bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pyrimethamine Induces Apoptosis of Melanoma Cells via a Caspase and Cathepsin Double-Edged Mechanism
Authors: Giammarioli Anna Maria , Maselli Angela , Casagrande Andrea , Gambardella Lucrezia , Gallina Angelo , Spada Massimo , Giovannetti Antonello , Proietti Enrico , Malorni Walter , Pierdominici Marina 
Published: July 2008

Abstract
The unresponsiveness of metastatic melanoma to conventional chemotherapeutic and biological agents is largely due to the development of resistance to apoptosis. Pyrimethamine belongs to the group of antifolate drugs, and in addition to antiprotozoan effects, it exerts a strong proapoptotic activity, which we recently characterized in human T lymphocytes. However, no data regarding pyrimethamine anticancer activity are available thus far. To this end, we examined the in vitro effects of pyrimethamine on apoptosis, cell cycle distribution, and cell proliferation of human metastatic melanoma cell lines. The in vivo antitumor potential of pyrimethamine was evaluated in a severe combined immunodeficiency (SCID) mouse xenotransplantation model. Our data indicate that pyrimethamine, when used at a clinically relevant concentration, induced apoptosis in metastatic melanoma cells via the activation of the cathepsin B and the caspase cascade (i.e., caspase-8 and caspase-9) and subsequent mitochondrial depolarization. This occurred independently from CD95/Fas engagement. Moreover, pyrimethamine induced a marked inhibition of cell growth and an S-phase cell cycle arrest. Results obtained in SCID mice, injected s.c. with metastatic melanoma cells and treated with pyrimethamine, indicated a significant inhibitory effect on tumor growth. In conclusion, our results suggest that pyrimethamine-induced apoptosis may be considered as a multifaceted process, in which different inducers or regulators of apoptosis are simultaneously implicated, thus permitting death defects of melanoma cells to be bypassed or overcome. On these bases, we hypothesize that pyrimethamine could represent an interesting candidate for the treatment of metastatic melanoma. [Cancer Res 2008;68(13):5291–300]
ATM Mediates Cytotoxicity of a Mutant Telomerase RNA in Human Cancer Cells
Authors: Stohr Bradley A. , Blackburn Elizabeth H. 
Published: July 2008

Abstract
Telomeres are elongated by the enzyme telomerase, which contains a template-bearing RNA (TER or TERC) and a protein reverse transcriptase. Overexpression of a particular mutant human TER with a mutated template sequence (MT-hTer-47A) in telomerase-positive cancer cells causes incorporation of mutant telomeric sequences, telomere uncapping, and initiation of a DNA damage response, ultimately resulting in cell growth inhibition and apoptosis. The DNA damage pathways underlying these cellular effects are not well understood. Here, we show that the ataxia-telangiectasia mutated (ATM) protein is activated and forms telomeric foci in response to MT-hTer-47A expression. Depletion of ATM from two cancer cell lines, including the p53-mutant UM-UC-3 bladder cancer line, rendered the cells largely unresponsive to MT-hTer-47A. Relative to ATM-competent controls, ATM-depleted cells showed increased proliferation and clonogenic survival and reduced cell death following MT-hTer-47A treatment. In contrast, ATM depletion sensitized the cancer cells to treatment with camptothecin, a topoisomerase inhibitor that induces DNA double-strand breaks. We show that the effects of ATM depletion on the MT-hTer-47A response were not due to decreased expression of MT-hTer-47A or reduced activity of telomerase at the telomere. Instead, ATM depletion allowed robust cancer cell growth despite the continued presence of dysfunctional telomeres containing mutant sequence. Notably, the number of end-to-end telomere fusions induced by MT-hTer-47A treatment was markedly reduced in ATM-depleted cells. Our results identify ATM as a key mediator of the MT-hTer-47A dysfunctional telomere response, even in cells lacking wild-type p53, and provide evidence that telomere fusions contribute to MT-hTer-47A cytotoxicity. [Cancer Res 2008;68(13):5309–17]
Molecular Subtypes of Breast Cancers Detected in Mammography Screening and Outside of Screening
Authors: Sihto Harri , Lundin Johan , Lehtimäki Tiina , Sarlomo-Rikala Maarit , Bützow Ralf , Holli Kaija , Sailas Liisa , Kataja Vesa , Lundin Mikael , Turpeenniemi-Hujanen Taina , Isola Jorma , Heikkilä Päivi , Joensuu Heikki 
Published: July 2008

