bluuebunny/crossref_metadata_2025_split huggingface dataset:
Construction and Characterization of Novel, Completely Human Serine Protease Therapeutics Targeting Her2/neu
Authors: Cao Yu , Mohamedali Khalid A. , Marks John W. , Cheung Lawrence H. , Hittelman Walter N. , Rosenblum Michael G. 
Published: March 2013

Abstract
Immunotoxins containing bacterial or plant toxins have shown promise in cancer-targeted therapy, but their long-term clinical use may be hampered by vascular leak syndrome and immunogenicity of the toxin. We incorporated human granzyme B (GrB) as an effector and generated completely human chimeric fusion proteins containing the humanized anti-Her2/neu single-chain antibody 4D5 (designated GrB/4D5). Introduction of a pH-sensitive fusogenic peptide (designated GrB/4D5/26) resulted in comparatively greater specific cytotoxicity although both constructs showed similar affinity to Her2/neu–positive tumor cells. Compared with GrB/4D5, GrB/4D5/26 showed enhanced and long-lasting cellular uptake and improved delivery of GrB to the cytosol of target cells. Treatment with nanomolar concentrations of GrB/4D5/26 resulted in specific cytotoxicity, induction of apoptosis, and efficient downregulation of PI3K/Akt and Ras/ERK pathways. The endogenous presence of the GrB proteinase inhibitor 9 did not impact the response of cells to the fusion construct. Surprisingly, tumor cells resistant to lapatinib or Herceptin, and cells expressing MDR-1 resistant to chemotherapeutic agents showed no cross-resistance to the GrB-based fusion proteins. Administration (intravenous, tail vein) of GrB/4D5/26 to mice bearing BT474 M1 breast tumors resulted in significant tumor suppression. In addition, tumor tissue excised from GrB/4D5/26–treated mice showed excellent delivery of GrB to tumors and a dramatic induction of apoptosis compared with saline treatment. This study clearly showed that the completely human, functionalized GrB construct can effectively target Her2/neu–expressing cells and displays impressive in vitro and in vivo activity. This construct should be evaluated further for clinical use. Mol Cancer Ther; 12(6); 979–91. ©2013 AACR.
PPP2R2C Loss Promotes Castration-Resistance and Is Associated with Increased Prostate Cancer-Specific Mortality
Authors: Bluemn Eric G. , Spencer Elysia Sophie , Mecham Brigham , Gordon Ryan R. , Coleman Ilsa , Lewinshtein Daniel , Mostaghel Elahe , Zhang Xiaotun , Annis James , Grandori Carla , Porter Christopher , Nelson Peter S. 
Published: March 2013

Abstract
Metastatic prostate cancers generally rely on androgen receptor (AR) signaling for growth and survival, even following systemic androgen-deprivation therapy (ADT). However, recent evidence suggests that some advanced prostate cancers escape ADT by using signaling programs and growth factors that bypass canonical AR ligand-mediated mechanisms. We used an in vitro high-throughput RNA interference (RNAi) screen to identify pathways in androgen-dependent prostate cancer cell lines whose loss-of-function promotes androgen ligand-independent growth. We identified 40 genes where knockdown promoted proliferation of both LNCaP and VCaP prostate cancer cells in the absence of androgen. Of these, 14 were downregulated in primary and metastatic prostate cancer, including two subunits of the protein phosphatase 2 (PP2A) holoenzyme complex: PPP2R1A, a structural subunit with known tumor-suppressor properties in several tumor types; and PPP2R2C, a PP2A substrate-binding regulatory subunit that has not been previously identified as a tumor suppressor. We show that loss of PPP2R2C promotes androgen ligand depletion-resistant prostate cancer growth without altering AR expression or canonical AR-regulated gene expression. Furthermore, cell proliferation induced by PPP2R2C loss was not inhibited by the AR antagonist MDV3100, indicating that PPP2R2C loss may promote growth independently of known AR-mediated transcriptional programs. Immunohistochemical analysis of PPP2R2C protein levels in primary prostate tumors determined that low PPP2R2C expression significantly associated with an increased likelihood of cancer recurrence and cancer-specific mortality. These findings provide insights into mechanisms by which prostate cancers resist AR-pathway suppression and support inhibiting PPP2R2C complexes or the growth pathway(s) activated by PPP2R2C as a therapeutic strategy. Mol Cancer Res; 11(6); 568–78. ©2013 AACR.
Physiological Difference in Autophagic Flux in Macrophages From 2 Mouse Strains Regulates Cholesterol Ester Metabolism
Authors: Robinet Peggy , Ritchey Brian , Smith Jonathan D. 
Published: March 2013

