bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of eIF2α Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy
Authors: Schewe Denis M. , Aguirre-Ghiso Julio A. 
Published: February 2009

Abstract
The proteasome inhibitor bortezomib (Velcade) effectively eradicates multiple myeloma (MM) cells, partly by activating endoplasmic reticulum (ER) stress apoptotic signaling. However, MM recurrences in bortezomib-treated patients are invariable. We have shown that ER stress signaling can also induce growth arrest and survival in cancer cells. Thus, we hypothesized that bortezomib therapy could induce quiescence and survival of residual MM cells, contributing to disease recurrence. Here, we report that in MM cells, proteasome inhibition with MG-132 or bortezomib results in a surviving cell fraction that enters a prolonged quiescent state (G0-G1 arrest). Mechanism analysis revealed that bortezomib-surviving quiescent cells attenuate eIF2α phosphorylation and induction of the ER stress proapoptotic gene GADD153. This occurs independently of the eIF2α upstream kinases PERK, GCN2, and PKR. In contrast, the prosurvival ER-chaperone BiP/Grp78 was persistently induced. The bortezomib-surviving quiescent fraction could be eradicated by a simultaneous or sequential combination therapy with salubrinal, an inhibitor of GADD34-PP1C phosphatase complex, and, in consequence, eIF2α dephosphorylation. This effect was mimicked by expression of a phosphorylated mimetic eIF2α-S51D mutant. Our data indicate that bortezomib can induce growth arrest in therapy-surviving MM cells and that attenuation of eIF2α phosphorylation contributes to this survival. Most importantly, this survival mechanism can be blocked by inhibiting eIF2α dephosphorylation. Thus, strategies that maintain eIF2α in a hyperphosphorylated state may be a novel therapeutic approach to maximize bortezomib-induced apoptosis and reduce residual disease and recurrences in this type of cancer. [Cancer Res 2009;69(4):1545–52]
Local Delivery of Poly Lactic-co-glycolic Acid Microspheres Containing Imatinib Mesylate Inhibits Intracranial Xenograft Glioma Growth
Authors: Benny Ofra , Menon Lata G. , Ariel Gilert , Goren Effrat , Kim Seung-Ki , Stewman Chaney , Black Peter M. , Carroll Rona S. , Machluf Marcelle 
Published: February 2009

AbstractPurpose: In an effort to develop new therapeutic strategies to treat malignant gliomas, we have designed poly (lactic-co-glycolic) acid (PLGA) microparticles that deliver imatinib mesylate, a small molecule tyrosine kinase inhibitor. The local continuous release of imatinib mesylate at the tumor site overcomes many obstacles associated with systemic delivery.Experimental Design: Polymeric microspheres were prepared from various compositions of PLGA and loaded with imatinib mesylate. Imatinib release profiles, biological activity, and effect on PDGFR-B phosphorylation were confirmed in vitro. The therapeutic efficacy of imatinib microspheres was examined in two s.c. and orthotopic human glioblastoma xenograft models.Results: A single local injection of PLGA microspheres loaded with a low concentration of imatinib mesylate led to 88% and 79% reduction in s.c. human (U87-MG) and murine (GL261) glioma tumors, respectively. PLGA-imatinib mesylate administered intracranially led to a 79% reduction in U87MG tumor volume. Immunohistochemical analysis showed a marked decrease in proliferation indices and tumor vessel density in the s.c. model and induction of apoptosis in an intracranial model.Conclusion: This is the first study to show the therapeutic efficacy of the local delivery of imatinib mesylate using a polymeric delivery system.
Small-Molecule Drugs Mimicking DNA Damage: A New Strategy for Sensitizing Tumors to Radiotherapy
Authors: Quanz Maria , Berthault Nathalie , Roulin Christophe , Roy Maryline , Herbette Aurélie , Agrario Céline , Alberti Christophe , Josserand Véronique , Coll Jean-Luc , Sastre-Garau Xavier , Cosset Jean-Marc , Larue Lionel , Sun Jian-Sheng , Dutreix Marie 
Published: February 2009

