bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Cigarette Smoking on Imatinib in Patients in the Soft Tissue and Bone Sarcoma Group of the EORTC
Authors: van Erp Nielka , Gelderblom Hans , van Glabbeke Martine , Van Oosterom Allan , Verweij Jaap , Guchelaar Henk-Jan , Debiec-Rychter Maria , Peng Bin , Blay Jean-Yves , Judson Ian 
Published: December 2008

AbstractPurpose: Smoking is a potent inducer of cytochrome P450 (CYP) 1A2 and may affect the pharmacokinetics of CYP1A2 metabolized drugs. The effect of smoking on the pharmacokinetics of imatinib, which is metabolized by CYP3A4 and partly by CYP1A2, is unknown. We studied the effect of smoking on imatinib pharmacokinetics, safety, and efficacy.Experimental Design: Imatinib pharmacokinetics, safety, and efficacy was analyzed in 45 patients with gastrointestinal stromal tumors (GIST) or soft-tissue sarcoma included in two European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group trials, including 15 smokers and 30 nonsmokers. Apparent oral clearance, distribution volume, elimination half-life, and dose-standardized area under the concentration curve (AUC) were assessed in 34 patients using nonlinear mixed-effect modeling.Results: Mean ± SD pharmacokinetic variables in smokers (n = 9) versus nonsmokers (n = 25) groups were 9.6 ± 5.5 versus 9.2 ± 4.6 L/h (apparent oral clearance), 216.5 ± 114.3 versus 207.0 ± 116.9 L (distribution volume), 16.1 ± 6.0 versus 16.5 ± 6.0 h (elimination half-life), and 133.6 ± 71.0 versus 142.3 ± 84.0 ng h/mL mg area under the concentration curve; P &gt; 0.05. Smokers experienced more grade 2/3 anemia (P = 0.010) and fatigue (P = 0.011) and those with GIST had a significantly shorter overall survival (P = 0.037) and time to progression (P = 0.052).Conclusions: This retrospective study suggests that the pharmacokinetics of imatinib is not affected by smoking. However, smokers have an increased risk of anemia and fatigue. Smokers with GIST have a shorter overall survival and time to progression.
A peptide inhibitor derived from p55PIK phosphatidylinositol 3-kinase regulatory subunit: a novel cancer therapy
Authors: Hu Junbo , Xia Xianmin , Cheng Aiwu , Wang Guihua , Luo Xuelai , Reed Michael F. , Fojo Tito , Oetting Alexis , Gong Jianping , Yen Paul M. 
Published: December 2008

Abstract
p55PIK, a regulatory subunit of phosphatidylinositol 3-kinase (PI3K), specifically interacts with retinoblastoma protein (Rb) through the unique NH2 terminus of p55PIK, N24. This interaction is critical for cell proliferation and cell cycle progression. To examine p55PIK as a potential target for cancer therapy, we generated an adenovirus expressing N24 (Ad-N24-GFP) and studied its effects on the proliferation of cultured cancer cells, including human colon (HT29) and thyroid (FTC236) cancer cells. Ad-N24-GFP blocked cell proliferation and induced cell cycle arrest in all cancer cell lines tested. N24 induced cell cycle arrest at G0-G1 phase in cell lines that expressed Rb. Interestingly, N24 inhibited cell proliferation by blocking cell cycle transition at both S and G2-M phases in FTC236 cells, which did not express Rb. When Rb was knocked down by short hairpin RNA in HT29 cells, N24 also inhibited cell cycle progression at S and G2-M phases, suggesting that p55PIK regulates cell cycle progression by Rb-dependent and Rb-independent mechanisms. Finally, Ad-N24-GFP markedly decreased the growth of xenograft tumors derived from HT29 and FTC236 cancer cells in athymic nude mice. Our data strongly suggest that N24 peptide is an effective anticancer therapy, which specifically inhibits PI3K signaling pathways mediated by p55PIK. Moreover, they show that the regulatory subunit of an enzyme, in addition to its catalytic subunit, can be an important target for drug development. [Mol Cancer Ther 2008;07(12):3719–28]
1,1-Bis(3′-indolyl)-1-(p-chlorophenyl)methane activates the orphan nuclear receptor Nurr1 and inhibits bladder cancer growth
Authors: Inamoto Teruo , Papineni Sabitha , Chintharlapalli Sudhakar , Cho Sung-Dae , Safe Stephen , Kamat Ashish M. 
Published: December 2008

