Michele , Erba Eugenio , Boldetti Andrea , Gianni' Maurizio , Fratelli Maddalena , Pisano Claudio , Merlini Lucio , Antoccia Antonio , Cenciarelli Chiara , Terao Mineko , Garattini Enrico 
Published: September 2008

Abstract
Retinoid-related molecules (RRM) are novel agents with tumor-selective cytotoxic/antiproliferative activity, a different mechanism of action from classic retinoids and no cross-resistance with other chemotherapeutics. ST1926 and CD437 are prototypic RRMs, with the former currently undergoing phase I clinical trials. We show here that ST1926, CD437, and active congeners cause DNA damage. Cellular and subcellular COMET assays, H2AX phosphorylation (γ-H2AX), and scoring of chromosome aberrations indicate that active RRMs produce DNA double-strand breaks (DSB) and chromosomal lesions in NB4, an acute myeloid leukemia (AML) cell line characterized by high sensitivity to RRMs. There is a direct quantitative correlation between the levels of DSBs and the cytotoxic/antiproliferative effects induced by RRMs. NB4.437r blasts, which are selectively resistant to RRMs, do not show any sign of DNA damage after treatment with ST1926, CD437, and analogues. DNA damage is the major mechanism underlying the antileukemic activity of RRMs in NB4 and other AML cell lines. In accordance with the S-phase specificity of the cytotoxic and antiproliferative responses of AML cells to RRMs, increases in DSBs are maximal during the S phase of the cell cycle. Induction of DSBs precedes inhibition of DNA replication and is associated with rapid activation of ataxia telangectasia mutated, ataxia telangectasia RAD3-related, and DNA-dependent protein kinases with subsequent stimulation of the p38 mitogen-activated protein kinase. Inhibition of ataxia telangectasia mutated and DNA-dependent protein kinases reduces phosphorylation of H2AX. Cells defective for homologous recombination are particularly sensitive to ST1926, indicating that this process is important for the protection of cells from the RRM-dependent DNA damage and cytotoxicity. [Mol Cancer Ther 2008;7(9):2941–54]
Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas
Authors: Smalley Keiran S.M. , Lioni Mercedes , Palma Maurizia Dalla , Xiao Min , Desai Brijal , Egyhazi Suzanne , Hansson Johan , Wu Hong , King Alastair J. , Van Belle Patricia , Elder David E. , Flaherty Keith T. , Herlyn Meenhard , Nathanson Katherine L. 
Published: September 2008

Abstract
Recent studies have shown that there is a considerable heterogeneity in the response of melanoma cell lines to MEK and BRAF inhibitors. In the current study, we address whether dysregulation of cyclin-dependent kinase 4 (CDK4) and/or cyclin D1 contribute to the BRAF inhibitor resistance of melanoma cells. Mutational screening identified a panel of melanoma cell lines that harbored both a BRAF V600E mutation and a CDK4 mutation: K22Q (1205Lu), R24C (WM39, WM46, and SK-Mel-28), and R24L (WM902B). Pharmacologic studies showed that the presence of a CDK4 mutation did not alter the sensitivity of these cell lines to the BRAF inhibitor. The only cell line with significant BRAF inhibitor resistance was found to harbor both a CDK4 mutation and a CCND1 amplification. Array comparative genomic hybridization analysis showed that CCND1 was amplified in 17% of BRAF V600E–mutated human metastatic melanoma samples, indicating the clinical relevance of this finding. As the levels of CCND1 amplification in cell lines are lower than those seen in clinical specimens, we overexpressed cyclin D1 alone and in the presence of CDK4 in a drug-sensitive melanoma line. Cyclin D1 overexpression alone increased resistance and this was enhanced when cyclin D1 and CDK4 were concurrently overexpressed. In conclusion, increased levels of cyclin D1, resulting from genomic amplification, may contribute to the BRAF inhibitor resistance of BRAF V600E–mutated melanomas, particularly when found in the context of a CDK4 mutation/overexpression. [Mol Cancer Ther 2008;7(9):2876–83]
Administration of PLK-1 small interfering RNA with atelocollagen prevents the growth of liver metastases of lung cancer
Authors: Kawata Eri , Ashihara Eishi , Kimura Shinya , Takenaka Kazumasa , Sato Kiyoshi , Tanaka Ruriko , Yokota Asumi , Kamitsuji Yuri , Takeuchi Miki , Kuroda Junya , Tanaka Fumihiro , Yoshikawa Toshikazu , Maekawa Taira 
Published: September 2008