Abstract
Purpose: The frequency and significance of gene expression profile-derived molecular subtypes of breast cancers found in mammography screening are unknown.
Experimental Design: We identified breast cancers diagnosed in women of any age living in defined geographic regions in Finland in 1991 to 1992 and collected clinical and pathologic data. Surrogates for the molecular subtypes were determined for 247 cancers found in organized mammography screening and 989 cancers detected outside of screening using immunohistochemistry or in situ hybridization. Molecular subtypes were defined as luminal A [estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-], luminal B (ER+ and/or PR+, HER2+), basal-like (ER-, PR-, HER2-, cytokeratin 5+, and/or HER1+), HER2+/ER- (ER-, PR-, and HER2+), and unclassified. The median follow-up time was 9.4 years.
Results: The luminal type A was common (73.7%) and the HER2+/ER- type is rare (5.7%) in screen-detected cancer, and only 16% were HER2 positive. Women with cancer diagnosed in screening at ages 50 to 69 years had similar molecular subtype distribution as women whose cancer was found outside of screening at age &gt;69 years. In a multivariate model, cancer detection at screening independently predicted favorable distant disease-free survival when the molecular subtype was included as a covariate in addition to age, histologic grade, and cancer size. Women with small (pT1N0M0) HER2-positive cancer had similar outcome regardless of the method of detection.
Conclusions: Molecular subtype distribution of screen-detected breast cancer differs from that of cancers found outside of screening and accounts in part for the better outcome of screen-detected cancer.
Interdecadal Trend and ENSO-Related Interannual Variability in Southern Hemisphere Blocking
Authors: Dong Li , Vogelsang Timothy J. , Colucci Stephen J. 
Published: July 2008

Abstract
The interdecadal trend and ENSO-related interannual variability in the frequency and intensity of atmospheric blocking in the Southern Hemisphere are analyzed by a statistical model that takes account of serial correlation in the datasets. Results suggest that an autoregressive process AR(1) fits the error term of the Southern Hemisphere blocking occurrence series, and a white-noise process AR(0) fits the error term of the Southern Hemisphere blocking intensity series reasonably well. It is found that the Southern Hemisphere blocking days have decreased over the past 52 yr (1948–99) but with an enhanced intensity. In addition, the Southern Hemisphere atmospheric blocking is found to occur more frequently in the warm phase of ENSO cycles, whereas the intensity of the Southern Hemisphere atmospheric blocking does not appear to be affected by ENSO cycles.
Observed Structure, Evolution, and Potential Intensity of Category 5 Hurricane Isabel (2003) from 12 to 14 September
Authors: Bell Michael M. , Montgomery Michael T. 
Published: July 2008

AbstractUnprecedented observations of Hurricane Isabel (2003) at category 5 intensity were collected from 12 to 14 September. This study presents a detailed analysis of the inner-core structure, atmospheric boundary layer, sea surface temperature, and outflow layer of a superintense tropical cyclone using high-resolution in situ flight-level, NCAR GPS dropwindsonde, Doppler radar, and satellite measurements. The analysis of the dropwindsonde and in situ data includes a comprehensive discussion of the uncertainties associated with this observational dataset and provides an estimate of the storm-relative axisymmetric inner-core structure using Barnes objective analysis. An assessment of gradient and thermal wind balance in the inner core is also presented. The axisymmetric data composites presented in this study suggest that Isabel built a reservoir of high moist entropy air by sea-to-air latent heat flux inside the low-level eye that was utilized as an additional energy source to nearly maintain its extreme intensity even after crossing the cool wake of Hurricane Fabian. It is argued here that the combined mean and asymmetric eddy flux of high moist entropy air from the low-level eye into the eyewall represents an additional power source or “turbo boost” to the hurricane heat engine. Recent estimates of the ratio of sea-to-air enthalpy and momentum exchange at high wind speeds are used to suggest that Isabel utilized this extra power to exceed the previously assumed intensity upper bound for the given environmental conditions on all three days. This discrepancy between a priori potential intensity theory and observations may be as high as 35 m s−1 on 13 September.
Extratropical Transition of Tropical Cyclones in the Western North Pacific: Their Frontal Evolution
Authors: Kitabatake Naoko 
Published: July 2008

