bluuebunny/crossref_metadata_2025_split huggingface dataset:
Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress
Authors: Jiang Chen Chen , Lucas Keryn , Avery-Kiejda Kelly A. , Wade Margaret , deBock Charles E. , Thorne Rick F. , Allen John , Hersey Peter , Zhang Xu Dong 
Published: August 2008

Abstract
We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress–induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress–induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1–deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Up-regulation of Mcl-1 was also due to increased transcription that involved the IRE1α and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress. [Cancer Res 2008;68(16):6708–17]
A Novel Diterpene Suppresses CWR22Rv1 Tumor Growth In vivo through Antiproliferation and Proapoptosis
Authors: Lin Feng-Min , Tsai Chin-Hsien , Yang Yu-Chih , Tu Wei-Chun , Chen Li-Ru , Liang Yun-Sa , Wang Sheng-Yang , Shyur Lie-Fen , Chien Shih-Chang , Cha Tai-Lung , Hsiao Pei-Wen 
Published: August 2008

Abstract
Androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers (PCa). As recurrent tumors restore AR activity independent of hormones, new therapies that abolish AR activity have been sought to prevent or delay the emergence of ablation-resistant disease. Here, we report that a novel abietane diterpene, 6-hydroxy-5,6-dehydrosugiol (HDHS), isolated from the stem bark of Cryptomeria japonica, was a potent AR antagonist in PCa cells. HDHS treatment of androgen-dependent LNCaP and androgen-responsive 22Rv1 cells induced apoptosis as shown by nucleosome release, activation of caspase-3 and caspase-7, and cleavage of poly(ADP-ribose) polymerase accompanied with concomitant up-regulation of tumor suppressor p53. HDHS also decreased the protein expression of cyclins (D1 and E), cyclin-dependent kinases (CDK2, CDK4, and CDK6), and retinoblastoma phosphorylation in PCa cells, which suggest cell cycle arrest in the G1 phase. Oral administration of HDHS at 0.5 and 2.5 mg/kg once daily for 24 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 22% and 39%, respectively, in association with decreased proliferation and increased apoptosis in tumor cells, which further correlated with increased levels of HDHS in plasma and tumors. Overall, our data suggest that HDHS has potential for use in chemoprevention and chemotherapy of PCa. [Cancer Res 2008;68(16):6634–42]
Focal Gains of VEGFA and Molecular Classification of Hepatocellular Carcinoma
Authors: Chiang Derek Y. , Villanueva Augusto , Hoshida Yujin , Peix Judit , Newell Philippa , Minguez Beatriz , LeBlanc Amanda C. , Donovan Diana J. , Thung Swan N. , Solé Manel , Tovar Victoria , Alsinet Clara , Ramos Alex H. , Barretina Jordi , Roayaie Sasan , Schwartz Myron , Waxman Samuel , Bruix Jordi , Mazzaferro Vincenzo , Ligon Azra H. , Najfeld Vesna , Friedman Scott L. , Sellers William R. , Meyerson Matthew , Llovet Josep M. 
Published: August 2008

Abstract
Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non–cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including “CTNNB1”, “proliferation”, “IFN-related”, a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the “CTNNB1” class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the “proliferation” class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies. [Cancer Res 2008;68(16):6779–88]
Suppression of Inhibitor of Differentiation 2, a Target of Mutant p53, Is Required for Gain-of-Function Mutations
Authors: Yan Wensheng , Liu Gang , Scoumanne Ariane , Chen Xinbin 
Published: August 2008

Abstract
Overexpression of mutant p53 is a common theme in human tumors, suggesting a tumor-promoting gain-of-function for mutant p53. To elucidate whether and how mutant p53 acquires its gain-of-function, mutant p53 is inducibly knocked down in the SW480 colon cancer cell line, which contains mutant p53(R273H/P309S), and the MIA PaCa-2 pancreatic cancer cell line, which contains mutant p53(R248W). We found that knockdown of mutant p53 markedly inhibits cell proliferation. In addition, knockdown of mutant p53 sensitizes tumor cells to growth suppression by various chemotherapeutic drugs. To determine whether a gene involved in cell growth and survival is regulated by mutant p53, gene expression profiling analysis was performed and showed that the expression level of Id2, a member of the inhibitor of differentiation (Id) family, was markedly increased upon knockdown of mutant p53. To confirm this, Northern blot analysis was performed and showed that the expression level of Id2 was regulated by various mutant p53s in multiple cell lines. In addition, we found that the Id2 promoter is responsive to mutant but not wild-type p53, and mutant p53 binds to the Id2 promoter. Consistent with these observations, expression of endogenous Id2 was found to be inhibited by exogenous mutant p53 in p53-null HCT116 cells. Finally, we showed that knockdown of Id2 can restore the proliferative potential of tumor cells inhibited by withdrawal of mutant p53. Together, these findings suggest that one mechanism by which mutant p53 acquires its gain-of-function is through the inhibition of Id2 expression. [Cancer Res 2008;68(16):6789–96]
Mouse Mesenchymal Stem Cells Expressing PAX-FKHR Form Alveolar Rhabdomyosarcomas by Cooperating with Secondary Mutations
Authors: Ren Yue-Xin , Finckenstein Friedrich Graf , Abdueva Diana A. , Shahbazian Violette , Chung Brile , Weinberg Kenneth I. , Triche Timothy J. , Shimada Hiroyuki , Anderson Michael J. 
Published: August 2008