Abstract
Liver metastasis is one of the most important prognostic factors in lung cancer patients. However, current therapies are not sufficient. RNA interference provides us a powerful and promising approach for treating human diseases including cancers. Herein, we investigated the in vitro effects of PLK-1 small interfering RNA (siRNA) on human lung cancer cell lines and the in vivo usage of PLK-1 siRNA with atelocollagen as a drug delivery system in a murine liver metastasis model of lung cancer. PLK-1 was overexpressed in cell lines and in cancerous tissues from lung cancer patients. PLK-1 siRNA treatment inhibited growth and induced apoptosis in a concentration-dependent manner. To verify in vivo efficacy, we confirmed that atelocollagen was a useful drug delivery system in our model of implanted luciferase-labeled A549LUC cells by detecting reduced bioluminescence after an i.v. injection of luciferase GL3 siRNA/atelocollagen. PLK-1 siRNA/atelocollagen was also successfully transfected into cells and inhibited the progression of metastases. This study shows the efficacy of i.v. administration of PLK-1 siRNA/atelocollagen for liver metastases of lung cancer. We believe siRNA therapy will be a powerful and promising strategy against advanced lung cancer. [Mol Cancer Ther 2008;7(9):2904–12]
An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer
Authors: Feldmann Georg , Fendrich Volker , McGovern Karen , Bedja Djahida , Bisht Savita , Alvarez Hector , Koorstra Jan-Bart M. , Habbe Nils , Karikari Collins , Mullendore Michael , Gabrielson Kathleen L. , Sharma Rajni , Matsui William , Maitra Anirban 
Published: September 2008

Abstract
Recent evidence suggests that blockade of aberrant Hedgehog signaling can be exploited as a therapeutic strategy for pancreatic cancer. Our previous studies using the prototype Hedgehog small-molecule antagonist cyclopamine had shown the striking inhibition of systemic metastases on Hedgehog blockade in spontaneously metastatic orthotopic xenograft models. Cyclopamine is a natural compound with suboptimal pharmacokinetics, which impedes clinical translation. In the present study, a novel, orally bioavailable small-molecule Hedgehog inhibitor, IPI-269609, was tested using in vitro and in vivo model systems. In vitro treatment of pancreatic cancer cell lines with IPI-269609 resembled effects observed using cyclopamine (i.e., Gli-responsive reporter knockdown, down-regulation of the Hedgehog target genes Gli1 and Ptch, as well as abrogation of cell migration and colony formation in soft agar). Single-agent IPI-269609 profoundly inhibited systemic metastases in orthotopic xenografts established from human pancreatic cancer cell lines, although Hedgehog blockade had minimal effect on primary tumor volume. The only discernible phenotype observed within the treated primary tumor was a significant reduction in the population of aldehyde dehydrogenase–bright cells, which we have previously identified as a clonogenic tumor-initiating population in pancreatic cancer. Selective ex vivo depletion of aldehyde dehydrogenase–bright cells with IPI-269609 was accompanied by significant reduction in tumor engraftment rates in athymic mice. Pharmacologic blockade of aberrant Hedgehog signaling might prove to be an effective therapeutic strategy for inhibition of systemic metastases in pancreatic cancer, likely through targeting subsets of cancer cells with tumor-initiating (“cancer stem cell”) properties. [Mol Cancer Ther 2008;7(9):2725–35]
How Well Does Water Activity Determine Homogeneous Ice Nucleation Temperature in Aqueous Sulfuric Acid and Ammonium Sulfate Droplets?
Authors: Swanson Brian D. 
Published: September 2008