Abstract
Extratropical transition (ET) in the western North Pacific during 2001–02 is examined in terms of frontal evolution and its environment using a gridded global analysis dataset produced by the Japan Meteorological Agency. According to the best-track data created by the Regional Specialized Meteorological Center (RSMC) Tokyo-Typhoon Center, 23 out of 52 (44%) tropical cyclones (TCs) completed ET during these two years. These ET cases are classified into three categories in terms of the lower-tropospheric equivalent potential temperature distributions, characteristics of the TCs, and their environments. Eight TCs (35% of all ET cases) had temporary warm secluded frontal patterns and then occluded patterns at the completion of ET, which is defined as a seclusion–occlusion (SO) type. This occurs downstream of an intense upper-tropospheric trough interacting with a TC, which is then likely to move northward while keeping its tropical characteristics and have a large impact on relatively high latitudes including all the Japan islands. Three TCs (13%) were apparently absorbed into vigorous preexisting fronts in the southwest of midlatitude cyclones; this situation is defined as a cold advection (CA) type. A TC of the CA type is likely to lose its tropical characteristics rapidly in strong cold advection that is equatorward of a relatively straight upper-tropospheric jet stream. The other 12 TCs (52%) were organized into an open-wave frontal cyclone, which is defined as an open-wave (OW) type. This has characteristics of both SO and CA and is more related to the midlatitude baroclinic zone compared with the SO type.
Prediction of Landfalling Hurricanes with the Advanced Hurricane WRF Model
Authors: Davis Christopher , Wang Wei , Chen Shuyi S. , Chen Yongsheng , Corbosiero Kristen , DeMaria Mark , Dudhia Jimy , Holland Greg , Klemp Joe , Michalakes John , Reeves Heather , Rotunno Richard , Snyder Chris , Xiao Qingnong 
Published: July 2008

Abstract
Real-time forecasts of five landfalling Atlantic hurricanes during 2005 using the Advanced Research Weather Research and Forecasting (WRF) (ARW) Model at grid spacings of 12 and 4 km revealed performance generally competitive with, and occasionally superior to, other operational forecasts for storm position and intensity. Recurring errors include 1) excessive intensification prior to landfall, 2) insufficient momentum exchange with the surface, and 3) inability to capture rapid intensification when observed. To address these errors several augmentations of the basic community model have been designed and tested as part of what is termed the Advanced Hurricane WRF (AHW) model. Based on sensitivity simulations of Katrina, the inner-core structure, particularly the size of the eye, was found to be sensitive to model resolution and surface momentum exchange. The forecast of rapid intensification and the structure of convective bands in Katrina were not significantly improved until the grid spacing approached 1 km. Coupling the atmospheric model to a columnar, mixed layer ocean model eliminated much of the erroneous intensification of Katrina prior to landfall noted in the real-time forecast.
An Objective Study of 500-hPa Moving Troughs in the Southern Hemisphere
Authors: Piva Everson D. , Gan Manoel A. , Rao V. Brahmananda 
Published: July 2008

