bluuebunny/crossref_metadata_2025_split huggingface dataset:
CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo
Authors: Wang Shih-Wei , Pan Shiow-Lin , Huang Yu-Chun , Guh Jih-Hwa , Chiang Po-Cheng , Huang Der-Yi , Kuo Sheng-Chu , Lee Kuo-Hsiung , Teng Che-Ming 
Published: February 2008

Abstract
Hepatocellular carcinoma is highly chemoresistant to currently available chemotherapeutic agents. In this study, 2′-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1), a synthetic 6,7-substituted 2-phenyl-4-quinolone, was identified as a potent and selective antitumor agent in human hepatocellular carcinoma. CHM-1 induced growth inhibition of HA22T, Hep3B, and HepG2 cells in a concentration-dependent manner but did not obviously impair the viability of normal cells at the IC50 for liver cancer cells. CHM-1-induced apoptosis was also characterized by immunofluorescence microscopy. CHM-1 interacted with tubulin at the colchicine-binding site, markedly inhibited tubulin polymerization both in vitro and in vivo, and disrupted microtubule organization. CHM-1 caused cell cycle arrest at G2-M phase by activating Cdc2/cyclin B1 complex activity. CHM-1-induced cell death, activation of Cdc2 kinase activity, and elevation of MPM2 phosphoepitopes were profoundly attenuated by roscovitine, a specific cyclin-dependent kinase inhibitor. CHM-1 did not modulate the caspase cascade, and the pan-caspase-inhibitor z-VAD-fmk did not abolish CHM-1-induced cell death. However, CHM-1 induced the translocation of apoptosis-inducing factor (AIF) from mitochondria to the nucleus. Small interfering RNA targeting of AIF substantially attenuated CHM-1-induced AIF translocation. Importantly, CHM-1 inhibited tumor growth and prolonged the lifespan in mice inoculated with HA22T cells. In conclusion, we show that CHM-1 exhibits a novel antimitotic antitumor activity against human hepatocellular carcinoma both in vitro and in vivo via a caspase-independent pathway. CHM-1 is a promising chemotherapeutic agent worthy of further development into a clinical trial candidate for treating cancer, especially hepatocellular carcinoma. [Mol Cancer Ther 2008;7(2):350–60]
Growth inhibition by STI571 in combination with radiation in human chronic myelogenous leukemia K562 cells
Authors: Huguet Florence , Giocanti Nicole , Hennequin Christophe , Croisy Martine , Touboul Emmanuel , Favaudon Vincent 
Published: February 2008

Abstract
Altered radiation responses by STI571 (Imatinib, Glivec), a specific inhibitor of the tyrosine kinase activity of Bcr-Abl, was assessed in K562 chronic myelogenous leukemia cells using growth inhibition and colony formation assays. Flow cytometry, Western blotting, and microscope observation were used to determine cell cycle redistribution, erythroid differentiation, apoptosis, necrosis, senescence, and expression and phosphorylation of effectors downstream from Bcr-Abl as endpoints. STI571 (≥24-h contact) retarded the growth of K562 cells and elicited reduction in the G2-phase content due to an efficient arrest in early S phase rather than to the disruption of the G2 checkpoint as confirmed by analysis of Lyn and CDK1 phosphorylation. STI571 brought about the inhibitory dephosphorylation of Bcr-Abl and STAT5, but the expression of DNA-PKcs and Rad51 was unaffected and the interaction between radiation and STI571 was strictly additive with regard to induction of apoptosis. Overall STI571 interacted cooperatively with radiation to retard the growth of K562 cells but did not affect intrinsic radiosensitivity. However, STI571 and radiation acted antagonistically with each other with regard to induction of senescence and erythroid differentiation. [Mol Cancer Ther 2008;7(2):398–406]
Preclinical pharmacokinetic/pharmacodynamic models of gefitinib and the design of equivalent dosing regimens in EGFR wild-type and mutant tumor models
Authors: Wang Shining , Guo Ping , Wang Xiaomin , Zhou Qingyu , Gallo James M. 
Published: February 2008

Abstract
Epidermal growth factor receptor (EGFR) inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic (PG) dimension to any pharmacokinetic (PK) and pharmacodynamic (PD) analysis. The goal of this investigation was to cast the combined PG/PK/PD variables into models that could be used to design equivalent PK/PD dosing regimens for gefitinib in genetically distinct tumor models. To this end, groups of mice bearing either s.c. LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors, an EGFR inhibitor-sensitizing mutation, were given gefitinib at doses of 10 mg/kg i.v., 50 mg/kg intraarterially, and 150 mg/kg p.o. In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral amounts of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (pERK), a PD end point that was shown to respond in a dose-dependent manner in each tumor type. Hybrid physiologically based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration profile, a tumor compartment depicting drug disposition in tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multiple-dose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. The novel concept of PK/PD equivalent dosing regimens could be applied in drug development and to delineate PG differences in drug activity. [Mol Cancer Ther 2008;7(2):407–17]
Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling
Authors: Yacoub Adly , Gupta Pankaj , Park Margaret A. , Rhamani Mohammed , Hamed Hossein , Hanna David , Zhang Guo , Sarkar Devanand , Lebedeva Irina V. , Emdad Luni , Koumenis Costas , Curiel David T. , Grant Steven , Fisher Paul B. , Dent Paul 
Published: February 2008