Abstract
Purpose: Enhanced DNA repair activity is often associated with tumor resistance to radiotherapy. We hypothesized that inhibiting DNA damage repair would sensitize tumors to radiation-induced DNA damage.
Experimental Design: A novel strategy for inhibiting DNA repair was tested. We designed small DNA molecules that mimic DNA double-strand breaks (called Dbait) and act by disorganizing damage signaling and DNA repair. We analyzed the effects of Dbait in cultured cells and on xenografted tumors growth and performed preliminary studies of their mechanism(s) of action.
Results: The selected Dbait molecules activate H2AX phosphorylation in cell culture and in xenografted tumors. In vitro, this activation correlates with the reduction of Nijmegen breakage syndrome 1 and p53-binding protein 1 repair foci formation after irradiation. Cells are sensitized to irradiation and do not efficiently repair DNA damage. In vivo, Dbait induces regression of radioresistant head and neck squamous cell carcinoma (Hep2) and melanoma (SK28 and LU1205) tumors. The combination of Dbait32Hc treatment and fractionated radiotherapy significantly enhanced the therapeutic effect. Tumor growth control by Dbait molecules depended directly on the dose and was observed with various irradiation protocols. The induction of H2AX phosphorylation in tumors treated with Dbait suggests that it acts in vivo through the induction of “false” DNA damage signaling and repair inhibition.
Conclusions: These data validate the concept of introducing small DNA molecules, which mimic DNA damage, to trigger “false” signaling of DNA damage and impair DNA repair of damaged chromosomes. This new strategy could provide a new method for enhancing radiotherapy efficiency in radioresistant tumors.
Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma
Authors: Milano Vanessa , Piao Yuji , LaFortune Tiffany , de Groot John 
Published: February 2009

Abstract
Glioblastoma is defined by its aggressive invasion, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and epidermal growth factor receptor by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phospho-SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. Reduction of invasive potential was observed in vitro at concentrations well below the IC50 of dasatinib, which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in focal adhesion kinase autophosphorylation. Cell cycle analysis revealed minimal G1 arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in light chain 3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a significant increase in cell cycle disruption and autophagic cell death. Dasatinib in combination with temozolomide more effectively increased the therapeutic efficacy of temozolomide than when dasatinib was combined with carboplatin or irinotecan. These results strongly support the clinical use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide. [Mol Cancer Ther 2009;8(2):394–406]
MAPK-independent impairment of T-cell responses by the multikinase inhibitor sorafenib
Authors: Houben Roland , Voigt Heike , Noelke Christiane , Hofmeister Valeska , Becker Juergen C. , Schrama David 
Published: February 2009

Abstract
Sorafenib, originally developed as CRAF inhibitor but soon recognized as a multikinase inhibitor, is currently widely tested for the treatment of different cancers either alone or in combination therapy. However, the clinical success, particularly in immunogenic tumors such as melanoma, was less than anticipated. Because T-cell activation is tightly regulated by a multitude of kinases, we scrutinized effects of sorafenib on immune responses. To this end, comprehensive in vitro studies revealed that the presence of sorafenib concentrations comparable with observed plasma levels in patients strongly impairs the activation of T cells. Notably, even established tumor-specific immune responses are influenced by sorafenib. Indeed, ELISPOT data of peripheral blood lymphocytes obtained from melanoma patients vaccinated against survivin show markedly diminished survivin-specific immune responses in the presence of sorafenib. Surprisingly, inhibition of T-cell activation was not associated with reduced extracellular signal-regulated kinase phosphorylation. In fact, on T-cell receptor stimulation phospho-extracellular signal-regulated kinase and phospho-mitogen-activated protein kinase kinase levels were found to be elevated in the presence of sorafenib, showing the complexity of signal transduction events following T-cell receptor stimulation. In conclusion, our data show that T-cell function is sensitive toward the multikinase inhibitor sorafenib in a mitogen-activated protein kinase-independent fashion. This observation has important implications for the use of sorafenib as therapy for immunogenic cancers. [Mol Cancer Ther 2009;8(2):433–40]
Including Atmospheric Layers in Vegetation and Urban Offline Surface Schemes
Authors: Masson Valéry , Seity Yann 
Published: February 2009