AbstractFrozen fraction measurements made using a droplet free-fall freezing tube apparatus are presented and used, along with other recent laboratory measurements, to evaluate how well both the water activity idea and the translated melting-point curve idea of Koop et al. predict homogeneous freezing-point temperatures for aqueous ammonium sulfate and sulfuric acid solution droplets. The new freezing-point temperature datasets agree with the previous lowest-temperature results for both solutes. The lowest measured freezing-point temperatures for aqueous ammonium sulfate solutions agree with a curve shaped like the translated melting-point curve. However, those for aqueous sulfuric acid solutions are significantly lower than predicted by the translated melting-point curve idea, and a single water activity freezing-point temperature curve does not represent the lowest-temperature freezing-point temperature data for both solutes. A linear extrapolation of the new aqueous sulfuric acid solution freezing data to low temperatures predicts that high critical supersaturations in cloud-free regions of the upper troposphere will occur when homogeneous ice nucleation in an aqueous sulfuric acid aerosol is the primary ice formation mechanism.
Effects of Tropical Deforestation on Global Hydroclimate: A Multimodel Ensemble Analysis
Authors: Hasler Natalia , Werth David , Avissar Roni 
Published: September 2008

Abstract
Two multimodel ensembles (MME) were produced with the GISS Model II (GM II), the GISS Atmosphere Model (AM), and the NCAR Community Climate System Model (CCSM) to evaluate the effects of tropical deforestation on the global hydroclimate. Each MME used the same 48-yr period but the two were differentiated by their land-cover types. In the “control” case, current vegetation was used, and in the “deforested” case, all tropical rain forests were converted to a mixture of shrubs and grassland. Globally, the control simulations produced with the three GCMs compared well to observations, both in the time mean and in the temporal variability, although various biases exist in the different tropical rain forests.
The local precipitation response to deforestation is very strong. The remote effect in the tropics (away from the deforested tropical areas) is strong as well, but the effects at midlatitudes are weaker. In the MME, the impacts tend to be attenuated relative to the individual models.
The significance of the geopotential and precipitation responses was evaluated with a bootstrap method, and results varied during the year. Tropical deforestation also produced anomalous fluxes in potential energy that were a direct response to the deforestation. These different analyses confirmed the existence of a teleconnection mechanism due to deforestation.
Tropical Water Vapor and Cloud Feedbacks in Climate Models: A Further Assessment Using Coupled Simulations
Authors: Sun De-Zheng , Yu Yongqiang , Zhang Tao 
Published: September 2008

Abstract
By comparing the response of clouds and water vapor to ENSO forcing in nature with that in Atmospheric Model Intercomparison Project (AMIP) simulations by some leading climate models, an earlier evaluation of tropical cloud and water vapor feedbacks has revealed the following two common biases in the models: 1) an underestimate of the strength of the negative cloud albedo feedback and 2) an overestimate of the positive feedback from the greenhouse effect of water vapor. Extending the same analysis to the fully coupled simulations of these models as well as other Intergovernmental Panel on Climate Change (IPCC) coupled models, it is found that these two biases persist. Relative to the earlier estimates from AMIP simulations, the overestimate of the positive feedback from water vapor is alleviated somewhat for most of the coupled simulations. Improvements in the simulation of the cloud albedo feedback are only found in the models whose AMIP runs suggest either a positive or nearly positive cloud albedo feedback. The strength of the negative cloud albedo feedback in all other models is found to be substantially weaker than that estimated from the corresponding AMIP simulations. Consequently, although additional models are found to have a cloud albedo feedback in their AMIP simulations that is as strong as in the observations, all coupled simulations analyzed in this study have a weaker negative feedback from the cloud albedo and therefore a weaker negative feedback from the net surface heating than that indicated in observations. The weakening in the cloud albedo feedback is apparently linked to a reduced response of deep convection over the equatorial Pacific, which is in turn linked to the excessive cold tongue in the mean climate of these models. The results highlight that the feedbacks of water vapor and clouds—the cloud albedo feedback in particular—may depend on the mean intensity of the hydrological cycle. Whether the intermodel variations in the feedback from cloud albedo (water vapor) in the ENSO variability are correlated with the intermodel variations of the feedback from cloud albedo (water vapor) in global warming has also been examined. While a weak positive correlation between the intermodel variations in the feedback of water vapor during ENSO and the intermodel variations in the water vapor feedback during global warming was found, there is no significant correlation found between the intermodel variations in the cloud albedo feedback during ENSO and the intermodel variations in the cloud albedo feedback during global warming. The results suggest that the two common biases revealed in the simulated ENSO variability may not necessarily be carried over to the simulated global warming. These biases, however, highlight the continuing difficulty that models have in simulating accurately the feedbacks of water vapor and clouds on a time scale of the observations available.
Southern Hemisphere Westerly Wind Control over the Ocean's Thermohaline Circulation
Authors: Sijp Willem P. , England Matthew H. 
Published: September 2008