Objective—

DBA/2 apoE
−/−
mice have ≈10-fold larger lesions than AKR apoE
−/−
mice. The objective of this study was to determine whether macrophages from these 2 strains had altered cholesterol metabolism that might play a role in their divergent atherosclerosis susceptibility.

Approach and Results—
AKR and DBA/2 macrophages incubated with acetylated low-density lipoprotein resulted in higher cholesterol ester (CE) and lower free cholesterol accumulation in the DBA/2 cells. However, these strains had equivalent acetylated low-density lipoprotein uptake and cholesterol esterification activity. Cholesterol efflux from unloaded cells to apolipoprotein A-I or high-density lipoprotein was similar in the 2 strains. However, on acetylated low-density lipoprotein loading, cholesterol efflux was impaired in the DBA/2 cells, but this impairment was corrected by loading in the presence of an inhibitor of cholesterol esterification. Thus, the cholesterol efflux capabilities are similar in these strains, but there seemed to be a defect in lipid droplet–stored CE mobilization in DBA/2 cells. Lalistat 1, a specific inhibitor of lysosomal acid lipase, completely blocked the hydrolysis of lipid droplet–stored CE, implying that lipid droplet autophagy is responsible for CE turnover in these cells. CE turnover was 2-fold slower in DBA/2 versus AKR cells. Autophagic flux, estimated by a fluorescent light chain 3-II reporter and the increase in p62 levels after chloroquine treatment, was higher in AKR versus DBA/2 macrophages, which had an apparent decrease in autophagosome fusion with lysosomes. When autophagy was activated by amino acid starvation, CE levels decreased in DBA/2 cells.

Conclusions—
Physiological regulation of autophagy in macrophages controls CE accumulation and may modify atherosclerosis susceptibility.
The Myeloperoxidase Product Hypochlorous Acid Generates Irreversible High-Density Lipoprotein Receptor Inhibitors
Authors: Binder Veronika , Ljubojevic Senka , Haybaeck Johannes , Holzer Michael , El-Gamal Dalia , Schicho Rudolf , Pieske Burkert , Heinemann Akos , Marsche Gunther 
Published: March 2013

Objective—
Elevated levels of advanced oxidation protein products have been described in several chronic inflammatory diseases, like chronic renal insufficiency, rheumatoid arthritis, and atherosclerosis. Recent findings revealed that advanced oxidation protein products are inhibitors of the major high–density lipoprotein receptor, scavenger receptor class B, type 1 (SR-BI). Here, we investigated which oxidation-induced structural alterations convert plasma albumin into a high-density lipoprotein–receptor inhibitor.

Approach and Results—

Exposure of albumin to the physiological oxidant, hypochlorous acid, generated high-affinity SR-BI ligands. Protection of albumin–lysine residues before exposure to hypochlorous acid as well as regeneration of
N
-chloramines after oxidation of albumin completely prevented binding of oxidized albumin to SR-BI, indicating that modification of albumin–lysine residues is required to generate SR-BI ligands. Of particular interest,
N
-chloramines within oxidized albumin promoted irreversible binding to SR-BI, resulting in permanent receptor blockade. We observed that the SR-BI inhibitory activity of albumin isolated from chronic kidney disease patients correlated with the content of the myeloperoxidase-specific oxidation product 3-chlorotyrosine and was associated with alterations in the composition of high-density lipoprotein.