Abstract
The present studies defined the biological effects of a GST fusion protein of melanoma differentiation-associated gene-7 (mda-7), GST-MDA-7 (1 and 30 nmol/L), on cell survival and cell signaling in primary human glioma cells in vitro. GST-MDA-7, in a dose- and time-dependent fashion killed glioma cells with diverse genetic characteristics; 1 nmol/L caused arrest without death, whereas 30 nmol/L caused arrest and killing after exposure. Combined inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT function was required to enhance 1 nmol/L GST-MDA-7 lethality in all cell types, whereas combined activation of MEK1 and AKT was required to suppress 30 nmol/L GST-MDA-7 lethality; both effects are mediated in part by modulating c-Jun NH2-terminal kinase (JNK) 1-3 activity. The geldanamycin 17AAG inhibited AKT and ERK1/2 in GBM cells and enhanced GST-MDA-7 lethality. JNK1-3 signaling promoted BAX activation and mitochondrial dysfunction. In GBM6 cells, GST-MDA-7 (30 nmol/L) transiently activated p38 mitogen-activated protein kinase, which was modestly protective against JNK1-3-induced toxicity, whereas GST-MDA-7 (300 nmol/L) caused prolonged intense p38 mitogen-activated protein kinase activation, which promoted cell death. In GBM12 cells that express full-length mutant activated ERBB1, inhibition of ERBB1 did not modify GST-MDA-7 lethality; however, in U118 established glioma cells, stable overexpression of wild-type ERBB1 and/or truncated active ERBB1vIII suppressed GST-MDA-7 lethality. Our data argue that combined inhibition of ERK1/2 and AKT function, regardless of genetic background, promotes MDA-7 lethality in human primary human glioma cells via JNK1-3 signaling and is likely to represent a more ubiquitous approach to enhancing MDA-7 toxicity in this cell type than inhibition of ERBB1 function. [Mol Cancer Ther 2008;7(2):314–29]
Association Analysis of Allelic Variants of USF1 in Coronary Atherosclerosis
Authors: Kristiansson Kati , Ilveskoski Erkki , Lehtimäki Terho , Peltonen Leena , Perola Markus , Karhunen Pekka J. 
Published: February 2008

Objective—USF1 regulates the transcription of more than 40 cardiovascular related genes and is well established as a gene associated with familial combined hyperlipidemia, a condition increasing the risk for coronary heart disease. No detailed data, however, exists on the impact of this gene to the critical outcome at the tissue level: different types of atherosclerotic lesions.Methods and Results—We analyzed the USF1 in 2 autopsy series of altogether 700 middle-aged men (the Helsinki Sudden Death Study) with quantitative morphometric measurements of coronary atherosclerosis. SNPrs2516839, tagging common USF1 haplotypes, associated with the presence of several types of atherosclerotic lesions, particularly with the proportion of advanced atherosclerotic plaques (P=0.02) and area of calcified lesions (P<0.001) of the coronary arteries. Importantly, carriers of risk alleles ofrs2516839also showed a 2-fold risk for sudden cardiac death (genotype TT versus CC; OR 2.10, 95% CI 1.17 to 3.75,P=0.04). The risk effect ofrs2516839was present also in aorta samples of the men.Conclusions—Our findings in this unique study sample suggest that USF1 contributes to atherosclerosis, the pathological arterial wall phenotype resulting in coronary heart disease and in its most dramatic consequence—sudden cardiac death.
Revisiting Low and List (1982): Evaluation of Raindrop Collision Parameterizations Using Laboratory Observations and Modeling
Authors: Barros Ana P. , Prat Olivier P. , Shrestha Prabhakar , Testik Firat Y. , Bliven Larry F. 
Published: February 2008