Abstract
The effect of the position of the Southern Hemisphere subpolar westerly winds (SWWs) on the thermohaline circulation (THC) of the World Ocean is examined. The latitudes of zero wind stress curl position exert a strong control on the distribution of overturning between basins in the Northern Hemisphere. A southward wind shift results in a stronger Atlantic THC and enhanced stratification in the North Pacific, whereas a northward wind shift leads to a significantly reduced Atlantic THC and the development of vigorous sinking (up to 1500-m depth) in the North Pacific. In other words, the Atlantic dominance of the meridional overturning circulation depends on the position of the zero wind stress curl over the Southern Ocean in the experiments. This position has a direct influence on the surface salinity contrast between the Pacific and the Atlantic, which is then further amplified by changes in the distribution of Northern Hemisphere sinking between these basins. The results show that the northward location of the SWW stress maximum inferred for the last glacial period may have contributed to significantly reduced North Atlantic Deep Water formation during this period, and perhaps an enhanced and deeper North Pacific THC. Also, a more poleward location of the SWW stress maximum in the current warming climate may entail stronger salinity stratification of the North Pacific.
Ability to Forecast Regional Soil Moisture with a Distributed Hydrological Model Using ECMWF Rainfall Forecasts
Authors: Schuurmans J. M. , Bierkens M. F. P. 
Published: September 2008

Abstract
This study mimics an online forecast system to provide nine day-ahead forecasts of regional soil moisture. It uses modified ensemble rainfall forecasts from the numerical weather prediction model of the European Centre for Medium-Range Weather Forecasts (ECMWF), which is provided by the Royal Netherlands Meteorological Office (KNMI). Both the individual ensembles as well as the mean of the ensembles are used as input for a hydrological model of a 70-km2 study area during March–November 2006. The outcomes are compared to the model run with high-resolution rainfall fields (based on 14 rain gauges within the study area and meteorological radar) as input. It is shown that the total spatial mean rainfall is forecasted very well for all lead times. The measured rainfall (spatial mean) shows a distribution with peaks at 0–1 and &gt;10 mm day−1. These peaks are underestimated by the ensemble mean of the forecasts and this underestimation increases with lead time. This is not the case when ensemble members are used. Besides, the modeled uncertainty in rainfall by ECMWF underestimates the true uncertainty for all lead times and the number of rainfall events (thresholds 0.1, 0.5, and 1.0 mm) is overestimated. Absolute temporal mean bias values in root zone storage—that is, soil moisture—larger than 1 mm start to show for lead times longer than 3 days. The lower and upper bounds of bias for a lead time of 9 days are approximately −4 and 7 mm, respectively (negative values mean the forecasted soil moisture is underestimated). The bias in root zone storage shows a spatial pattern that represents the spatial pattern of total rainfall: areas with less rainfall than spatial average show a negative bias and vice versa. Local differences within this spatial pattern are due to land use and soil type. The results suggest that ensemble forecasts of soil moisture using ensemble rainfall forecasts from ECMWF are of practical use for water management, even at regional scales.
ASCAT Soil Moisture: An Assessment of the Data Quality and Consistency with the ERS Scatterometer Heritage
Authors: Naeimi Vahid , Bartalis Zoltan , Wagner Wolfgang 
Published: September 2008

Abstract
This article presents a first comparison between remotely sensed surface soil moisture retrieved with the European Remote Sensing Satellite-2 (ERS-2) scatterometer (SCAT) and the corresponding product provided by the Advanced Scatterometer (ASCAT) on board Meteorological Operation satellite (MetOp), the first of a series of three satellites providing, among other things, continuity of global soil moisture observations using active microwave techniques for the next 15 yr. Three months of collocated 2007 data were used from the SCAT and ASCAT, limited to two study regions with different land cover composition. The result of the assessment is satisfactory and ensures consistency of migrating soil moisture retrieval from the long-term SCAT dataset to ASCAT measurements. The influence of a shift of observation incidence angle ranges between the two instrument generations was not found to be significant for the soil moisture retrieval. The correlation coefficients (R) between two relative soil moisture (normalized water content) datasets compared in different incidence angle ranges are around 0.90 with root-mean-square error (RMSE) values in the order of 8.5. Results are expected to improve slightly further once the calibration of the ASCAT instrument is finalized.
Seasonal Variations of the Seychelles Dome Simulated in the CMIP3 Models
Authors: Yokoi Takaaki , Tozuka Tomoki , Yamagata Toshio 
Published: September 2008

