bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcription Factor Stat5 Synergizes with Androgen Receptor in Prostate Cancer Cells
Authors: Tan Shyh-Han , Dagvadorj Ayush , Shen Feng , Gu Lei , Liao Zhiyong , Abdulghani Junaid , Zhang Ying , Gelmann Edward P. , Zellweger Tobias , Culig Zoran , Visakorpi Tapio , Bubendorf Lukas , Kirken Robert A. , Karras James , Nevalainen Marja T. 
Published: January 2008

Abstract
The molecular mechanisms underlying progression of prostate cancer to the hormone-independent state are poorly understood. Signal transducer and activator of transcription 5a and 5b (Stat5a/b) is critical for the viability of human prostate cancer cells. We have previously shown that Stat5a/b is constitutively active in high-grade human prostate cancer, but not in normal prostate epithelium. Furthermore, activation of Stat5a/b in primary human prostate cancer predicted early disease recurrence. We show here that transcription factor Stat5a/b is active in 95% of clinical hormone-refractory human prostate cancers. We show for the first time that Stat5a/b synergizes with androgen receptor (AR) in prostate cancer cells. Specifically, active Stat5a/b increases transcriptional activity of AR, and AR, in turn, increases transcriptional activity of Stat5a/b. Liganded AR and active Stat5a/b physically interact in prostate cancer cells and, importantly, enhance nuclear localization of each other. The work presented here provides the first evidence of synergy between AR and the prolactin signaling protein Stat5a/b in human prostate cancer cells. [Cancer Res 2008;68(1):236–48]
Two Distinct Local Relapse Subtypes in Invasive Breast Cancer: Effect on their Prognostic Impact
Authors: Casalini Patrizia , Carcangiu Maria Luisa , Tammi Raija , Auvinen Päivi , Kosma Veli-Matti , Valagussa Pinuccia , Greco Marco , Balsari Andrea , Ménard Sylvie , Tagliabue Elda 
Published: January 2008

Abstract
Purpose: Local relapse (LR) remains an important concern in breast cancer surveillance. Given the unique opportunity to study local recurrences in the breast in the absence of irradiation, we tested the possibility of identifying a particular tumor feature that might account for LR.
Experimental Design: Archival specimens from 235 patients belonging to the control arm (no radiotherapy) of the Milan 3 Trial were retrieved and included in this study. H&E-stained histologic slides were reviewed for diagnostic reassessment. A panel of biological variables was assessed by immunohistochemical/cytochemical staining.
Results: Onset of LR was significantly linked only to patient's age, with a hazard ratio (HR) to relapse reduced by 60% in patients &gt;50 years of age (P = 0.002). Univariate and multivariate Cox analyses in women ≤50 years of age indicated that only expression of hyaluronan in tumor cells was associated with LR risk (HR, 2.48; P = 0.0364 and HR, 2.34; P = 0.0580, respectively). In patients &gt;50 years of age, lymph node and estrogen receptor status were significantly predictive of LR (HR, 3.34; P = 0.0113 and HR, 0.39; P = 0.0424, respectively). Multivariate analysis indicated that apart from lymph node positivity (HR, 3.48; P = 0.0120), none of the variables associated with LR in univariate analysis displayed an independent LR-predictive power. LR had a strong prognostic impact on distant metastasis in patients &gt;50 years of age, whereas in younger women, LR did not affect the risk of metastasis.
Conclusions: These results support the notion that LR arises from two distinct mechanisms, one that is more frequent in young patients, associated with host characteristics, and is not linked with prognosis, and another that is less frequent, but is associated with tumor aggressiveness which represents a peculiar and distinct marker of breast tumor malignancy.
Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients
Authors: Zeppernick Felix , Ahmadi Rezvan , Campos Benito , Dictus Christine , Helmke Burkhard M. , Becker Natalia , Lichter Peter , Unterberg Andreas , Radlwimmer Bernhard , Herold-Mende Christel C. 
Published: January 2008

AbstractPurpose: The CD133 antigen has been identified as a putative stem cell marker in normal and malignant brain tissues. In gliomas, it is used to enrich a subpopulation of highly tumorigenic cancer cells. According to the cancer stem cell hypothesis, CD133-positive cells determine long-term tumor growth and, therefore, are suspected to influence clinical outcome. To date, a correlation between CD133 expression in primary tumor tissues and patients' prognosis has not been reported.Experimental Design: To address this question, we analyzed the expression of the CD133 stem cell antigen in a series of 95 gliomas of various grade and histology by immunohistochemistry on cryostat sections. Staining data were correlated with patient outcome.Results: By multivariate survival analysis, we found that both the proportion of CD133-positive cells and their topological organization in clusters were significant (P &lt; 0.001) prognostic factors for adverse progression-free survival and overall survival independent of tumor grade, extent of resection, or patient age. Furthermore, proportion of CD133-positive cells was an independent risk factor for tumor regrowth and time to malignant progression in WHO grade 2 and 3 tumors.Conclusions: These findings constitute the first conclusive evidence that CD133 stem cell antigen expression correlates with patient survival in gliomas, lending support to the current cancer stem cell hypothesis.
Cardiac Toxicity in Breast Cancer Survivors: Review of Potential Cardiac Problems
Authors: Bird Brian R.J. Healey , Swain Sandra M. 
Published: January 2008