Abstract
Raindrop collision and breakup is a stochastic process that affects the evolution of drop size distributions (DSDs) in precipitating clouds. Low and List have remained the obligatory reference on this matter for almost three decades. Based on a limited number of drop sizes (10), Low and List proposed generalized parameterizations of collisional breakup across the raindrop spectra that are standard building blocks for numerical models of rainfall microphysics. Here, recent laboratory experiments of drop collision at NASA’s Wallops Island Facility (NWIF) using updated high-speed imaging technology with the objective of assessing the generality of Low and List are reported. The experimental fragment size distributions (FSDs) for the collision of selected drop pairs were evaluated against explicit simulations using a dynamical microphysics model (Prat and Barros, with parameterizations based on Low and List updated by McFarquhar). One-to-one comparison of the FSDs shows similar distributions; however, the model was found to underestimate the fragment numbers observed in the smallest diameter range (e.g., D &lt; 0.2 mm), and to overestimate the number of fragments produced when small drops (diameter DS ≥ 1mm) and large drops (diameter DL ≥ 3mm) collide. This effect is particularly large for fragments in the 0.5–1.0-mm range, and more so for filament breakup (the most frequent type of breakup observed in laboratory conditions), reflecting up to 30% uncertainty in the left-hand side of the FSD (i.e., the submillimeter range). For coalescence, the NWIF experiments confirmed the drop collision energy cutoff (ET) estimated by Low and List (i.e., ET &gt; 5.0 μJ). Finally, the digital imagery of the laboratory experiments was analyzed to determine the characteristic time necessary to reach stability in relevant statistical properties. The results indicate that the temporal separation between particle (i.e., single hydrometeor) and population behavior, that is, the characteristic time scale to reach homogeneity in the NWIF raindrop populations, is 160 ms, which provides a lower bound to the governing time scale in population-based microphysical models.
Geographical Variations of the Influence of Low-Frequency Variability on Lower-Tropospheric Extreme Westerly Wind Events
Authors: Yin Jeffrey H. , Branstator Grant W. 
Published: February 2008

Abstract
A conceptual framework is developed for quantifying the relationship between low-frequency variability and extreme events. In this framework, variability is decomposed into low-frequency and synoptic components using complementary 10-day low-pass and high-pass filters, and a distinction is made between two ways that low-frequency variability influences extremes: the additive effect, which neglects the dependence of synoptic variability on the low-frequency state, and the multiplicative effect, which is due to the dependence of synoptic variability on the low-frequency state. The influence of various factors on the relationship between low-frequency variability and extreme events is decomposed and quantified by generating a series of simple synthetic datasets based on different assumptions about low-frequency and synoptic variability and their relationship.
These techniques are used to study the relationship between low-frequency variability and extreme westerly wind events in three datasets, an 1158-yr GCM simulation and two reanalysis datasets, with similar results for all three. Geographical variations in the low-frequency–extreme relationship are only partially explained by geographical variations in the low-frequency–synoptic variance ratio; the non-Gaussianity of low-frequency and synoptic variability and the relationship between synoptic variance and the low-frequency state are also found to be important. The simple synthetic datasets that include these factors provide good estimates of the magnitude and probability of extremes. Implications for predictability and applications to more complex low-frequency–extreme relationships are discussed.
Interdecadal Variability of Western North Pacific Tropical Cyclone Tracks
Authors: Liu Kin Sik , Chan Johnny C. L. 
Published: February 2008

Abstract
This study examines the interdecadal variability of the tropical cyclone (TC) tracks over the western North Pacific (WNP) during the 1960–2005 period. An empirical orthogonal function analysis of the 10-yr Gaussian-filtered annual frequency of TC occurrence shows three leading modes of TC occurrence patterns. The first mode is related to the variation of TC activity in the areas near Japan and its east. The second mode is characterized by a northeast–southwest dipole of TC occurrence anomalies along the southeast coast of China and an east–west dipole near Japan and its east. The third mode is similar to the second mode, except for the absence of the east–west dipole. These patterns are shown to be related to the decadal changes in the prevailing TC tracks.
Two characteristic flow patterns related to the first and third modes of TC occurrence pattern are identified. The first pattern is characterized by a north–south dipole of 500-hPa geopotential anomalies over the WNP. Such a pattern may affect the strength and westward extension of the subtropical high and the midlevel steering flow and hence the TC occurrence pattern. The Pacific decadal oscillation (PDO) is found to display a similar dipole-like structure. The decadal variability of TC tracks may therefore be partly attributed to the PDO signal. The second characteristic pattern shows a series of anomalous midlevel atmospheric circulations extending from the sea east of Japan to the south coast of China, which may explain the other part of the decadal variations.
The Diurnal Cycle of Clouds and Precipitation along the Sierra Madre Occidental Observed during NAME-2004: Implications for Warm Season Precipitation Estimation in Complex Terrain
Authors: Nesbitt Stephen W. , Gochis David J. , Lang Timothy J. 
Published: February 2008

