bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for the Ubiquitin Protease UBP43 as an Antineoplastic Target
Authors: Guo Yongli , Chinyengetere Fadzai , Dolinko Andrey V. , Lopez-Aguiar Alexandra , Lu Yun , Galimberti Fabrizio , Ma Tian , Feng Qing , Sekula David , Freemantle Sarah J. , Andrew Angeline S. , Memoli Vincent , Dmitrovsky Ethan 
Published: July 2012

Abstract
New pharmacologic targets are needed for lung cancer. One candidate pathway to target is composed of the E1-like ubiquitin-activating enzyme (UBE1L) that associates with interferon-stimulated gene 15 (ISG15), which complexes with and destabilizes cyclin D1. Ubiquitin protease 43 (UBP43/USP18) removes ISG15 from conjugated proteins. This study reports that gain of UBP43 stabilized cyclin D1, but not other D-type cyclins or cyclin E. This depended on UBP43 enzymatic activity; an enzymatically inactive UBP43 did not affect cyclin D1 stability. As expected, small interfering RNAs that reduced UBP43 expression also decreased cyclin D1 levels and increased apoptosis in a panel of lung cancer cell lines. Forced cyclin D1 expression rescued UBP43 apoptotic effects, which highlighted the importance of cyclin D1 in conferring this. Short hairpin RNA-mediated reduction of UBP43 significantly increased apoptosis and reduced murine lung cancer growth in vitro and in vivo after transplantation of these cells into syngeneic mice. These cells also exhibited increased response to all-trans-retinoic acid, interferon, or cisplatin treatments. Notably, gain of UBP43 expression antagonized these effects. Normal-malignant human lung tissue arrays were examined independently for UBP43, cyclin D1, and cyclin E immunohistochemical expression. UBP43 was significantly (P &lt; 0.01) increased in the malignant versus normal lung. A direct relationship was found between UBP43 and cyclin D1 (but not cyclin E) expression. Differential UBP43 expression was independently detected in a normal-malignant tissue array with diverse human cancers. Taken together, these findings uncovered UBP43 as a previously unrecognized antineoplastic target. Mol Cancer Ther; 11(9); 1968–77. ©2012 AACR.
Impact of Screening Test Performance and Cost on Mortality Reduction and Cost-effectiveness of Multimodal Ovarian Cancer Screening
Authors: Drescher Charles W. , Hawley Sarah , Thorpe Jason D. , Marticke Simone , McIntosh Martin , Gambhir Sanjiv S. , Urban Nicole 
Published: July 2012

Abstract
Ongoing ovarian cancer screening trials are investigating the efficacy of a two-step screening strategy using currently available blood and imaging tests [CA125 and transvaginal sonography (TVS)]. Concurrently, efforts to develop new biomarkers and imaging tests seek to improve screening performance beyond its current limits. This study estimates the mortality reduction, years of life saved, and cost-effectiveness achievable by annual multimodal screening using increasing CA125 to select women for TVS, and predicts improvements achievable by replacing currently available screening tests with hypothetical counterparts with better performance characteristics. An existing stochastic microsimulation model is refined and used to screen a virtual cohort of 1 million women from ages 45 to 85 years. Each woman is assigned a detailed disease course and screening results timeline. The preclinical behavior of CA125 and TVS is simulated using empirical data derived from clinical trials. Simulations in which the disease incidence and performance characteristics of the screening tests are independently varied are conducted to evaluate the impact of these factors on overall screening performance and costs. Our results show that when applied to women at average risk, annual screening using increasing CA125 to select women for TVS achieves modest mortality reduction (∼13%) and meets currently accepted cost-effectiveness guidelines. Screening outcomes are relatively insensitive to second-line test performance and costs. Identification of a first-line test that does substantially better than CA125 and has similar costs is required for screening to reduce ovarian mortality by at least 25% and be reasonably cost-effective. Cancer Prev Res; 5(8); 1015–24. ©2012 AACR.
DDX5 Regulates DNA Replication and Is Required for Cell Proliferation in a Subset of Breast Cancer Cells
Authors: Mazurek Anthony , Luo Weijun , Krasnitz Alexander , Hicks James , Powers R. Scott , Stillman Bruce 
Published: June 2012