Abstract
A formulation to include prognostic atmospheric layers in offline surface schemes is derived from atmospheric equations. Whereas multilayer schemes developed previously need a complex coupling between atmospheric-model levels and surface-scheme levels, the coupling proposed here remains simple. This is possible because the atmospheric layers interacting with the surface scheme are independent of the atmospheric model that could be coupled above. The surface boundary layer (SBL; both inside and just above the canopy) is resolved prognostically, taking into account large-scale forcing, turbulence, and, if any, drag and canopy forces and surface fluxes. This formulation allows one to retrieve the logarithmic law in neutral conditions, and it has been validated when coupled to a 3D atmospheric model. Systematic comparisons with 2-m observations and 10-m wind have been made for 2 months. The SBL scheme is able to model the 2-m temperature accurately, as well as the 10-m wind, without any use of analytical interpolation. The largest improvement takes place during stable conditions (i.e., by night), during which analytical laws and interpolation methods are known to be less accurate, and in mountainous areas, in which nocturnal low-level flow is strongly influenced by surface cooling. The prognostic SBL scheme is shown to solve the nighttime physical disconnection problem between surface and atmosphere models. The inclusion of the SBL into the urban Town Energy Balance scheme is presented in a paper by Hamdi and Masson in which the ability of the method to simulate the profiles of both mean and turbulent quantities from above the building down to the road surface is shown using data from the Basel Urban Boundary Layer Experiment (BUBBLE). The proposed method will allow the inclusion of the detailed physics of the multilayer schemes (e.g., the interactions of the SBL flow with forest or urban canopy) into a single-layer scheme that is easily coupled with atmospheric models.
Parameterization of Cloud Drop Activation Based on Analytical Asymptotic Solutions to the Supersaturation Equation
Authors: Khvorostyanov Vitaly I. , Curry Judith A. 
Published: February 2009

Abstract
Toward improving parameterization of cloud droplet activation in cloud and climate models, the integro–differential equation for supersaturation is solved analytically for the algebraic size spectrum of the cloud condensation nuclei (CCN) that is equivalent to the lognormal spectrum. The analytical solutions are obtained for four limiting cases that are combinations of two different values of the updraft vertical velocity (small and large) and two different values of the condensation coefficient that correspond to pure and polluted cloud drops. The characteristics of the CCN can vary within each limit. Thus, these four limits and interpolation among them cover the vast majority of cloudy conditions. Analytical expressions are obtained for the time of CCN activation, maximum supersaturation, and the concentration of activated droplets.
For small updraft vertical velocities, these quantities are the products of the power laws by six variables: CCN concentration, mean radius, soluble fraction, vertical velocities, surface tension, and condensation coefficient. At large updraft vertical velocities, the activation time and maximum supersaturation are the products of the power laws of only two variables—CCN concentration and vertical velocity—and are independent of the CCN physicochemical properties. The first limit is a generalization of the Twomey power laws, with Twomey’s coefficient CT and index k expressed via CCN physicochemical properties; the other three limits are new. The accuracy and regions of validity of these limits are determined by comparison with the exact numerical solution to the supersaturation equation. These solutions can be used for parameterization of drop activation in cloud and climate models and for control of numerical solutions. An advantage of this method is that it does not require running parcel models, and the drop concentrations can be obtained from lookup tables or as simple interpolation among the limiting solutions for the instantaneous model parameters.
Numerical Simulations of Conditionally Unstable Flows over a Mountain Ridge
Authors: Miglietta Mario Marcello , Rotunno Richard 
Published: February 2009