Abstract
Using outputs from the “twentieth-century climate in coupled models” (20c3m) control run of the Coupled Model Intercomparison Project, phase 3 (CMIP3), coupled GCMs, the authors have examined how seasonal variations of the Seychelles Dome (SD) are simulated in the southwestern Indian Ocean. The observed SD shows a dominant semiannual signal due to the semiannual variation in the local Ekman upwelling resulting from a combination of two terms related to the wind stress curl and the zonal wind stress. However, all models fail to reproduce this important mechanism. In particular, the latter contribution—that determined by the seasonal variation of the zonal wind stress associated with the Indian monsoon—is not well simulated. Successful models need to reproduce the asymmetric nature of the monsoon: a shorter and stronger summer monsoon and a longer and weaker winter monsoon. Possible remedies for the model bias are also discussed.
Seasonal Kinetic Energy Variability of Near-Inertial Motions
Authors: Silverthorne Katherine E. , Toole John M. 
Published: September 2008

Abstract
Seasonal variability of near-inertial horizontal kinetic energy is examined using observations from a series of McLane Moored Profiler moorings located at 39°N, 69°W in the western North Atlantic Ocean in combination with a one-dimensional, depth-integrated kinetic energy model. The time-mean kinetic energy and shear vertical wavenumber spectra of the high-frequency motions at the mooring site are in reasonable agreement with the Garrett–Munk internal wave description. Time series of depth-dependent and depth-integrated near-inertial kinetic energy are calculated from available mooring data after filtering to isolate near-inertial-frequency motions. These data document a pronounced seasonal cycle featuring a wintertime maximum in the depth-integrated near-inertial kinetic energy deriving chiefly from the variability in the upper 500 m of the water column. The seasonal signal in the near-inertial kinetic energy is most prominent for motions with vertical wavelengths greater than 100 m but observable wintertime enhancement is seen down to wavelengths of the order of 10 m. Rotary vertical wavenumber spectra exhibit a dominance of clockwise-with-depth energy, indicative of downward energy propagation and implying a surface energy source. A simple depth-integrated near-inertial kinetic energy model consisting of a wind forcing term and a dissipation term captures the order of magnitude of the observed near-inertial kinetic energy as well as its seasonal cycle.
Baroclinicity Influences on Storm Divergence and Stratiform Rain: Subtropical Upper-Level Disturbances
Authors: Hopper Larry J. , Schumacher Courtney 
Published: September 2008

Abstract
Divergence structures associated with the spectrum of precipitating systems in the subtropics and midlatitudes are not well documented. A mesoscale model is used to quantify the relative importance different baroclinic environments have on divergence profiles for storms primarily caused by upper-level disturbances in southeastern Texas, a subtropical region. The divergence profiles simulated for a subset of the modeled storms are consistent with those calculated from an S-band Doppler radar. Realistic convective and stratiform divergence signals are also generated when applying a two-dimensional convective–stratiform separation algorithm to reflectivities derived from the mesoscale model, although the model appears to underestimate stratiform rain area. Divergence profiles from the modeled precipitating systems vary in magnitude and structure across the wide range of baroclinicities common in southeastern Texas. Barotropic storms more characteristic of the tropics generate the most elevated divergence (and thus diabatic heating) structures with the largest magnitudes. In addition, stratiform rain regions in barotropic storms contain thicker, more elevated midlevel convergence signatures than more baroclinic storms. As the degree of baroclinicity increases, stratiform area fractions generally increase while the levels of nondivergence (LNDs) decrease. However, some weakly baroclinic storms contain stratiform area fractions and/or divergence profiles with magnitudes and LNDs that are similar to barotropic storms, despite having lower tropopause heights and less deep convection. Additional convection forms after the passage of barotropic and weakly baroclinic storms that contain elevated divergence signatures, circumstantially suggesting that heating at upper levels may cause diabatic feedbacks that help to drive regions of persistent convection in the subtropics.