Abstract
Alveolar rhabdomyosarcomas (ARMS) are highly malignant soft-tissue sarcomas that arise in children, adolescents, and young adults. Although formation and expression of the PAX-FKHR fusion genes is thought to be the initiating event in this cancer, the role of PAX-FKHR in the neoplastic process remains largely unknown in a progenitor cell that is undefined. We hypothesize that PAX-FKHR determine the ARMS progenitor to the skeletal muscle lineage, which when coupled to the inactivation and/or activation of critical cell signaling pathways leads to the formation of ARMS. Because a number of studies have proposed that mesenchymal stem cells (MSC) are the progenitor for several of the sarcomas, we tested this hypothesis in MSCs. We show that PAX-FKHR induce skeletal myogenesis in MSCs by transactivating MyoD and myogenin. Despite exhibiting enhanced growth in vitro, the PAX-FKHR–expressing populations do not form colonies in soft agar or tumors in mice. Expression of dominant-negative p53, or the SV40 early region, elicits tumor formation in some of the PAX-FKHR–expressing populations. Additional activation of the Ras signaling pathway leads to highly malignant tumor formation for all of the populations. The PAX-FKHR–expressing tumors were shown to have histologic, immunohistochemical, and gene expression profiles similar to human ARMS. Our results show the critical role played by PAX-FKHR in determining the molecular, myogenic, and histologic phenotype of ARMS. More importantly, we identify MSCs as a progenitor that can give rise to ARMS. [Cancer Res 2008;68(16):6587–97]
Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging
Authors: Schnell Christian R. , Stauffer Frédéric , Allegrini Peter R. , O'Reilly Terence , McSheehy Paul M.J. , Dartois Celine , Stumm Michael , Cozens Robert , Littlewood-Evans Amanda , García-Echeverría Carlos , Maira Sauveur-Michel 
Published: August 2008

Abstract
Dysregulated angiogenesis and high tumor vasculature permeability, two vascular endothelial growth factor (VEGF)-mediated processes and hallmarks of human tumors, are in part phosphatidylinositol 3-kinase (PI3K) dependent. NVP-BEZ235, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, was found to potently inhibit VEGF-induced cell proliferation and survival in vitro and VEGF-induced angiogenesis in vivo as shown with s.c. VEGF-impregnated agar chambers. Moreover, the compound strongly inhibited microvessel permeability both in normal tissue and in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Similarly, tumor interstitial fluid pressure, a phenomenon that is also dependent of tumor permeability, was significantly reduced by NVP-BEZ235 in a dose-dependent manner on p.o. administration. Because RAD001, a specific mTOR allosteric inhibitor, was ineffective in the preceding experiments, we concluded that the effects observed for NVP-BEZ235 are in part driven by PI3K target modulation. Hence, tumor vasculature reduction was correlated with full blockade of endothelial nitric oxide (NO) synthase, a PI3K/Akt-dependent but mTORC1-independent effector involved in tumor permeability through NO production. In the BN472 tumor model, early reduction of permeability, as detected by Ktrans quantification using the dynamic contrast-enhanced magnetic resonance imaging contrasting agent P792 (Vistarem), was found to be a predictive marker for late-stage antitumor activity by NVP-BEZ235. [Cancer Res 2008;68(16):6598–607]
K-Ras Nanoclustering Is Subverted by Overexpression of the Scaffold Protein Galectin-3
Authors: Shalom-Feuerstein Ruby , Plowman Sarah J. , Rotblat Barak , Ariotti Nicholas , Tian Tianhai , Hancock John F. , Kloog Yoel 
Published: August 2008