Abstract
Numerical simulations of conditionally unstable flows impinging on a mesoscale mountain ridge have been performed with an explicitly resolving cloud model to investigate the statistically stationary features of the solution precipitation characteristics. The simulations are performed on a three-dimensional domain and at high resolution (grid spacing: 250 m) to properly resolve cellular-scale features. Although the environmental conditions are specified by a simplified idealized conditionally unstable sounding, there are still quite a few external parameters, so only a limited portion of the parameter space was explored. Numerical solutions were first carried out for different uniform-wind profiles impinging on a bell-shaped ridge 2000 m high. In the experiments with weaker environmental wind speeds (2.5 m s−1), the cold-air outflow, caused by the evaporative cooling of rain from precipitating convective cells, is the main mechanism for cell redevelopment and movement; this outflow produces new convective cells near the head of the up- and downstream density currents, which rapidly propagate far from the ridge so that no rainfall is produced close to the ridge at later times. For larger wind speeds (10 and 20 m s−1), there is less time for upwind, evaporation-induced cold-pool formation before air parcels reach the ridge top and descend downwind. For the intermediate wind speed (10 m s−1), evaporation is effective in generating a cold pool only on the downstream side of the ridge, in a region where the air is unsaturated and slow moving. Further experiments with different ridge heights and half-widths were carried out in order to analyze their effect on the distribution and intensity of precipitation. Dimensional analysis reveals that the maximum (nondimensional) rainfall rate mainly depends on the ratio of mountain height to the level of free convection, the ridge aspect ratio, and a parameter that measures the ratio of advective to convective time scales.
A High-Resolution Record of Atmospheric Dust Composition and Variability since a.d. 1650 from a Mount Everest Ice Core
Authors: Kaspari S. , Mayewski P. A. , Handley M. , Kang S. , Hou S. , Sneed S. , Maasch K. , Qin D. 
Published: February 2009

Abstract
A Mount Everest ice core analyzed at high resolution for major and trace elements (Sr, Cs, Ba, La, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb, Lu, Bi, U, Tl, Al, S, Ca, Ti, V, Cr, Mn, Fe, Co) and spanning the period a.d. 1650–2002 is used to investigate the sources of and variations in atmospheric dust through time. The chemical composition of dust varies seasonally, and peak dust concentrations occur during the winter–spring months. Significant correlations between the Everest dust record and dust observations at stations suggest that the Everest record is representative of regional variations in atmospheric dust loading. Back-trajectory analysis in addition to a significant correlation of Everest dust concentrations and the Total Ozone Mapping Spectrometer (TOMS) aerosol index indicates that the dominant winter sources of dust are the Arabian Peninsula, Thar Desert, and northern Sahara. Factors that contribute to dust generation at the surface include soil moisture and temperature, and the long-range transport of dust aerosols appears to be sensitive to the strength of 500-mb zonal winds. There are periods of high dust concentration throughout the 350-yr Mount Everest dust record; however, there is an increase in these periods since the early 1800s. The record was examined for recent increases in dust emissions associated with anthropogenic activities, but no recent dust variations can be conclusively attributed to anthropogenic inputs of dust.
The 1997/98 Summer Rainfall Season in Southern Africa. Part II: Model Simulations and Coupled Model Forecasts
Authors: Lyon Bradfield , Mason Simon J. 
Published: February 2009