Conclusions—
Given that several potential atheroprotective activities of high-density lipoprotein are mediated by SR-BI, the present results raise the possibility that oxidized plasma albumin, through permanent SR-BI blockade, contributes to the pathophysiology of cardiovascular disease.
Role of BCL2-Associated Athanogene 1 in Differential Sensitivity of Human Endothelial Cells to Glucocorticoids
Authors: Mata-Greenwood Eugenia , Stewart John M. , Steinhorn Robin H. , Pearce William J. 
Published: March 2013

Objective—
Chronic therapy with synthetic glucocorticoids has been associated with cardiovascular side effects, although differential interindividual susceptibility to glucocorticoids has been observed. The objective of this study was to identify the molecular mechanisms leading to differential glucocorticoid responses in endothelial cells.

Approach and Results—
We tested the sensitivity of 42 human umbilical vein endothelial cells (HUVECs) to dexamethasone as determined by changes in gene expression, promoter transactivation, and procoagulant activity. We identified that 16 HUVECs were sensitive in every test, 14 HUVECs were sensitive in at least 1 test and 12 HUVECs were resistant in every test to dexamethasone. Nuclear translocation assays revealed that Dex-sensitive HUVECs have higher basal and Dex-stimulated levels of nuclear glucocorticoid receptor compared with Dex-resistant HUVECs. Cycloheximide assays revealed that Dex-resistant HUVECs have significantly shorter glucocorticoid receptor protein half-lives than Dex-sensitive HUVECs. Dex-resistant HUVECs have a stronger interaction of glucocorticoid receptor with the proteasomal recruiting protein, BCL2-associated athanogene 1 (BAG1), as shown by immunoprecipitation assays. Silencing BAG1 expression increased Dex-sensitivity in resistant HUVECs, whereas BAG1 overexpression decreased Dex-sensitivity in sensitive HUVECs. Finally, Dex-resistant HUVECs presented higher BAG1 expression than Dex-sensitive HUVECs.

Conclusions—
In vitro endothelial sensitivity to Dex varies within individuals and is inversely proportional to BAG1 protein expression and glucocorticoid receptor protein turnover.
Tumor Necrosis Factor Receptor–Associated Factor 2 Signaling Provokes Adverse Cardiac Remodeling in the Adult Mammalian Heart
Authors: Divakaran Vijay G. , Evans Sarah , Topkara Veli K. , Diwan Abhinav , Burchfield Jana , Gao Feng , Dong Jianwen , Tzeng Huei-Ping , Sivasubramanian Natarajan , Barger Philip M. , Mann Douglas L. 
Published: March 2013

Background—
Tumor necrosis factor superfamily ligands provoke a dilated cardiac phenotype signal through a common scaffolding protein termed tumor necrosis factor receptor–associated factor 2 (TRAF2); however, virtually nothing is known about TRAF2 signaling in the adult mammalian heart.

Methods and Results—

We generated multiple founder lines of mice with cardiac-restricted overexpression of TRAF2 and characterized the phenotype of mice with higher expression levels of TRAF2 (myosin heavy chain [MHC]-TRAF2
HC
). MHC-TRAF2
HC
transgenic mice developed a time-dependent increase in cardiac hypertrophy, left ventricular dilation, and adverse left ventricular remodeling, and a significant decrease in LV+dP/dt and LV−dP/dt when compared with littermate controls (
P
<0.05 compared with littermate). During the early phases of left ventricular remodeling, there was a significant increase in total matrix metalloproteinase activity that corresponded with a decrease in total myocardial fibrillar collagen content. As the MHC-TRAF2
HC
mice aged, there was a significant decrease in total matrix metalloproteinase activity accompanied by an increase in total fibrillar collagen content and an increase in myocardial tissue inhibitor of metalloproteinase-1 levels. There was a significant increase in nuclear factor–κB activation at 4 to 12 weeks and jun N-terminal kinases activation at 4 weeks in the MHC-TRAF2
HC
mice. Transciptional profiling revealed that >95% of the hypertrophic/dilated cardiomyopathy–related genes that were significantly upregulated genes in the MHC-TRAF2
HC
hearts contained κB elements in their promoters.