Abstract
Understanding factors required for DNA replication will enrich our knowledge of this important process and potentially identify vulnerabilities that can be exploited in cancer therapy. We applied an assay that measures the stability of maintenance of an episomal plasmid in human tissue culture cells to screen for new DNA replication factors. We identify an important role for DDX5 in G1–S-phase progression where it directly regulates DNA replication factor expression by promoting the recruitment of RNA polymerase II to E2F-regulated gene promoters. We find that the DDX5 locus is frequently amplified in breast cancer and that breast cancer–derived cells with amplification of DDX5 are much more sensitive to its depletion than breast cancer cells and a breast epithelial cell line that lacks DDX5 amplification. Our results show a novel role for DDX5 in cancer cell proliferation and suggest DDX5 as a therapeutic target in breast cancer treatment.
Significance: DDX5 is required for cell proliferation by controlling the transcription of genes expressing DNA replication proteins in cancer cells in which the DDX5 locus is amplified, and this has uncovered a dependence on DDX5 for cell proliferation. Given the high frequency of DDX5 amplification in breast cancer, our results highlight DDX5 as a promising candidate for targeted therapy of breast tumors with DDX5 amplification, and indeed we show that DDX5 inhibition sensitizes a subset of breast cancer cells to trastuzumab. Cancer Discov; 2(9); 812–25. ©2012 AACR.
This article is highlighted in the In This Issue feature, p. 753.
Racial and Ethnic Differences in Incident Hospitalized Heart Failure in Postmenopausal Women
Authors: Eaton Charles B. , Abdulbaki Abdulrahman M. , Margolis Karen L. , Manson JoAnn E. , Limacher Marian , Klein Liviu , Allison Matthew A. , Robinson Jennifer G. , Curb J. David , Martin Lisa A. , Liu Simin , Howard Barbara V. 
Published: July 2012

Background—
The differences in the incidence of heart failure by race/ethnicity and the potential mechanisms for these differences are largely unexplored in women.

Methods and Results—
A total of 156 143 postmenopausal women free of self-reported heart failure enrolled from 1993 to 1998 at 40 clinical centers throughout the United States as part of the Women's Health Initiative and were followed up until 2005, for an average of 7.8 years, for incident hospitalized heart failure. Incident rates, hazard ratios (HRs), and 95% confidence intervals were determined by use of the Cox proportional hazard model comparing racial/ethnic groups, and population-attributable risk percentages were calculated for each racial/ethnic group. Blacks had the highest age-adjusted incidence of heart failure (380 in 100 000 person-years), followed by whites (274), Hispanics (193), and Asian/Pacific Islanders (103). The excess risk in blacks compared with whites (age-adjusted HR=1.45) was significantly attenuated by adjustment for household income (HR=0.97) and diabetes mellitus (HR=0.89), but the lower risk in Hispanics (age-adjusted HR=0.72) and Asian/Pacific Islanders (age-adjusted HR=0.44) remained despite adjustment for traditional risk factors, socioeconomic status, lifestyle, and access-to-care variables. The effect of adjustment for interim coronary heart disease on nonwhite versus white HRs for heart failure differed by race/ethnic group.

Conclusions—
Asian/Pacific Islander and Hispanic women have a lower incidence of heart failure and black women have higher rates of heart failure compared with white women. The excess risk of incident heart failure in black women is explained largely by adjustment for lower household incomes and diabetes mellitus in black women, whereas the lower rates of heart failure in Asian/Pacific Islanders and Hispanics are largely unexplained by the risk factors measured in this study.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000611.
Ca
2+
-Stimulated Adenylyl Cyclase AC1 Generates Efficient Biological Pacing as Single Gene Therapy and in Combination With HCN2
Authors: Boink Gerard J.J. , Nearing Bruce D. , Shlapakova Iryna N. , Duan Lian , Kryukova Yelena , Bobkov Yevgeniy , Tan Hanno L. , Cohen Ira S. , Danilo Peter , Robinson Richard B. , Verrier Richard L. , Rosen Michael R. 
Published: June 2012

Background—

Biological pacing performed solely via HCN2 gene transfer in vivo results in relatively slow idioventricular rates and only moderate autonomic responsiveness. We induced biological pacing using the Ca
2+
-stimulated adenylyl cyclase AC1 gene expressed alone or in combination with HCN2 and compared outcomes with those with single-gene HCN2 transfer.