Abstract
As breast cancer survival is increased by the diagnosis of earlier-stage disease and treatments improve, the side effects of cancer treatments, such as cardiotoxicity, remain clinically important. Although physicians have known for 30 years that anthracyclines cause acute and chronic cardiotoxicity, the cardiotoxic effects of radiation therapy, hormonal therapy (including tamoxifen and the aromatase inhibitors), and chemotherapy with taxanes and trastuzumab treatment have emerged more recently. This review examines the cardiac toxicity of adjuvant therapy, monitoring for early changes and existing guidelines for monitoring cardiac function in patients with breast cancer.
Bendamustine (Treanda) Displays a Distinct Pattern of Cytotoxicity and Unique Mechanistic Features Compared with Other Alkylating Agents
Authors: Leoni Lorenzo M. , Bailey Brandi , Reifert Jack , Bendall Heather H. , Zeller Robert W. , Corbeil Jacques , Elliott Gary , Niemeyer Christina C. 
Published: January 2008

AbstractPurpose: Bendamustine has shown clinical activity in patients with disease refractory to conventional alkylator chemotherapy. The purpose of this study was to characterize the mechanisms of action of bendamustine and to compare it with structurally related compounds.Experimental Design: Bendamustine was profiled in the National Cancer Institute in vitro antitumor screen. Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard.Results: Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism.Conclusion: These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile.
Using Pharmacokinetic and Pharmacodynamic Modeling and Simulation to Evaluate Importance of Schedule in Topotecan Therapy for Pediatric Neuroblastoma
Authors: Panetta John C. , Schaiquevich Paula , Santana Victor M. , Stewart Clinton F. 
Published: January 2008

Abstract
Purpose: The study aims to use mathematical modeling and simulation to assess the relative contribution of topotecan systemic exposure and scheduling in the activity and myelosuppression of topotecan in pediatric patients with neuroblastoma.
Experimental Design: Pharmacokinetic and pharmacodynamic data were obtained from a phase II study for pediatric patients with high-risk neuroblastoma. The topotecan dosage was individualized to attain a topotecan lactone area under the plasma concentration-time curve between 80 and 120 ng/mL h and given over a protracted schedule (i.e., 10 days). Four mathematical models describing topotecan pharmacokinetics, tumor growth, and neutrophil and platelet dynamics were developed. The models were combined to simulate and compare different topotecan treatment strategies with respect to systemic exposure and schedule.
Results: The median change in tumor volume was significantly different between schedules (5% increase for D × 5 versus 60% decrease for D × 5 × 2; P &lt; 0.0001) when administering the same total systemic exposure. Whereas protracted schedules showed increased neutropenia (median of 7 versus 12 days below an absolute neutrophil count of 500/μL; P &lt; 0.0001) and thrombocytopenia (median of 3 versus 10 days below a platelet count of 20,000/μL; P &lt; 0.00001), simulations showed that delays in topotecan therapy would not be required. Simulations showed that an increase in topotecan exposure on the D × 5 schedule by 2.4-fold resulted in a modest decrease in tumor volume (i.e., median percentage change tumor volume of 24% versus 3%).
Conclusions: The present mathematical model gave an innovative approach to determining relevant topotecan schedules for possible evaluation in the clinic, which could lead to improved tumor response with minimized toxicities.
A Phase II Clinical Trial of Sorafenib in Androgen-Independent Prostate Cancer
Authors: Dahut William L. , Scripture Charity , Posadas Edwin , Jain Lokesh , Gulley James L. , Arlen Philip M. , Wright John J. , Yu Yunkai , Cao Liang , Steinberg Seth M. , Aragon-Ching Jeanny B. , Venitz Jürgen , Jones Elizabeth , Chen Clara C. , Figg William D. 
Published: January 2008

AbstractPurpose: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC).Experimental Design: Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles.Results: Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimenn. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC0-12) and maximum concentration (Cmax) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (tmax) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively.Conclusions: Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.
Effects of Salt Compensation on the Climate Model Response in Simulations of Large Changes of the Atlantic Meridional Overturning Circulation*
Authors: Stocker Thomas F. , Timmermann Axel , Renold Manuel , Timm Oliver 
Published: January 2008