AbstractNurr1 is an orphan nuclear receptor and a member of the nerve growth factor I-B subfamily of transcription factors with no known endogenous ligand or stimulator. We show, for the first time, evidence that Nurr1 is expressed in a panel of 11 human bladder cancer cell lines. A new class of methylene-substituted diindolylmethanes (C-DIM) were screened and 1,1-bis(3′-indolyl)-1-(p-chlorophenyl)methane (DIM-C-pPhCl) activated the ligand-binding domain of Nurr1. Treatment of bladder cancer cells with Nurr1-active C-DIM resulted in decreased cell survival (MTT assay) and induction of cell death pathways, resulting in poly(ADP-ribose) polymerase cleavage and DNA fragmentation. The specificity of the Nurr1-active compound was shown using RNA interference in 253J B-V cells, whereby small interfering RNA against Nurr1 attenuated ligand-dependent activation of Nurr1 and poly(ADP-ribose) polymerase cleavage. Furthermore, activation of Nurr1 resulted in stimulation of tumor necrosis factor-related apoptosis-inducing ligand and small interfering RNA experiments attenuated tumor necrosis factor-related apoptosis-inducing ligand production. In an orthotopic model of human bladder tumors established in nude mice, administration of a Nurr1-active C-DIM suppressed bladder cancer growth. These results identify Nurr1 as a potential target for bladder cancer therapy and also identify a novel agent for activating Nurr1. [Mol Cancer Ther 2008;7(12):3825–33]
c-Src-p38 Mitogen-Activated Protein Kinase Signaling Is Required for Akt Activation in Response to Ionizing Radiation
Authors: Kim Min-Jung , Byun Joo-Yun , Yun Chang-Hwan , Park In-Chul , Lee Kee-Ho , Lee Su-Jae 
Published: December 2008

Abstract
The Akt and mitogen-activated protein kinase (MAPK) pathways have been implicated in tumor cell survival and contribute to radiation resistance. However, the molecular basis for link between MAPK and Akt in cell survival response to radiation is unclear. Here, we show that c-Src-Rac1-p38 MAPK pathway signals Akt activation and cell survival in response to radiation. Ionizing radiation triggered Thr308 and Ser473 phosphorylation of Akt. Exposure of cells to radiation also induced p38 MAPK and c-Jun NH2-terminal kinase activations. Inhibition of c-Jun NH2-terminal kinase suppressed radiation-induced cell death, whereas inhibition of p38 MAPK effectively increased sensitivity to radiation. Interestingly, inhibition of p38 MAPK completely attenuated radiation-induced Ser473 phosphorylation of Akt but did not affect Thr308 phosphorylation. Conversely, overexpression of p38 MAPK enhanced Ser473 phosphorylation of Akt in response to radiation. In addition, inhibition of p38 MAPK failed to alter phosphoinositide 3-kinase and phosphoinositide-dependent protein kinase activities. Ectopic expression of RacN17, dominant-negative form of Rac1, inhibited p38 MAPK activation and Ser473 phosphorylation of Akt. Following exposure to radiation, c-Src was selectively activated among Src family tyrosine kinases. Inhibition of c-Src attenuated Rac1 and p38 MAPK activations and Ser473 phosphorylation of Akt. Our results support the notion that the c-Src-Rac1-p38 MAPK pathway is required for activation of Akt in response to radiation and plays a cytoprotective role against radiation in human cancer cells. (Mol Cancer Res 2008;6(12):1872–80)
Down-Regulation of hsa-miR-10a in Chronic Myeloid Leukemia CD34+ Cells Increases USF2-Mediated Cell Growth
Authors: Agirre Xabier , Jiménez-Velasco Antonio , San José-Enériz Edurne , Garate Leire , Bandrés Eva , Cordeu Lucia , Aparicio Oscar , Saez Borja , Navarro Germán , Vilas-Zornoza Amaia , Pérez-Roger Ignacio , García-Foncillas Jesús , Torres Antonio , Heiniger Anabel , Calasanz María José , Fortes Puri , Román-Gómez José , Prósper Felipe 
Published: December 2008

