bluuebunny/crossref_metadata_2025_split huggingface dataset:
Natural BH3 mimetic (-)-gossypol chemosensitizes human prostate cancer via Bcl-xL inhibition accompanied by increase of Puma and Noxa
Authors: Meng Yang , Tang Wenhua , Dai Yao , Wu Xiaoqing , Liu Meilan , Ji Qing , Ji Min , Pienta Kenneth , Lawrence Theodore , Xu Liang 
Published: July 2008

AbstractAntiapoptotic members of the Bcl-2 family proteins are overexpressed in prostate cancer and are promising molecular targets for modulating chemoresistance of prostate cancer. (-)-Gossypol, a natural BH3 mimetic, is a small-molecule inhibitor of Bcl-2/Bcl-xL/Mcl-1 currently in phase II clinical trials as an adjuvant therapy for human prostate cancer. Our objective is to examine the chemosensitization potential of (-)-gossypol in prostate cancer and its molecular mechanisms of action. (-)-Gossypol inhibited cell growth and induced apoptosis through mitochondria pathway in human prostate cancer PC-3 cells and synergistically enhanced the antitumor activity of docetaxel both in vitro and in vivo in PC-3 xenograft model in nude mouse. (-)-Gossypol blocked the interactions of Bcl-xL with Bax or Bad in cancer cells by fluorescence resonance energy transfer assay and overcame the Bcl-xL protection of FL5.12 model cells on interleukin-3 withdrawal. Western blot and real-time PCR studies showed that a dose-dependent increase of the proapoptotic BH3-only proteins Noxa and Puma contributed to the cell death induced by (-)-gossypol and to the synergistic effects of (-)-gossypol and docetaxel. The small interfering RNA knockdown studies showed that Noxa and Puma are required in the (-)-gossypol-induced cell death. Taken together, these data suggest that (-)-gossypol exerts its antitumor activity through inhibition of the antiapoptotic protein Bcl-xL accompanied by an increase of proapoptotic Noxa and Puma. (-)-Gossypol significantly enhances the antitumor activity of chemotherapy in vitro and in vivo, representing a promising new regime for the treatment of human hormone-refractory prostate cancer with Bcl-2/Bcl-xL/Mcl-1 overexpression. [Mol Cancer Ther 2008;7(7):2192–202]
Destabilization of ERBB2 Transcripts by Targeting 3′ Untranslated Region Messenger RNA Associated HuR and Histone Deacetylase-6
Authors: Scott Gary K. , Marx Corina , Berger Crystal E. , Saunders Laura R. , Verdin Eric , Schäfer Stefan , Jung Manfred , Benz Christopher C. 
Published: July 2008

Abstract
In addition to repressing ERBB2 promoter function, histone deacetylase (HDAC) inhibitors induce the accelerated decay of mature ERBB2 transcripts; the mechanism mediating this transcript destabilization is unknown but depends on the 3′ untranslated region (UTR) of ERBB2 mRNA. Using ERBB2-overexpressing human breast cancer cells (SKBR3), the mRNA stability factor HuR was shown to support ERBB2 transcript integrity, bind and endogenously associate with a conserved U-rich element within the ERBB2 transcript 3′ UTR, coimmunoprecipitate with RNA-associated HDAC activity, and colocalize with HDAC6. HDAC6 also coimmunoprecipitates with HuR in an RNA-dependent manner and within 6 hours of exposure to a pan-HDAC inhibitor dose, that does not significantly alter cytosolic HuR levels or HuR binding to ERBB2 mRNA. Cellular ERBB2 transcript levels decline while remaining physically associated with HDAC6. Knockdown of HDAC6 protein by small interfering RNA partially suppressed the ERBB2 transcript decay induced by either pan-HDAC or HDAC6-selective enzymatic inhibitors. Three novel hydroxamates, ST71, ST17, and ST80 were synthesized and shown to inhibit HDAC6 with 14-fold to 31-fold greater selectivity over their binding and inhibition of HDAC1. Unlike more potent pan-HDAC inhibitors, these HDAC6-selective inhibitors produced dose-dependent growth arrest of ERBB2-overexpressing breast cancer cells by accelerating the decay of mature ERBB2 mRNA without repressing ERBB2 promoter function. In sum, these findings point to the therapeutic potential of HuR and HDAC6-selective inhibitors, contrasting ERBB2 stability effects induced by HDAC6 enzymatic inhibition and HDAC6 protein knockdown, and show that ERBB2 transcript stability mechanisms include exploitable targets for the development of novel anticancer therapies. (Mol Cancer Res 2008;6(7):1250–8)
Tumor-Derived Extracellular Mutations of PTPRT/PTPρ Are Defective in Cell Adhesion
Authors: Yu Jianshi , Becka Scott , Zhang Peng , Zhang Xiaodong , Brady-Kalnay Susann M. , Wang Zhenghe 
Published: July 2008