Abstract
The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction. The mechanism underlying K-Ras nanoclustering is unknown. We show here that K-Ras.GTP recruits Galectin-3 (Gal-3) from the cytosol to the plasma membrane where it becomes an integral nanocluster component. Importantly, we show that the cytosolic level of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. The β-sheet layers of the Gal-3 carbohydrate recognition domain contain a hydrophobic pocket that may accommodate the farnesyl group of K-Ras. V125A substitution within this hydrophobic pocket yields a dominant negative Gal-3(V125A) mutant that inhibits K-Ras activity. Gal-3(V125A) interaction with K-Ras.GTP reduces K-Ras.GTP nanocluster formation, which abrogates signal output from the Raf/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) pathway. Gal-3(V125A) negatively regulates cell growth and reduces cellular transformation. Thus, regulation of K-Ras nanocluster formation and signal output by Gal-3 critically depends on the integrity of the Gal-3 hydrophobic pocket. These results show that Gal-3 overexpression in breast cancer cells, which increases K-Ras signal output, represents oncogenic subversion of plasma membrane nanostructure. [Cancer Res 2008;68(16):6608–16]
A Novel Acetylenic Tricyclic bis-(Cyano Enone) Potently Induces Phase 2 Cytoprotective Pathways and Blocks Liver Carcinogenesis Induced by Aflatoxin
Authors: Liby Karen , Yore Mark M. , Roebuck Bill D. , Baumgartner Karen J. , Honda Tadashi , Sundararajan Chitra , Yoshizawa Hidenori , Gribble Gordon W. , Williams Charlotte R. , Risingsong Renee , Royce Darlene B. , Dinkova-Kostova Albena T. , Stephenson Katherine K. , Egner Patricia A. , Yates Melinda S. , Groopman John D. , Kensler Thomas W. , Sporn Michael B. 
Published: August 2008

Abstract
A novel acetylenic tricyclic bis-(cyano enone), TBE-31, is a lead compound in a series of tricyclic compounds with enone functionalities in rings A and C. Nanomolar concentrations of this potent multifunctional molecule suppress the induction of the inflammatory protein, inducible nitric oxide synthase, activate phase 2 cytoprotective enzymes in vitro and in vivo, block cell proliferation, and induce differentiation and apoptosis of leukemia cells. Oral administration of TBE-31 also significantly reduces formation of aflatoxin-DNA adducts and decreases size and number of aflatoxin-induced preneoplastic hepatic lesions in rats by &gt;90%. Because of the two cyano enones in rings A and C, TBE-31 may directly interact with DTT and protein targets such as Keap1 that contain reactive cysteine residues. The above findings suggest that TBE-31 should also be tested for chemoprevention and chemotherapy in relevant models of cancer and against other chronic, degenerative diseases in which inflammation and oxidative stress contribute to disease pathogenesis. [Cancer Res 2008;68(16):6727–33]
Numerical Simulations of the Formation of Hurricane Gabrielle (2001)
Authors: Musgrave K. D. , Davis C. A. , Montgomery M. T. 
Published: August 2008

Abstract
This study examines the formation of Hurricane Gabrielle (2001), focusing on whether an initial disturbance and vertical wind shear were favorable for development. This examination is performed by running numerical experiments using the fifth-generation Pennsylvania State University–National Center for Atmospheric Research Mesoscale Model (MM5). Gabrielle is chosen as an interesting case to study since it formed in the subtropics only a few days before making landfall in Florida. Three simulations are run: a control run and two sensitivity experiments. The control run is compared with observations to establish the closeness of the model output to Gabrielle’s observed formation. The two sensitivity experiments are designed to test the response of the developing tropical cyclone to alterations in the initial conditions. The first sensitivity experiment removes the initial (or precursor) disturbance, a midtropospheric vortex located over Florida. The second sensitivity experiment reduces the vertical wind shear over the area of formation. The control run produces a system comparable to Gabrielle. The convection in the control run is consistently located downshear of the center of circulation. In the first sensitivity experiment, with the removal of the initial disturbance, no organized system develops. This indicates the importance of the midtropospheric vortex in Gabrielle’s formation. The second sensitivity experiment, which reduces the vertical wind shear over the area of Gabrielle’s formation, produces a system that can be identified as Gabrielle. This system, however, is weaker than both the control run and the observations of Gabrielle. This study provides direct evidence of a favorable influence of modest vertical wind shear on the formation of a tropical cyclone in this case.
Error Covariance Modeling in the GMAO Ocean Ensemble Kalman Filter
Authors: Keppenne Christian L. , Rienecker Michele M. , Jacob Jossy P. , Kovach Robin 
Published: August 2008