Abstract
This is the second of a two-part investigation of rainfall in southern Africa during the strong El Niño of 1997/98. In Part I it was shown that widespread drought in southern Africa, typical of past El Niño events occurring between 1950 and 2000, generally failed to materialize during the 1997/98 El Niño, most notably during January–March (JFM) 1998. Here output from three atmospheric general circulation models (AGCMs) forced with observed sea surface temperatures (SSTs) and seasonal forecasts from three coupled models are examined to see to what extent conditions in JFM 1998 could have potentially been anticipated.
All three AGCMs generated widespread drought conditions across southern Africa, similar to those during past El Niño events, and did a generally poor job in generating the observed rainfall and atmospheric circulation anomaly patterns, particularly over the eastern and southern Indian Ocean. In contrast, two of the three coupled models showed a higher probability of wetter conditions in JFM 1998 than for past El Niño events, with an enhanced moisture flux from the Indian Ocean, as was observed. However, neither the AGCMs nor the coupled models generated anomalous stationary wave patterns consistent with observations over the South Atlantic and Pacific. The failure of any of the models to reproduce an enhanced Angola low (favoring rainfall) associated with an anomalous wave train in this region suggests that the coupled models that did indicate wetter conditions in JFM 1998 compared to previous El Niño episodes may have done so, at least partially, for the wrong reasons. The general inability of the climate models used in this study to generate key features of the seasonal climate over southern Africa in JFM 1998 suggests that internal atmospheric variability contributed to the observed rainfall and circulation patterns that year. With the caveat that current climate models may not properly respond to SST boundary forcing important to simulating southern Africa climate, this study finds that the JFM 1998 rainfall in southern Africa may have been largely unpredictable on seasonal time scales.
Implication of the Madden–Julian Oscillation in the 40-Day Variability of the West African Monsoon
Authors: Pohl Benjamin , Janicot Serge , Fontaine Bernard , Marteau Romain 
Published: February 2009

Abstract
Madden–Julian oscillations (MJOs) are extracted over the Indo-Pacific basin using a local mode analysis. The convective perturbations are then projected over a larger domain to evaluate their remote consequences over the West African monsoon (WAM) intraseasonal variability. Rather weak (4–6 W m−2) convective fluctuations occurring in phase with those over the southern Indian basin are found over Africa, confirming the results of Matthews. In reverse, 40-day fluctuations in the WAM, similarly detected and projected over a widened area, demonstrate that a large majority of these events are embedded in the larger-scale patterns of the MJO. The regional amplitude of intraseasonal perturbations of the West African convection is not statistically associated with the amplitude of the MJO over the Indian basin but is instead closely related to background vertical velocity anomalies over Africa, possibly embedded in changes in the regional Walker-type circulation. Subsiding motion over Africa is recorded during the most energetic convective perturbations in the WAM.
Composites analyses over the MJO life cycle, as depicted by the real-time daily indices developed by Wheeler and Hendon, show that positive outgoing longwave radiation (OLR) anomalies during the dry phase are of larger amplitude and spatially more coherent than negative anomalies during the wet phase, especially over the Sahel region. Over West Africa, the phase of suppressed convection is thus of greater importance for the region than the phase of enhanced convection. Rain gauge records fully confirm these results. The MJO appears to be significantly involved in the occurrences of dry spells during the monsoon over the Sahel, whereas large-scale convective clusters are only restricted to the equatorial latitudes and thus affect the Guinean belt, which experiences its short dry season at this time of the year.
Tidal Conversion by Supercritical Topography
Authors: Balmforth Neil J. , Peacock Thomas 
Published: February 2009

Abstract
Calculations are presented of the rate of energy conversion of the barotropic tide into internal gravity waves above topography on the ocean floor. The ocean is treated as infinitely deep, and the topography consists of periodic obstructions; a Green function method is used to construct the scattered wavefield. The calculations extend the previous results of Balmforth et al. for subcritical topography (wherein waves propagate along rays whose slopes exceed that of the topography everywhere), by allowing the obstacles to be arbitrarily steep or supercritical (so waves propagate at shallower angles than the topographic slopes and are scattered both up and down). A complicated pattern is found for the dependence of energy conversion on ε, the ratio of maximum topographic slope to wave slope, and the ratio of obstacle amplitude and separation. This results from a sequence of constructive and destructive interferences between scattered waves that has implications for computing tidal conversion rates for the global ocean.