Abstract
Receptor protein tyrosine phosphatase T (PTPRT/PTPρ) is frequently mutated in human cancers including colon, lung, gastric, and skin cancers. More than half of the identified tumor-derived mutations are located in the extracellular part of PTPρ. However, the functional significance of those extracellular domain mutations remains to be defined. Here we report that the extracellular domain of PTPρ mediates homophilic cell-cell aggregation. This homophilic interaction is very specific because PTPρ does not interact with its closest homologue, PTPμ, in a cell aggregation assay. We further showed that all five tumor-derived mutations located in the NH2-terminal MAM and immunoglobulin domains impair, to varying extents, their ability to form cell aggregates, indicating that those mutations are loss-of-function mutations. Our results suggest that PTPρ may play an important role in cell-cell adhesion and that mutational inactivation of this phosphatase could promote tumor migration and metastasis. (Mol Cancer Res 2008;6(7):1106–13)
Transforming Growth Factor-β–Mediated Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Expression and Apoptosis in Hepatoma Cells Requires Functional Cooperation between Smad Proteins and Activator Protein-1
Authors: Herzer Kerstin , Grosse-Wilde Anne , Krammer Peter H. , Galle Peter R. , Kanzler Stephan 
Published: July 2008

Abstract
Transforming growth factor-β (TGF-β) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. We recently identified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-β–induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-β up-regulates TRAIL expression. The 5′-flanking region of the TRAIL gene was isolated and characterized. Deletion mutants of the 5′-untranslated region of the TRAIL gene revealed a region comprising nucleotides −1950 to −1100 responsible for TRAIL induction following treatment with TGF-β. Within this region, we have identified an activator protein-1 (AP-1) site indispensable for TGF-β–mediated induction of TRAIL. Activation of this AP-1 site is mediated by a JunD·FosB heterodimer. Expression of DNSmad4, DNJunD, or DNFosB significantly impairs TGF-β–mediated activation of the TRAIL promoter. Furthermore, with tRNA interference targeting Smad4, junD, FosB, we could abolish TRAIL expression and, subsequently, TGF-β–induced TRAIL-mediated apoptosis in hepatoma cells. Our results reveal a new AP-1 site within the TRAIL promoter functionally involved in TGF-β–induced TRAIL expression and apoptosis in hepatomas and thus provide evidence for the underlying mechanism by which TGF-β might regulate cell death in liver cancer. (Mol Cancer Res 2008;6(7):1169–77)
The Pak4 Protein Kinase Plays a Key Role in Cell Survival and Tumorigenesis in Athymic Mice
Authors: Liu Yingying , Xiao Hang , Tian Yanmei , Nekrasova Tanya , Hao Xingpei , Lee Hong Jin , Suh Nanjoo , Yang Chung S. , Minden Audrey 
Published: July 2008