Abstract
In practical applications of the ensemble Kalman filter (EnKF) for ocean data assimilation, the computational burden and memory limitations usually require a trade-off between ensemble size and model resolution. This is certainly true for the NASA Global Modeling and Assimilation Office (GMAO) ocean EnKF used for ocean climate analyses. The importance of resolution for the adequate representation of the dominant current systems means that small ensembles, with their concomitant sampling biases, have to be used. Hence, strategies have been sought to address sampling problems and to improve the performance of the EnKF for a given ensemble size. Approaches assessed herein consist of spatiotemporal filtering of background-error covariances, improving the system-noise representation, imposing a steady-state error covariance model, and speeding up the analysis by performing the most expensive operation of the analysis on a coarser computational grid. A judicious combination of these approaches leads to significant performance improvements, especially with very small ensembles.
The Boundary Layer Winds in Hurricanes Danielle (1998) and Isabel (2003)
Authors: Schwendike Juliane , Kepert Jeffrey D. 
Published: August 2008

Abstract
This paper describes the boundary layer wind structure and dynamics of Hurricanes Danielle (1998) and Isabel (2003), based on the analysis of high-resolution global positioning system dropwindsonde data and simulation of the flow by a three-dimensional boundary layer model produced by Kepert and Wang. The observations show that the hurricane boundary layer has a complex three-dimensional structure with large variability over small distances. The analysis emphasizes three aspects: the degree of gradient-wind balance, the radially varying depth of the boundary layer, and the strength of the near-surface wind speed relative to that at a higher level. Each aspect is compared both with results obtained in a simulation of the individual storm by Kepert and Wang’s model and with theoretical predictions. The observations show that the boundary layer depth decreases toward the center of the storm, consistent with theoretical arguments. The strongest azimuthal winds occur near the top of, but still within, the frictional inflow layer. These strong azimuthal winds are marginally supergradient in Hurricane Danielle but strongly so in Hurricane Isabel, where the imbalance amounts to approximately 10 m s−1 near the radius of maximum winds and is statistically significantly nonzero. This layer of supergradient flow is surmounted by a layer of outflow, in which the flow returns to gradient balance. The maximum storm-relative azimuthal wind occurs in the left front of Hurricane Danielle, and the strongest inflow is located in the right front. These asymmetries rotate anticyclonically with height, but there is also a clear wavenumber-2 asymmetry superimposed, which shows less rotation with height and is possibly forced by environmental factors associated with the storm’s impending recurvature. In Hurricane Isabel, the azimuthal wind maximum is located in the left rear and the inflow maximum in the left front, with neither showing much tendency to vary in azimuth with height. The ratio of the near-surface wind speed to that farther aloft increases toward the storm center for both storms. The largest values are located near the radius of maximum wind, and in general higher values are found on the left of the storm’s track than on the right. Simulations of the two storms with the boundary layer model are able to explain several of these factors; they also show some ability to reproduce individual dropsonde wind observed profiles. Important is that the model predicts weakly supergradient flow in Danielle and strongly supergradient flow in Isabel, in excellent agreement with the observational analysis. Based on these simulations, physical arguments, and earlier studies, the authors conclude that the differences between these storms in this respect result from their differing radial profiles of gradient wind and argue that the occurrence of supergradient flow in the upper boundary layer of individual hurricanes should be readily predictable.
On the Sensitivity Equations of Four-Dimensional Variational (4D-Var) Data Assimilation
Authors: Daescu Dacian N. 
Published: August 2008

Abstract
The equations of the forecast sensitivity to observations and to the background estimate in a four-dimensional variational data assimilation system (4D-Var DAS) are derived from the first-order optimality condition in unconstrained minimization. Estimation of the impact of uncertainties in the specification of the error statistics is considered by evaluating the sensitivity to the observation and background error covariance matrices. The information provided by the error covariance sensitivity analysis is used to identify the input components for which improved estimates of the statistical properties of the errors are of most benefit to the analysis and forecast. A close relationship is established between the sensitivities within each input pair data/error covariance such that once the observation and background sensitivities are available the evaluation of the sensitivity to the specification of the corresponding error statistics requires little additional computational effort. The relevance of the 4D-Var sensitivity equations to assess the data impact in practical applications is discussed. Computational issues are addressed and idealized 4D-Var experiments are set up with a finite-volume shallow-water model to illustrate the theoretical concepts. Time-dependent observation sensitivity and potential applications to improve the model forecast are presented. Guidance provided by the sensitivity fields is used to adjust a 4D-Var DAS to achieve forecast error reduction through assimilation of supplementary data and through an accurate specification of a few of the background error variances.