Abstract
MicroRNAs (miRNA) are small noncoding, single-stranded RNAs that inhibit gene expression at a posttranscriptional level, whose abnormal expression has been described in different tumors. The aim of our study was to identify miRNAs potentially implicated in chronic myeloid leukemia (CML). We detected an abnormal miRNA expression profile in mononuclear and CD34+ cells from patients with CML compared with healthy controls. Of 157 miRNAs tested, hsa-miR-10a, hsa-miR-150, and hsa-miR-151 were down-regulated, whereas hsa-miR-96 was up-regulated in CML cells. Down-regulation of hsa-miR-10a was not dependent on BCR-ABL1 activity and contributed to the increased cell growth of CML cells. We identified the upstream stimulatory factor 2 (USF2) as a potential target of hsa-miR-10a and showed that overexpression of USF2 also increases cell growth. The clinical relevance of these findings was shown in a group of 85 newly diagnosed patients with CML in which expression of hsa-miR-10a was down-regulated in 71% of the patients, whereas expression of USF2 was up-regulated in 60% of the CML patients, with overexpression of USF2 being significantly associated with decreased expression of hsa-miR-10a (P = 0.004). Our results indicate that down-regulation of hsa-miR-10a may increase USF2 and contribute to the increase in cell proliferation of CML implicating a miRNA in the abnormal behavior of CML. (Mol Cancer Res 2008;6(12):1830–40)
DNA Methylation Represses IFN-γ–Induced and Signal Transducer and Activator of Transcription 1–Mediated IFN Regulatory Factor 8 Activation in Colon Carcinoma Cells
Authors: McGough Jon M. , Yang Dafeng , Huang Shuang , Georgi David , Hewitt Stephen M. , Röcken Christoph , Tänzer Marc , Ebert Matthias P.A. , Liu Kebin 
Published: December 2008

Abstract
IFN regulatory factor 8 (IRF8) is both constitutively expressed and IFN-γ inducible in hematopoietic and nonhematopoietic cells. We have shown that IRF8 expression is silenced by DNA methylation in human colon carcinoma cells, but the molecular mechanism underlying methylation-dependent IRF8 silencing remains elusive. In this study, we observed that IRF8 protein level is inversely correlated with the methylation status of the IRF8 promoter and the metastatic phenotype in human colorectal carcinoma specimens in vivo. Demethylation treatment or knocking down DNMT1 and DNMT3b expression rendered the tumor cells responsive to IFN-γ to activate IRF8 transcription in vitro. Bisulfite genomic DNA sequencing revealed that the entire CpG island of the IRF8 promoter is methylated. Electrophoresis mobility shift assay revealed that DNA methylation does not directly inhibit IFN-γ–activated phosphorylated signal transducer and activator of transcription 1 (pSTAT1) binding to the IFN-γ activation site element in the IRF8 promoter in vitro. Chromatin immunoprecipitation assay revealed that pSTAT1 is associated with the IFN-γ activation site element of the IRF8 promoter in vivo regardless of the methylation status of the IRF8 promoter. However, DNA methylation results in preferential association of PIAS1, a potent inhibitor of pSTAT1, with pSTAT1 in the methylated IRF8 promoter region. Silencing methyl-CpG binding domain protein 1 (MBD1) expression resulted in IRF8 activation by IFN-γ in human colon carcinoma cells with methylated IRF8 promoter. Our data thus suggest that human colon carcinoma cells silence IFN-γ–activated IRF8 expression through MBD1-dependent and PIAS1-mediated inhibition of pSTAT1 function at the methylated IRF8 promoter. (Mol Cancer Res 2008;6(12):1841–51)
Specific Activity of Class II Histone Deacetylases in Human Breast Cancer Cells
Authors: Duong Vanessa , Bret Caroline , Altucci Lucia , Mai Antonello , Duraffourd Céline , Loubersac Julie , Harmand Pierre-Olivier , Bonnet Sandrine , Valente Sergio , Maudelonde Thierry , Cavailles Vincent , Boulle Nathalie 
Published: December 2008