Abstract
The location and movement of 500-hPa troughs using an automated method are studied with data from a 24-yr period with the objective of determining the trough formation and dissipation regions in the Southern Hemisphere. To identify the 500-hPa mobile troughs, an objective method that uses the Eulerian centripetal acceleration (ECA) is developed. On average, 868 troughs per year were identified by the method, with an increase in trend during the period studied. The troughs have an average lifetime of 4.3 days, being longer (shorter) in subtropical (high) latitudes. The average calculated phase velocity was 13.6 m s−1, being higher (lower) in middle (high) latitudes. The troughs are normally found in the 60°–40°S latitudinal band, with maximum occurrence at 50°S. The longitudinal distribution of trough genesis has three maximum regions: over the Drake Strait and the South Atlantic Ocean, over the Indian Ocean around 50°S, and over the southwestern Pacific Ocean between 150°E and 150°W. The trough dissipation regions are less concentrated than the genesis regions and also show three maxima: over the west of the Andes, south of the African continent, and south of Australia. The seasonal variation in the trough dissipation shows that the 30°–40°S band is more active during winter than in summer. The difference between the genesis and dissipation location is that formation occurs more in middle and high latitudes, while dissipation is more common in the 40°–30°S latitude belt.
A Linear Analysis of the NCAR CCSM Finite-Volume Dynamical Core
Authors: Skamarock William C. 
Published: July 2008

Abstract
The NCAR Community Climate System Model (CCSM) finite-volume atmospheric core uses a C–D-grid discretization to solve the equations of motion. A linear analysis of this discretization shows that it behaves as a D grid to leading order; it possesses the poor response of the D grid for short-wavelength divergent modes, the poor response of the C and D grids for short-wavelength rotational modes, and is only first-order accurate in time and damping. The scheme combines a modified forward–backward time integration for gravity waves with forward-in-time upwind-biased advection schemes, and the solver uses a vector-invariant form of the momentum equations. Other approaches using these equations are considered that circumvent some of the problems inherent in the current approach.
Using Observed Spatial Correlation Structures to Increase the Skill of Subseasonal Forecasts
Authors: Koster Randal D. , Bell Thomas L. , Reichle Rolf H. , Suarez Max J. , Schubert Siegfried D. 
Published: July 2008

Abstract
Model deficiencies limit a subseasonal or seasonal forecast system’s ability to produce accurate predictions. In this paper, an approach for transforming the output of a forecast system into a revised forecast is presented; it is designed to correct for some of the deficiencies in the system (particularly those associated with the spatial correlation structures of the forecasted fields) and thereby increase forecast skill. The approach, based on the joint consideration of the correlation structures present in the observational record and the inherent potential predictability of the model, is tested on a preexisting subseasonal forecast experiment. It is shown to produce modest but significant increases in the accuracy of forecasted precipitation and near-surface air temperature at monthly time scales.
Tests of an Adjoint Mesoscale Model with Explicit Moist Physics on the Cloud Scale
Authors: Amerault Clark , Zou Xiaolei , Doyle James 
Published: July 2008

Abstract
An adjoint modeling system based upon the Naval Research Laboratory’s Coupled Ocean–Atmosphere Mesoscale Prediction System’s atmospheric component has been developed. The system includes the adjoint model of the explicit moist physics parameterization, which allows for gradients with respect to the initial hydrometeor concentrations to be calculated. This work focuses on the ability of the system to calculate evolved perturbations and gradients for the hydrometeor variables. Tests of the tangent linear and adjoint models for an idealized convective case at high model resolution (4-km horizontal grid spacing) are presented in this study. The tangent linear approximation is shown to be acceptable for all model variables (including the hydrometeors) with sizable perturbations for forecasts of 1 h. The adjoint model was utilized with the same convective case to demonstrate its applicability in four-dimensional variational data assimilation experiments. Identical twin experiments were conducted where the adjoint model produced gradients for all model variables, leading to improved analyses and forecasts. The best agreement between model forecasts and simulated observations occurred when information on all model variables was assimilated. In the case where only conventional data were assimilated, the agreement was not as good in the early forecast period. However, the hydrometeor values spun up quickly, and at later times, the forecast performed almost as well as when all data were assimilated.
Preliminary Impact Studies Using Global Positioning System Radio Occultation Profiles at NCEP
Authors: Cucurull L. , Derber J. C. , Treadon R. , Purser R. J. 
Published: July 2008