Methods and Results—

We implanted adenoviral HCN2, AC1, or HCN2/AC1 constructs into the left bundle branches of atrioventricular-blocked dogs. During steady-state gene expression (days 5–7), differences between AC1, HCN2/AC1, and HCN2 alone were evident in basal beating rate, escape time, and dependence on electronic backup pacing. In HCN2, AC1, and HCN2/AC1, these parameters were as follows: basal beating rate: 50±1.5, 60±5.0, and 129±28.9 bpm (
P
<0.05 for HCN2/AC1 versus HCN2 or AC1 alone), respectively; escape time: 2.4±0.2, 1.3±0.2, and 1.1±.0.4 seconds (
P
<0.05 for AC1 and HCN2/AC1 versus HCN2); and percent electronic beats: 34±8%, 2±1%, and 6±2% (
P
<0.05 for AC1 and HCN2/AC1 versus HCN2). Instantaneous (SD1) and long-term (SD2) heart rate variability and circadian rhythm analyzed via 24-hour Holter recordings showed a shift toward greater sensitivity to parasympathetic modulation in animals injected with AC1 and a high degree of sympathetic modulation in animals injected with HCN2/AC1.

Conclusion—
AC1 or HCN2/AC1 overexpression in left bundle branches provides highly efficient biological pacing and greater sensitivity to autonomic modulation than HCN2 alone.
Western-Style Fast Food Intake and Cardiometabolic Risk in an Eastern Country
Authors: Odegaard Andrew O. , Koh Woon Puay , Yuan Jian-Min , Gross Myron D. , Pereira Mark A. 
Published: July 2012

Background—
Western-style fast food contributes to a dietary pattern portending poor cardiometabolic health in the United States. With globalization, this way of eating is becoming more common in developing and recently developed populations.

Methods and Results—
We examined the association of Western-style fast food intake with risk of incident type 2 diabetes mellitus and coronary heart disease mortality in Chinese Singaporeans. This analysis included men and women 45 to 74 years of age who enrolled in the Singapore Chinese Health Study from 1993 to 1998. For CHD mortality, 52 584 participants were included and 1397 deaths were identified through December 31, 2009, via registry linkage. For type 2 diabetes mellitus, 43 176 participants were included and 2252 cases were identified during the follow-up interview (1999–2004) and validated. Hazard ratios for incident type 2 diabetes mellitus and coronary heart disease mortality were estimated with thorough adjustment for demographic, lifestyle, and dietary factors. Chinese Singaporeans with relatively frequent intake of Western-style fast food items (≥2 times per week) had an increased risk of developing type 2 diabetes mellitus (hazard ratio, 1.27; 95% confidence interval, 1.03–1.54) and dying of coronary heart disease (hazard ratio, 1.56; 95% confidence interval, 1.18–2.06) relative to their peers with little or no reported intake. These associations were not materially altered by adjustments for overall dietary pattern, energy intake, and body mass index.

Conclusions—
Western-style fast food intake is associated with increased risk of developing type 2 diabetes mellitus and of coronary heart disease mortality in an Eastern population. These findings suggest the need for further attention to global dietary acculturation in the context of ongoing epidemiological and nutrition transitions.
Elevated Vascular Endothelial Growth Factor Receptor-2 Abundance Contributes to Increased Angiogenesis in Vascular Endothelial Growth Factor Receptor-1–Deficient Mice
Authors: Ho Vivienne C. , Duan Li-Juan , Cronin Chunxia , Liang Bruce T. , Fong Guo-Hua 
Published: June 2012

Background—

Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline
Vegfr-1
−/−
embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy.