AbstractThis study examines the spatial and temporal variability in the diurnal cycle of clouds and precipitation tied to topography within the North American Monsoon Experiment (NAME) tier-I domain during the 2004 NAME enhanced observing period (EOP, July–August), with a focus on the implications for high-resolution precipitation estimation within the core of the monsoon. Ground-based precipitation retrievals from the NAME Event Rain Gauge Network (NERN) and Colorado State University–National Center for Atmospheric Research (CSU–NCAR) version 2 radar composites over the southern NAME tier-I domain are compared with satellite rainfall estimates from the NOAA Climate Prediction Center Morphing technique (CMORPH) and Precipitation Estimation from Remotely Sensed Information Using Artificial Neural Networks (PERSIANN) operational and Tropical Rainfall Measuring Mission (TRMM) 3B42 research satellite estimates along the western slopes of the Sierra Madre Occidental (SMO). The rainfall estimates are examined alongside hourly images of high-resolution Geostationary Operational Environmental Satellite (GOES) 11-μm brightness temperatures.An abrupt shallow to deep convective transition is found over the SMO, with the development of shallow convective systems just before noon on average over the SMO high peaks, with deep convection not developing until after 1500 local time on the SMO western slopes. This transition is shown to be contemporaneous with a relative underestimation (overestimation) of precipitation during the period of shallow (deep) convection from both IR and microwave precipitation algorithms due to changes in the depth and vigor of shallow clouds and mixed-phase cloud depths. This characteristic life cycle in cloud structure and microphysics has important implications for ice-scattering microwave and infrared precipitation estimates, and thus hydrological applications using high-resolution precipitation data, as well as the study of the dynamics of convective systems in complex terrain.
Platform Motion Effects on Measurements of Turbulence and Air–Sea Exchange over the Open Ocean
Authors: Miller Scott D. , Hristov Tihomir S. , Edson James B. , Friehe Carl A. 
Published: February 2008

AbstractPlatform motion contaminates turbulence statistics measured in the surface layer over the ocean and therefore adds uncertainty to the understanding and parameterization of air–sea exchange. A modification to the platform motion–correction procedure of Edson et al. is presented that explicitly accounts for misalignment between anemometers and motion sensors. The method is applied to a high-resolution dataset, including four levels of turbulence within 20 m of the ocean surface, measured over deep ocean waves using the stable research platform R/P FLIP. The average error magnitude of the air–sea momentum flux (wind stress) from the four sensors during a 6-day period (10-m wind speed 2–14 m s−1) was 15% ± 1%, and varied systematically with measurement height. Motion and sensor-mounting offsets caused wind stress to be underestimated by 15% at 18.1 m, 13% at 13.8 m, and 11% at 8.7 m, and to be overestimated by 3% at 3.5 m. Sensor misalignment contributed to one-third of the correction to the wind stress. The motion correction reduced some measured artifacts in the wind that could otherwise be interpreted in terms of air–sea interaction, such as the angle between wind and wind stress vectors, while other features remained in the corrected wind, such as apparent upward momentum transfer from ocean to the atmosphere during low wind. These results demonstrate the complex interaction between motion and wind turbulence, and reinforce the necessity to measure and correct for platform motion. Finally, it is shown that the effects of motion on wind stress measured using R/P FLIP are much smaller than in situ measurements made using a conventional research ship.
Climatology of High Wind Events in the Owens Valley, California
Authors: Zhong Shiyuan , Li Ju , Whiteman C. David , Bian Xindi , Yao Wenqing 
Published: February 2008

AbstractThe climatology of high wind events in the Owens Valley, California, a deep valley located just east of the southern Sierra Nevada, is described using data from six automated weather stations distributed along the valley axis in combination with the North American Regional Reanalysis dataset. Potential mechanisms for the development of strong winds in the valley are examined.Contrary to the common belief that strong winds in the Owens Valley are westerly downslope windstorms that develop on the eastern slope of the Sierra Nevada, strong westerly winds are rare in the valley. Instead, strong winds are highly bidirectional, blowing either up (northward) or down (southward) the valley axis. High wind events are most frequent in spring and early fall and they occur more often during daytime than during nighttime, with a peak frequency in the afternoon. Unlike thermally driven valley winds that blow up valley during daytime and down valley during nighttime, strong winds may blow in either direction regardless of the time of the day. The southerly up-valley winds appear most often in the afternoon, a time when there is a weak minimum of northerly down-valley winds, indicating that strong wind events are modulated by local along-valley thermal forcing.Several mechanisms, including downward momentum transfer, forced channeling, and pressure-driven channeling all play a role in the development of southerly high wind events. These events are typically accompanied by strong south-southwesterly synoptic winds ahead of an upper-level trough off the California coast. The northerly high wind events, which typically occur when winds aloft are from the northwest ahead of an approaching upper-level ridge, are predominantly caused by the passage of a cold front when fast-moving cold air behind the surface front undercuts and displaces the warmer air in the valley. Forced channeling by the sidewalls of the relatively narrow valley aligns the wind direction with the valley axis and enhances the wind speeds.