AbstractFreshwater hosing experiments with a comprehensive coupled climate model and a coupled model of intermediate complexity are performed with and without global salt compensation in order to investigate the robustness of the bipolar seesaw. In both cases, a strong reduction of the Atlantic meridional overturning circulation is induced, and a warming in the South Atlantic results. When a globally uniform salt flux is applied at the surface in order to keep the global mean salinity constant, this causes additional widespread warming in the Southern Ocean. It is shown that this warming is mainly due to heat transport anomalies that are induced by the specific parameterization in ocean models to represent eddy mixing. Surface salt fluxes tend to move outcropping isopycnals equatorward. As the density perturbation originates at the surface, changes in isopycnal slopes are generated that lead to anomalies in the bolus velocity field. The associated bolus heat flux convergence creates a warming enhancing the bipolar seesaw response, particularly in the Southern Ocean. The importance of this mechanism is illustrated in coupled model simulations in which this parameterization in the ocean model component is switched on or off. Additional experiments in which the same total amount of freshwater is delivered at rates 10 times smaller show that the effect of the global salt compensation is not important in this case, but that the eddy-mixing parameterization is still responsible for a substantial temperature response in the Southern Ocean.
The Granular Sea Ice Model in Spherical Coordinates and Its Application to a Global Climate Model
Authors: Sedlacek Jan , Lemieux Jean-François , Mysak Lawrence A. , Tremblay L. Bruno , Holland David M. 
Published: January 2008

Abstract
The granular sea ice model (GRAN) from Tremblay and Mysak is converted from Cartesian to spherical coordinates. In this conversion, the metric terms in the divergence of the deviatoric stress and in the strain rates are included. As an application, the GRAN is coupled to the global Earth System Climate Model from the University of Victoria. The sea ice model is validated against standard datasets. The sea ice volume and area exported through Fram Strait agree well with values obtained from in situ and satellite-derived estimates. The sea ice velocity in the interior Arctic agrees well with buoy drift data. The thermodynamic behavior of the sea ice model over a seasonal cycle at one location in the Beaufort Sea is validated against the Surface Heat Budget of the Arctic Ocean (SHEBA) datasets. The thermodynamic growth rate in the model is almost twice as large as the observed growth rate, and the melt rate is 25% lower than observed. The larger growth rate is due to thinner ice at the beginning of the SHEBA period and the absence of internal heat storage in the ice layer in the model. The simulated lower summer melt is due to the smaller-than-observed surface melt.
Connection between Spring Conditions and Peak Summer Monsoon Rainfall in South America: Role of Soil Moisture, Surface Temperature, and Topography in Eastern Brazil
Authors: Grimm Alice M. , Pal Jeremy S. , Giorgi Filippo 
Published: January 2008

Abstract
A link between peak summer monsoon rainfall in central-east Brazil, composing part of the South American monsoon core region, and antecedent conditions in spring is disclosed. Rainfall in this region during part of spring holds a significant inverse correlation with rainfall in peak summer, especially during ENSO years. A surface–atmosphere feedback hypothesis is proposed to explain this relationship: low spring precipitation leads to low spring soil moisture and high late spring surface temperature; this induces a topographically enhanced low-level anomalous convergence and cyclonic circulation over southeast Brazil that enhances the moisture flux from northern and central South America into central-east Brazil, setting up favorable conditions for excess rainfall. Antecedent wet conditions in spring lead to opposite anomalies. The main links in this hypothesis are confirmed through correlation analysis of observed data: spring precipitation is negatively correlated to late spring surface temperature in central-east Brazil, and surface temperature in southeast Brazil is positively correlated with peak summer monsoon precipitation in central-east Brazil. The intermediary links of the surface–atmosphere feedback are tested in sensitivity experiments with the regional climate model version 3 (RegCM3). These experiments confirm that the proposed links are possible: the reduced soil moisture in central-east Brazil is shown to increase the surface temperature and produce a cyclonic anomaly over southeast Brazil, as well as increased precipitation in central-east Brazil. A crucial role of the mountains of southeast Brazil in anchoring the patterns of intraseasonal variability, and sustaining the “dipolelike” precipitation mode observed over South America, is suggested. The low predictability of monsoon rainfall anomalies in central-east Brazil during the austral summer might be partially ascribed to the fact that the models do not well reproduce the topographical features and the land–atmosphere interactions that are important for the variability in that region.
Heterogeneous Distribution of Rainfall and Discharge Regimes in the Ecuadorian Amazon Basin
Authors: Laraque A. , Ronchail J. , Cochonneau G. , Pombosa R. , Guyot J. L. 
Published: January 2008