Abstract
Although numerous studies have underlined the role of histone deacetylases (HDAC) in breast physiology and tumorigenesis, little is known on the particular contribution of the various classes of HDACs in these processes. Using estrogen receptor-α (ERα)–positive MCF-7 breast cancer cells, the effects of MC1575 and MC1568, two novel class II–specific HDAC inhibitors, were analyzed on cell proliferation, apoptosis, and estrogen signaling. The specificity of these HDAC inhibitors was validated by measuring histone and α-tubulin acetylation and by the specific in vitro inhibition of recombinant HDAC4 using histone and nonhistone substrates, contrasting with the lack of inhibition of class I HDACs. In addition, MC1575 did not inhibit class I HDAC gene expression, thus confirming the specific targeting of class II enzymes. Similar to trichostatin A (TSA), MC1575 displayed a dose-dependent antiproliferative effect and induced cell cycle arrest although this blockade occurred at a different level than TSA. Moreover, and in contrast to TSA, MC1575 had no effect on MCF-7 cells apoptosis. Interestingly, MC1575 was able to increase p21waf1/CIP1 mRNA levels but did not regulate the expression of other genes such as cyclin D1, p27, p14ARF, Bcl2, Baxα, Trail-R1, and Trail-R2. Finally, MC1575 strongly induced ERβ gene expression but did not decrease ERα expression, nor did it switch hydroxytamoxifen to an agonist activity. Altogether, these data suggest that the class II HDAC subfamily may exert specific roles in breast cancer progression and estrogen dependence. (Mol Cancer Res 2008;6(12):1908–19)
Common Anatomical and External Coding for Hands and Feet in Tactile Attention: Evidence from Event-related Potentials
Authors: Heed Tobias , Röder Brigitte 
Published: December 2008

AbstractRecent studies have suggested that the location of tactile stimuli is automatically recoded from anatomical into external coordinates, independent of the task requirements. However, research has mainly involved the two hands, which may not be representative for the whole body because they are excessively used for the visually guided manipulation of objects and tools. We recorded event-related potentials (ERPs) while participants received tactile stimuli to the hands and feet, but attended only one limb. The hands were placed near the feet either in an uncrossed or a crossed posture, thus varying the spatial distance of each hand from each foot. Centro-parietal ERPs 100–140 msec poststimulus were more positive when stimulating the anatomically same-side hand while attending a foot. They were also more positive when the Euclidean distance between the stimulated hand and the attended foot was small rather than large. When a foot was stimulated and a hand attended, a similar modulation of foot ERPs was observed for the right foot. To assess the spatial distance between two limbs in space, the external location of both must be known. The present ERP results therefore suggest that not only the hands but also other body parts are remapped into external coordinates. The use of both anatomical and external coordinates may facilitate the control of actions toward tactile events and the choice of the most suitable effector.
Monitoring in Language Perception: Mild and Strong Conflicts Elicit Different ERP Patterns
Authors: van de Meerendonk Nan , Kolk Herman H. J. , Vissers Constance Th. W. M. , Chwilla Dorothee J. 
Published: December 2008

Abstract
In the language domain, most studies of error monitoring have been devoted to language production. However, in language perception, errors are made as well and we are able to detect them. According to the monitoring theory of language perception, a strong conflict between what is expected and what is observed triggers reanalysis to check for possible perceptual errors, a process reflected by the P600. This is at variance with the dominant view that the P600 reflects syntactic reanalysis or repair, after syntactic violations or ambiguity. In the present study, the prediction of the monitoring theory of language perception was tested, that only a strong conflict between expectancies triggers reanalysis to check for possible perceptual errors, reflected by the P600. Therefore, we manipulated plausibility, and hypothesized that when a critical noun is mildly implausible in the given sentence (e.g., “The eye consisting of among other things a pupil, iris, and eyebrow …”), a mild conflict arises between the expected and unexpected event; integration difficulties arise due to the unexpectedness but they are resolved successfully, thereby eliciting an N400 effect. When the noun is deeply implausible however (e.g., “The eye consisting of among other things a pupil, iris, and sticker …”), a strong conflict arises; integration fails and reanalysis is triggered, eliciting a P600 effect. Our hypothesis was confirmed; only when the conflict between the expected and unexpected event is strong enough, reanalysis is triggered.
El Niño–Southern Oscillation Impacts on Rice Production in Luzon, the Philippines
Authors: Roberts Martha G. , Dawe David , Falcon Walter P. , Naylor Rosamond L. 
Published: December 2008