Methods and Results—

We performed Cre-
lox
P–mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell proliferation and facilitated angiogenesis of blood vessels that matured and perfused properly. Vascular permeability was normal at the basal level but elevated in response to high doses of exogenous VEGF-A. In the postinfarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of the VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of
Vegfr-2
+/−
heterozygosity into
Vegfr-1
somatic knockout mice.

Conclusions—
Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1–deficient mice.
Cloud-Resolving Model Simulations with One- and Two-Way Couplings via the Weak Temperature Gradient Approximation
Authors: Daleu C. L. , Woolnough S. J. , Plant R. S. 
Published: June 2012

AbstractA cloud-resolving model is modified to implement the weak temperature gradient approximation in order to simulate the interactions between tropical convection and the large-scale tropical circulation. The instantaneous domain-mean potential temperature is relaxed toward a reference profile obtained from a radiative–convective equilibrium simulation of the cloud-resolving model. For homogeneous surface conditions, the model state at equilibrium is a large-scale circulation with its descending branch in the simulated column. This is similar to the equilibrium state found in some other studies, but not all. For this model, the development of such a circulation is insensitive to the relaxation profile and the initial conditions.Two columns of the cloud-resolving model are fully coupled by relaxing the instantaneous domain-mean potential temperature in both columns toward each other. This configuration is energetically closed in contrast to the reference-column configuration. No mean large-scale circulation develops over homogeneous surface conditions, regardless of the relative area of the two columns. The sensitivity to nonuniform surface conditions is similar to that obtained in the reference-column configuration if the two simulated columns have very different areas, but it is markedly weaker for columns of comparable area. The weaker sensitivity can be understood as being a consequence of a formulation for which the energy budget is closed. The reference-column configuration has been used to study the convection in a local region under the influence of a large-scale circulation. The extension to a two-column configuration is proposed as a methodology for studying the influence on local convection of changes in remote convection.
Investigating the Use of a Genesis Potential Index for Tropical Cyclones in the North Atlantic Basin
Authors: Bruyère Cindy L. , Holland Greg J. , Towler Erin 
Published: June 2012

AbstractLarge-scale environmental variables known to be linked to the formation of tropical cyclones have previously been used to develop empirical indices as proxies for assessing cyclone frequency from large-scale analyses or model simulations. Here the authors examine the ability of two recent indices, the genesis potential (GP) and the genesis potential index, to reproduce observed North Atlantic cyclone annual frequency variations and trends. These skillfully estimate the mean seasonal variation of observed cyclones, but they struggle with reproducing interannual frequency variability and change. Examination of the independent contributions by the four terms that make up the indices finds that potential intensity and shear have significant skill, while moisture and vorticity either do not contribute to or degrade the indices’ capacity to reproduce observed interannual variability. It is also found that for assessing basinwide cyclone frequency, averaging indices over the whole basin is less skillful than its application to the general area off the coast of Africa broadly covering the main development region (MDR).These results point to a revised index, the cyclone genesis index (CGI), which comprises only potential intensity and vertical shear. Application of the CGI averaged over the MDR demonstrates high and significant skill at reproducing interannual variations and trends in all-basin cyclones across both reanalyses. The CGI also provides a more accurate reproduction of seasonal variations than the original GP. Future work applying the CGI to other tropical cyclone basins and to the downscaling of relatively course climate simulations is briefly addressed.
Storm-Track Activity in IPCC AR4/CMIP3 Model Simulations
Authors: Chang Edmund K. M. , Guo Yanjuan , Xia Xiaoming , Zheng Minghua 
Published: June 2012