Abstract
Pak4 is a member of the B group of p21-activated (Pak) kinases, originally identified as an effector protein for Cdc42. Although Pak4 is expressed at low levels in most adult tissues, it is highly overexpressed in tumor cell lines. Here, we show that Pak4 is also overexpressed in primary tumors, including colon, esophageal, and mammary tumors. Overexpression of Pak4 also leads to tumor formation in athymic mice, whereas deletion of Pak4 inhibits tumorigenesis. Although a constitutively active Pak4 mutant was previously shown to promote oncogenic transformation in cultured cells, our results are the first to show that Pak4 also promotes tumorigenesis in experimental animals. Furthermore, these results show for the first time that not only constitutively active Pak4, but also wild-type Pak4, is transforming, when experimental animals are used. These results are highly significant because wild-type Pak4, rather than activated Pak4, is overexpressed in tumor cells. Our results suggest that overexpression or activation of Pak4 is a key step in oncogenic transformation, due to its ability to promote cell survival and subsequent uncontrolled proliferation. The finding that Pak4 is up-regulated in so many types of cancers indicates that Pak4 may play a vital role in a wide range of different types of cancer. This makes it an attractive candidate for drug therapy for different types of cancer. (Mol Cancer Res 2008;6(7):1215–24)
Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells
Authors: Liu Pei-Yao , Chan James Yi-Hsin , Lin Hsiu-Chen , Wang Sung-Ling , Liu Shu-Ting , Ho Ching-Liang , Chang Li-Chien , Huang Shih-Ming 
Published: July 2008

Abstract
Zac1 is a novel seven–zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21WAF1/Cip1 promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21WAF1/Cip1 gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A–induced p21WAF1/Cip1 protein expression might be mediated through a p53-independent and HDAC deacetylase–independent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21WAF1/Cip1 gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells. (Mol Cancer Res 2008;6(7):1204–14)
3D Chaotic Model for Subgrid Turbulent Dispersion in Large Eddy Simulations
Authors: Lacorata Guglielmo , Mazzino Andrea , Rizza Umberto 
Published: July 2008

Abstract
A 3D multiscale kinematic velocity field is introduced as a model to simulate Lagrangian turbulent dispersion. The incompressible velocity field is a nonlinear deterministic function, periodic in space and time, that generates chaotic mixing of Lagrangian trajectories. Relative dispersion properties, for example Richardson’s law, are correctly reproduced under two basic conditions: 1) the velocity amplitudes of the spatial modes must be related to the corresponding wavelengths through the Kolmogorov scaling and 2) the problem of the lack of a “sweeping effect” of the small eddies by the large eddies, common to kinematic simulations, has to be taken into account. It is shown that, as far as Lagrangian dispersion is concerned, the model presented herein can be successfully applied as an additional subgrid contribution for large eddy simulations of the planetary boundary layer flow.
Stably Stratified Flows: A Model with No Ri(cr)*
Authors: Canuto V. M. , Cheng Y. , Howard A. M. , Esau I. N. 
Published: July 2008

Abstract
A large set of laboratory, direct numerical simulation (DNS), and large eddy simulation (LES) data indicates that in stably stratified flows turbulent mixing exists up to Ri ∼ O(100), meaning that there is practically no Ri(cr). On the other hand, traditional local second-order closure (SOC) models entail a critical Ri(cr) ∼ O(1) above which turbulence ceases to exist and are therefore unable to explain the above data. The authors suggest how to modify the recent SOC model of Cheng et al. to reproduce the above data for arbitrary Ri.
Tracking Gravity Waves in Baroclinic Jet-Front Systems
Authors: Lin Yonghui , Zhang Fuqing 
Published: July 2008