AbstractThis study uses regression analysis to evaluate the relationships among sea surface temperature anomalies (SSTA) averaged over the Niño-3.4 region (5°N–5°S, 120°–170°W), rainfall, and rice production, area harvested, and yield in Luzon, the large island on which most Philippine rice is grown. Previous research on Philippine rice production and El Niño–Southern Oscillation (ENSO) has found negative associations between El Niño events and rice yields in rainfed systems. This analysis goes further and shows that both irrigated and rainfed ecosystems are impacted. It also compares impacts on area harvested and yield. Variations in average July–September Niño-3.4 SSTAs explain approximately 29% of the interannual variations in the deviations of total January–June (dry season) rice production from a polynomial trend for 1970–2005. In contrast, no impact was found on July–December production in either year t or t + 1. The impact of ENSO on dry-season rice production in Luzon appears to be primarily due to changes in area harvested rather than yield. Production declines for rainfed ecosystems are relatively larger than for irrigated ecosystems: a 1°C increase in average July–September Niño-3.4 SSTA is associated with a 3.7% decrease in irrigated dry-season production but with a 13.7% decline in rainfed dry-season production.
The Environment of Precipitating Shallow Cumulus Convection
Authors: Nuijens Louise , Stevens Bjorn , Siebesma A. Pier 
Published: December 2008

Abstract
Quantitative estimates of precipitation in a typical undisturbed trade wind region are derived from 2 months of radar reflectivity data and compared to the meteorological environment determined from soundings, surface flux, and airborne-lidar data. Shallow precipitation was ubiquitous, covering on average about 2% of the region and contributing to at least half of the total precipitation. Echo fractions on the scale of the radar domain range between 0% and 10% and vary greatly within a period from a few hours to a day. Variability in precipitation relates most strongly to variability in humidity and the zonal wind speed, although greater inversion heights and deeper clouds are also evident at times of more rain. The analysis herein suggests that subtle fluctuations in both the strength of the easterlies and in subsidence play a major role in regulating humidity and hence precipitation, even within a given meteorological regime (here, the undisturbed trades).
The Maximum Intensity of Tropical Cyclones in Axisymmetric Numerical Model Simulations
Authors: Bryan George H. , Rotunno Richard 
Published: December 2008

Abstract
An axisymmetric numerical model is used to evaluate the maximum possible intensity of tropical cyclones. As compared with traditionally formulated nonhydrostatic models, this new model has improved mass and energy conservation in saturated conditions. In comparison with the axisymmetric model developed by Rotunno and Emanuel, the new model produces weaker cyclones (by ∼10%, in terms of maximum azimuthal velocity); the difference is attributable to several approximations in the Rotunno–Emanuel model. Then, using a single specification for initial conditions (with a sea surface temperature of 26°C), the authors conduct model sensitivity tests to determine the sensitivity of maximum azimuthal velocity (υmax) to uncertain aspects of the modeling system. For fixed mixing lengths in the turbulence parameterization, a converged value of υmax is achieved for radial grid spacing of order 1 km and vertical grid spacing of order 250 m. The fall velocity of condensate (Vt) changes υmax by up to 60%, and the largest υmax occurs for pseudoadiabatic thermodynamics (i.e., for Vt &gt; 10 m s−1). The sensitivity of υmax to the ratio of surface exchange coefficients for entropy and momentum (CE/CD) matches the theoretical result, υmax ∼ (CE/CD)1/2, for nearly inviscid flow, but simulations with increasing turbulence intensity show less dependence on CE/CD; this result suggests that the effect of CE/CD is less important than has been argued previously. The authors find that υmax is most sensitive to the intensity of turbulence in the radial direction. However, some settings, such as inviscid flow, yield clearly unnatural structures; for example, υmax exceeds 110 m s−1, despite a maximum observed intensity of ∼70 m s−1 for this environment. The authors show that turbulence in the radial direction limits maximum axisymmetric intensity by weakening the radial gradients of angular momentum (which prevents environmental air from being drawn to small radius) and of entropy (which is consistent with weaker intensity by consideration of thermal wind balance). It is also argued that future studies should consider parameterized turbulence as an important factor in simulated tropical cyclone intensity.
Insulin Devices
Authors: Spollett Geralyn 
Published: December 2008

Purpose The purpose of this article was to identify and address barriers to initiating insulin therapy in patients with type 2 diabetes. Results Insulin pen devices address many of the mechanical barriers associated with a syringe and vial. In addition, pen devices are increasingly being improved, offering long-term pen users benefits over earlier pen users. These devices can be tailored to address the specific needs of different patient populations, such as elderly patients or those with visual or manual dexterity disabilities. Although insulin devices offer benefits over the syringe and vial, features desirable in the ideal pen have not been established. Conclusions Data suggest that currently available insulin pens possess various features that make them suitable for particular patients. Individual needs of each patient should be considered before an insulin pen device is prescribed.