Abstract
The climatological storm-track activity simulated by 17 Intergovernmental Panel on Climate Change Fourth Assessment Report (IPCC AR4)/phase 3 of the Coupled Model Intercomparison Project (CMIP3) models is compared to that in the interim ECMWF Re-Analysis (ERA-Interim). Nearly half of the models show significant biases in storm-track amplitude: four models simulate storm tracks that are either significantly (&gt;20%) too strong or too weak in both hemispheres, while four other models have interhemispheric storm-track ratios that are biased by over 10%. Consistent with previous studies, storm-track amplitude is found to be negatively correlated with grid spacing. The interhemispheric ratio of storm-track activity is highly correlated with the interhemispheric ratio of mean available potential energy, and this ratio is biased in some model simulations due to biases in the midlatitude temperature gradients. In terms of geographical pattern, the storm tracks in most CMIP3 models exhibit an equatorward bias in both hemispheres. For the seasonal cycle, most models can capture the equatorward migration and strengthening of the storm tracks during the cool season, but some models exhibit biases in the amplitude of the seasonal cycle.
Possible implications of model biases in storm-track climatology have been investigated. For both hemispheres, models with weak storm tracks tend to have larger percentage changes in storm-track amplitudes over the seasonal cycle. Under global warming, for the NH, models with weak storm tracks tend to project larger percentage changes in storm-track amplitude whereas, for the SH, models with large equatorward biases in storm-track latitude tend to project larger poleward shifts. Preliminary results suggest that CMIP5 model projections also share these behaviors.
Influence of Ocean and Atmosphere Components on Simulated Climate Sensitivities
Authors: Winton Michael , Adcroft Alistair , Griffies Stephen M. , Hallberg Robert W. , Horowitz Larry W. , Stouffer Ronald J. 
Published: June 2012

Abstract
The influence of alternative ocean and atmosphere subcomponents on climate model simulation of transient sensitivities is examined by comparing three GFDL climate models used for phase 5 of the Coupled Model Intercomparison Project (CMIP5). The base model ESM2M is closely related to GFDL’s CMIP3 climate model version 2.1 (CM2.1), and makes use of a depth coordinate ocean component. The second model, ESM2G, is identical to ESM2M but makes use of an isopycnal coordinate ocean model. The authors compare the impact of this “ocean swap” with an “atmosphere swap” that produces the GFDL Climate Model version 3 (CM3) by replacing the AM2 atmospheric component with AM3 while retaining a depth coordinate ocean model. The atmosphere swap is found to have much larger influence on sensitivities of global surface temperature and Northern Hemisphere sea ice cover. The atmosphere swap also introduces a multidecadal response time scale through its indirect influence on heat uptake. Despite significant differences in their interior ocean mean states, the ESM2M and ESM2G simulations of these metrics of climate change are very similar, except for an enhanced high-latitude salinity response accompanied by temporarily advancing sea ice in ESM2G. In the ESM2G historical simulation this behavior results in the establishment of a strong halocline in the subpolar North Atlantic during the early twentieth century and an associated cooling, which are counter to observations in that region. The Atlantic meridional overturning declines comparably in all three models.
Modeling the Atmospheric Response to Irrigation in the Great Plains. Part II: The Precipitation of Irrigated Water and Changes in Precipitation Recycling
Authors: Harding Keith J. , Snyder Peter K. 
Published: June 2012

Abstract
The rapid expansion of irrigation in the Great Plains since World War II has resulted in significant water table declines, threatening the long-term sustainability of the Ogallala Aquifer. As discussed in Part I of this paper, the Weather Research and Forecasting Model (WRF) was modified to simulate the effects of irrigation at subgrid scales. Simulations of nine April–October periods (three drought, three normal, and three pluvial) over the Great Plains were completed to assess the full impact of irrigation on the water budget. Averaged over all simulated years, irrigation over the Great Plains contributes to May–September evapotranspiration increases of approximately 4% and precipitation increases of 1%, with localized increases of up to 20%. Results from these WRF simulations are used along with a backward trajectory analysis to identify where evapotranspiration from irrigated fields falls as precipitation (i.e., irrigation-induced precipitation) and how irrigation impacts precipitation recycling. On average, only 15.8% of evapotranspiration from irrigated fields falls as precipitation over the Great Plains, resulting in 5.11 mm of May–September irrigation-induced precipitation and contributing to 6.71 mm of recycled precipitation. Reductions in nonrecycled precipitation suggest that irrigation reduces precipitation of moisture advected into the region. The heaviest irrigation-induced precipitation is coincident with simulated and observed precipitation increases, suggesting that observed precipitation increases in north-central Nebraska are strongly related to evapotranspiration of irrigated water. Water losses due to evapotranspiration are much larger than irrigation-induced precipitation and recycled precipitation increases, confirming that irrigation results in net water loss over the Great Plains.