Abstract
Using a two-dimensional Fourier decomposition and a four-dimensional ray-tracing technique, the propagating characteristics and source mechanisms of mesoscale gravity waves simulated in idealized baroclinic jet-front systems are investigated. The Fourier decomposition successfully separates the simulated gravity waves from a complex background flow in the troposphere. Four groups of gravity waves in the lower stratosphere are identified from the spectral decomposition. One is a northward-propagating short-scale wave packet with horizontal wavelength of ∼150 km, and another is a northeastward-propagating medium-scale wave packet with horizontal wavelength of ∼350 km. Both of these are most pronounced in the exit region of the upper-tropospheric jet. A third group exists in the deep trough region above (and nearly perpendicular to) the jet, and a fourth group far to the south of the jet right above the surface cold front, both of which are short-scale waves and have a horizontal wavelength of ∼100–150 km.
Ray-tracing analysis suggests that the medium-scale gravity waves originate from the upper-tropospheric jet-front system where there is maximum imbalance, though contributions from the surface fronts cannot be completely ruled out. The shorter-scale, northward-propagating gravity waves in the jet-exit region, on the other hand, may originate from both the upper-tropospheric jet-front system and the surface frontal system. The shorter-scale gravity waves in the deep trough region across the jet (and those right above the surface cold fronts) are almost certain to initiate from the surface frontal system. Ray-tracing analysis also reveals a very strong influence of the spatial and temporal variability of the complex background flow on the characteristics of gravity waves as they propagate.
Distance-Scaled Water Concentrations versus Mass-Median Drop Size, Temperature, and Altitude in Supercooled Clouds
Authors: Jeck Richard K. 
Published: July 2008

AbstractAbout 28 000 nautical miles (n mi) of select in-flight measurements of liquid water content (LWC), droplet sizes, temperature, and other variables in supercooled clouds from a variety of research projects over portions of North America, Europe, and the northern oceans have been compiled into a computerized database for obtaining new statistics on the ranges, frequency of occurrence, and interrelationships of the variables.The LWCs are averaged over uniform cloud intervals of variable length. LWC probabilities are then generated as a function of averaging distance, temperature, droplet mass-median diameter (MMD), altitude, and freezing-level height. These variously scaled LWCs (different averaging intervals from 1 s to 200 n mi) are easily accommodated by distance-based graphing (LWC versus averaging distance). These graphs provide realistic LWCs for modeling, and they can serve as a common reference for comparing LWC measurements over any averaging scale.Maximum recorded LWCs are about 1.6 g m−3 in stratiform clouds and about 5 g m−3 in convective clouds, both over short (&lt;0.5 km) distances. A sharp MMD mode near 15 μm appears to be a stable condition in which the LWCs can be the largest and extend the farthest. The larger the MMD above the mode, the shorter its spatial extent will be, the rarer its occurrence, and the lower the maximum LWC that can be present.
Emergence and Secondary Instability of Ekman Layer Rolls
Authors: Dubos T. , Barthlott C. , Drobinski P. 
Published: July 2008

Abstract
The authors revisit the idealized scenario by which long-lived rolls are believed to emerge in the neutral planetary boundary layer, that is, through the saturation of the shear instability of the neutrally stratified Ekman flow.
First, the nonlinear stages of the primary instability are studied, using a constant turbulent viscosity with Reynolds numbers up to 1000. Two-dimensional equilibrated rolls are found to exist, as predicted earlier based on a weakly nonlinear expansion. However, the flow may not saturate into those equilibrated rolls if the turbulent Reynolds number is too high. Second, a linear stability analysis of these equilibrated rolls is performed, which finds that they are subject to a three-dimensional instability. The growth rate of the most unstable mode is comparable to the growth rate of the primary instability; the selected horizontal length scale is about 4 times shorter. The unstable mode draws its energy by interacting with both across-roll and along-roll shear, the latter interaction being stronger.
The latitude and the direction of the geostrophic wind affect the dynamics through the horizontal component of the Coriolis vector; their influence is investigated in both studies. At Reynolds numbers sufficiently higher than the threshold of the primary instability, the saturated rolls depend negligibly on latitude and wind direction. However, the growth rate of the secondary instability depends substantially on latitude and wind direction over the range of Reynolds numbers considered.
Scaling Laws and Regime Transitions of Macroturbulence in Dry Atmospheres
Authors: Schneider Tapio , Walker Christopher C. 
Published: July 2008