Abstract
The hydrology of the Ecuadorian Amazon basin is still poorly documented. The research developed between the Institute for Research and Development (IRD) and the National Institute of Meteorology and Hydrology (INAMHI) of Ecuador takes advantage of a newly available rainfall and discharge dataset to explore spatial distribution and regimes in this region (135 600 km2). Forty-seven rainfall and 27 discharge stations were retained over a 30-yr period (1965–94). A new annual isoyets map is proposed for the Amazon basin of Ecuador. The most striking result is a high spatial regime variability, to the extent that out-of-phase regimes are found in nearby stations. Indeed, in high intra-Andean basins there is a marked bimodal rainfall regime, with maxima in March–April and in October and a minimum from June to August. On the contrary, as moisture transport reaches a maximum in June, a rainfall peak can also be observed at the same time on slopes to the east due to the moist easterlies. In the lowlands, a bimodal regime is observed as in the intra-Andean basin; as water vapor is abundant, seasonal variability is not as strong as in the Andes. Discharge regimes are related to rainfall regimes. However, even if no delay is observed between maximum rainfall and maximum discharge in the inner Andean basins, a delay varying from one to two months is observed in larger basins. Soil conditions also affect the discharge regime in the upper and inner Andes: paramo soils (a kind of tundra formation) release water, in particular after the March–April rainfall peak, and sustain the dry season runoff.
Flash Flood Forecasting for Small Urban Watersheds in the Baltimore Metropolitan Region
Authors: Javier Julie Rose N. , Smith James A. , Meierdiercks Katherine L. , Baeck Mary Lynn , Miller Andrew J. 
Published: January 2008

Abstract
The utility of distributed hydrologic models in combination with high-resolution Weather Surveillance Radar-1988 Doppler (WSR-88D) rainfall estimates for flash flood forecasting in urban drainage basins is examined through model simulations of 10 flood events in the 14.3 km2 Dead Run watershed of Baltimore County, Maryland. The hydrologic model consists of a simple infiltration model and a geomorphological instantaneous unit hydrograph–based representation of hillslope and channel response. Analyses are based on high-resolution radar rainfall estimates from the Sterling, Virginia, WSR-88D and observations from a nested network of 6 stream gauges in the Dead Run watershed and a network of 17 rain gauge stations in Dead Run. For the three largest flood peaks in Dead Run, including the record flood on 7 July 2004, hydrologic model forecasts do not capture the pronounced attenuation of flood peaks. Hydraulic controls imposed by valley bottom constrictions associated with bridges and bridge abutments are a dominant element of the extreme flood response of small urban watersheds. Model analyses suggest that a major limitation on the accuracy of flash flood forecasting in urban watersheds is imposed by storm water management infrastructure. Model analyses also suggest that there is potential for improving model forecasts through the utilization of information on initial soil moisture storage. Errors in the rainfall field, especially those linked to bias correction, are the largest source of uncertainty in quantitative flash flood forecasting. Bias correction of radar rainfall estimates is an important element of flash flood forecasting systems.
A Practical Approach to Sequential Estimation of Systematic Error on Near-Surface Mesoscale Grids
Authors: Hacker Joshua P. , Rife Daran L. 
Published: January 2008

Abstract
Statistical analysis arguments are used to construct an estimation algorithm for systematic error of near-surface temperatures on a mesoscale grid. The systematic error is defined as the observed running-mean error, and an averaging length of 7 days is shown to be acceptable. Those errors are spread over a numerical weather prediction model grid via the statistical analysis equation. Two covariance models are examined: 1) a stationary, isotropic function tuned with the observed running-mean errors and 2) dynamic estimates derived from a recent history of running-mean forecasts. Prediction of error is possible with a diurnal persistence model, where the error at one time of day can be estimated from data with lags of 24-h multiples. The approach is tested on 6 months of 6-h forecasts with the fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5) over New Mexico. Results show that for a quantity such as 2-m temperature, the systematic component of error can be effectively predicted on the grid. The gridded estimates fit the observed running-mean errors well. Cross validation shows that predictions of systematic error result in a substantial error reduction where observations are not available. The error estimates show a diurnal evolution, and are not strictly functions of terrain elevation. Observation error covariances, localization operators, and covariance functions in the isotropic case must be tuned for a specific forecast system and observing network, but the process is straightforward. Taken together, the results suggest an effective method for systematic error estimation on near-surface mesoscale grids in the absence of a useful ensemble. Correction for those errors may provide benefits to forecast users.