Abstract
Following the successful launch of the Constellation Observing System for Meteorology, Ionosphere and Climate (COSMIC) satellites in April 2006, NCEP’s Environmental Modeling Center (EMC) is planning to use the COSMIC data in its next-generation Global Data Assimilation System. In preparation for the assimilation of GPS radio occultation (RO) data from COSMIC and other missions, NCEP/EMC has developed the infrastructure necessary to use profiles of refractivity and bending angle in an operational framework. In both forward operators, horizontal gradients of refractivity have been neglected and each operator has been tuned with its corresponding quality control checks and error characterization. In this paper, the benefits of the assimilation of profiles of GPS RO on top of the current observations being regularly used in operations are analyzed. In addition, differences between the assimilation of bending angle and refractivity are discussed. To avoid unrealistic increments within the higher model layers, experiments not using GPS RO observations above 30 km are also performed. This stratospheric data assimilation problem was present in earlier experiments with GPS RO data at NCEP/EMC and impacted the forecast in the lower-atmospheric levels as well as the stratosphere. Some characteristics of the assimilation of profiles of bending angle are also discussed. Data from the Challenging Minisatellite Payload (CHAMP) satellite are available in non–real time at NOAA and have been used to perform the experiments examined herein.
Reliable Probabilistic Quantitative Precipitation Forecasts from a Short-Range Ensemble Forecasting System during the 2005/06 Cool Season
Authors: Yussouf Nusrat , Stensrud David J. 
Published: July 2008

Abstract
A simple binning technique developed to produce reliable probabilistic quantitative precipitation forecasts (PQPFs) from a multimodel short-range ensemble forecasting system is evaluated during the cool season of 2005/06. The technique uses forecasts and observations of 3-h accumulated precipitation amounts from the past 12 days to adjust the present day’s 3-h quantitative precipitation forecasts from each ensemble member for each 3-h forecast period. Results indicate that the PQPFs obtained from this simple binning technique are significantly more reliable than the raw (original) ensemble forecast probabilities. Brier skill scores and areas under the relative operating characteristic curve also reveal that this technique yields skillful probabilistic forecasts of rainfall amounts during the cool season. This holds true for accumulation periods of up to 48 h. The results obtained from this wintertime experiment parallel those obtained during the summer of 2004. In an attempt to reduce the effects of a small sample size on two-dimensional probability maps, the simple binning technique is modified by implementing 5- and 9-point smoothing schemes on the adjusted precipitation forecasts. Results indicate that the smoothed ensemble probabilities remain an improvement over the raw (original) ensemble forecast probabilities, although the smoothed probabilities are not as reliable as the unsmoothed adjusted probabilities. The skill of the PQPFs also is increased as the ensemble is expanded from 16 to 22 members during the period of study. These results reveal that simple postprocessing techniques have the potential to provide greatly improved probabilistic guidance of rainfall events for all seasons of the year.
The Influence of Near-Surface, High-Entropy Air in Hurricane Eyes on Maximum Hurricane Intensity
Authors: Bryan George H. , Rotunno Richard 
Published: July 2008

Abstract
Using a time-dependent axisymmetric numerical model, the authors evaluate whether high-entropy air near the surface in hurricane eyes can substantially increase hurricanes’ maximum intensity. This local high-entropy anomaly is ultimately created by surface entropy fluxes in the eye. Therefore, simulations are conducted in which these surface fluxes are set to zero; results show that the high-entropy anomaly is eliminated, yet the axisymmetric tangential wind speed is only slightly weakened (by ∼4%, on average). These results contradict the hypothesis that transport of high-entropy air from the eye into the eyewall can significantly increase the maximum axisymmetric intensity of hurricanes. In fact, all simulations (with or without high-entropy anomalies) have an intensity that is 25–30 m s−1 higher than Emanuel’s theoretical maximum intensity. Further analysis demonstrates that less then 3% of the total surface-entropy input to the hurricane comes from the eye, and therefore the total magnitude of entropy transport between the eye and eyewall is a negligible component of the entropy budget of the simulated hurricanes. This latter finding is consistent with a cursory comparison with observations.