Abstract
In simulations of a wide range of circulations with an idealized general circulation model, clear scaling laws of dry atmospheric macroturbulence emerge that are consistent with nonlinear eddy–eddy interactions being weak. The simulations span several decades of eddy energies and include Earth-like circulations and circulations with multiple jets and belts of surface westerlies in each hemisphere. In the simulations, the eddy available potential energy and the barotropic and baroclinic eddy kinetic energy scale linearly with each other, with the ratio of the baroclinic eddy kinetic energy to the barotropic eddy kinetic energy and eddy available potential energy decreasing with increasing planetary radius and rotation rate. Mean values of the meridional eddy flux of surface potential temperature and of the vertically integrated convergence of the meridional eddy flux of zonal momentum generally scale with functions of the eddy energies and the energy-containing eddy length scale, with a few exceptions in simulations with statically near-neutral or neutral extratropical thermal stratifications. Eddy energies scale with the mean available potential energy and with a function of the supercriticality, a measure of the near-surface slope of isentropes. Strongly baroclinic circulations form an extended regime in which eddy energies scale linearly with the mean available potential energy. Mean values of the eddy flux of surface potential temperature and of the vertically integrated eddy momentum flux convergence scale similarly with the mean available potential energy and other mean fields.
The scaling laws for the dependence of eddy fields on mean fields exhibit a regime transition between a regime in which the extratropical thermal stratification and tropopause height are controlled by radiation and convection and a regime in which baroclinic entropy fluxes modify the extratropical thermal stratification and tropopause height. At the regime transition, for example, the dependence of the eddy flux of surface potential temperature and the dependence of the vertically integrated eddy momentum flux convergence on mean fields changes—a result with implications for climate stability and for the general circulation of an atmosphere, including its tropical Hadley circulation.
Internal Variability of the Winter Stratosphere. Part II: Time-Dependent Forcing
Authors: Scott R. K. , Polvani L. M. , Waugh D. W. 
Published: July 2008

Abstract
This paper considers the effect of time-dependent lower boundary wave forcing on the internal variability found to appear spontaneously in a stratosphere-only model when the forcing is perfectly steady. While the time-dependent forcing is found to modulate the internal variability, leading in some cases to frequency locking of the upper-stratospheric response to the forcing, the temporal and spatial structure of the variability remains similar to the case when the forcing is time independent. Experiments with a time-periodic modulation of the forcing amplitude indicate that the wave flux through the lower boundary is only partially related to the instantaneous forcing, but is more significantly influenced by the condition of the polar vortex itself. In cases of purely random wave forcing with zero time mean, the stratospheric response is similar to that obtained with steady forcing of magnitude equal to the root-mean-square of the time-varying forcing.
The Dynamics of Atmospherically Driven Intraseasonal Polar Motion
Authors: Feldstein Steven B. 
Published: July 2008

AbstractThe atmospheric dynamical processes that drive intraseasonal polar motion are examined with National Centers for Environmental Prediction–National Center for Atmospheric Research reanalysis data and with pole position data from the International Earth Rotation Service. The primary methodology involves the regression of different atmospheric variables against the polar motion excitation function.A power spectral analysis of the polar motion excitation function finds a statistically significant peak at 10 days. Correlation calculations show that this peak is associated with the 10-day, first antisymmetric, zonal wavenumber 1, normal mode of the atmosphere. A coherency calculation indicates that the atmospheric driving of polar motion is mostly confined to two frequency bands, with periods of 7.5–13 and 13–90 days. Regressions of surface pressure reveal that the 7.5–13-day band corresponds to the 10-day atmospheric normal mode and the 13–90-day band to a quasi-stationary wave.The regressions of pole position and the various torques indicate not only that the equatorial bulge torque dominates the mountain and friction torques but also that the driving by the equatorial bulge torque accounts for a substantial fraction of the intraseasonal polar motion. Furthermore, although the 10-day and quasi-stationary wave contributions to the equatorial bulge torque are similar, the response in the pole position is primarily due to the quasi-stationary wave.Additional calculations of regressed power spectra and meridional heat fluxes indicate that the atmospheric wave pattern that drives polar motion is itself excited by synoptic-scale eddies. Regressions of pole position with separate torques from either hemisphere show that most of the pole displacement arises from the equatorial bulge torque from the winter hemisphere. Together with the above findings on wave–wave interactions, these results suggest that synoptic-scale eddies in the winter hemisphere excite the quasi-stationary wave, which in turn drives the polar motion through the equatorial bulge torque.