Conclusions—
These results show for the first time that targeted overexpression of TRAF2 is sufficient to mediate adverse cardiac remodeling in the heart.
Acute Aortic Dissection Determines the Fate of Initially Untreated Aortic Segments in Marfan Syndrome
Authors: Schoenhoff Florian S. , Jungi Silvan , Czerny Martin , Roost Eva , Reineke David , Matyas Gabor , Steinmann Beat , Schmidli Juerg , Kadner Alexander , Carrel Thierry 
Published: March 2013

Background—
The aim of the current study was to investigate incidence and causes of surgical interventions in primarily nontreated aortic segments after previous aortic repair in patients with Marfan syndrome.

Methods and Results—

Retrospective analysis of 86 consecutive Marfan syndrome patients fulfilling Ghent criteria that underwent 136 aortic surgeries and were followed at this institution in the past 15 years. Mean follow-up was 8.8±6.8 y. Thirty-day, 6-month, 1-year, and overall mortality was 3.5%, 5.8%, 7.0%, and 12.8%, respectively. Ninety-two percent of patients initially presented with aortic root, ascending aortic or arch lesions, whereas 8% presented with descending aortic or thoraco-abdominal lesions. Primary presentation was acute aortic dissection (AAD) in 36% (77% type A, 23% type B) and aneurismal disease in 64%. Secondary complete arch replacement had to be performed in only 6% of patients without AAD, but in 36% with AAD (
P
=0.0005). In patients without AAD, 11% required surgery on primarily nontreated aortic segments (5 of 6 patients experienced type B dissection during follow-up), whereas in patients after AAD, 48% underwent surgery of initially nontreated aortic segments (42% of patients with type A and 86% of those with type B dissection;
P
=0.0002).

Conclusions—
The need for surgery in primarily nontreated aortic segments is precipitated by an initial presentation with AAD. Early elective surgery is associated with low mortality and reintervention rates. Type B dissection in patients with Marfan syndrome is associated with a high need for extensive aortic repair, even if the dissection is being considered uncomplicated by conventional criteria.
The Impact of Green Tea and Coffee Consumption on the Reduced Risk of Stroke Incidence in Japanese Population
Authors: Kokubo Yoshihiro , Iso Hiroyasu , Saito Isao , Yamagishi Kazumasa , Yatsuya Hiroshi , Ishihara Junko , Inoue Manami , Tsugane Shoichiro 
Published: March 2013

Background and Purpose—
Few prospective studies have examined the impact of both green tea and coffee consumption on strokes. We investigated the association of the combination of those consumption with stroke incidence in a general population.

Methods—
We studied 82 369 Japanese (aged 45–74 years; without cardiovascular disease [CVD] or cancer in 1995 and 1998 for Cohort I and II, respectively) who received 13 years of mean follow-up through the end of 2007. Green tea and coffee consumption was assessed by self-administered food frequency questionnaire at baseline.

Results—

In the 1 066 718 person-years of follow-up, we documented the incidence of strokes (n=3425) and coronary heart disease (n=910). Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios (95% confidence intervals) of all strokes were 0.86 (0.78–0.95) and 0.80 (0.73–0.89) in green tea 2 to 3 and ≥4 cups/d, respectively. Higher green tea consumption was associated with inverse risks of CVD and strokes subtypes. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios (95% confidence intervals) of all strokes were 0.89 (0.80–0.99), 0.80 (0.72–0.90), and 0.81 (0.72–0.91) for coffee 3 to 6 times/week and 1 and ≥2 times/day, respectively. Coffee consumption was associated with an inverse risk of CVD and cerebral infarction. Higher green tea or coffee consumption reduced the risks of CVD and stroke subtypes (especially in intracerebral hemorrhage,
P
for interaction between green tea and coffee=0.04). None of the significant association was observed in coronary heart disease.

Conclusions—
Higher green tea and coffee consumption were inversely associated with risk of CVD and stroke in general population.
Antithesis and the One/Many in Aeschylus’ Septem
Authors: Allison June W. 
Published: March 2013

AbstractSeptemexhibits several types of antithesis. The artistic function of the antithetical modes seems to be to maintain the tension between contraries, such as Thebans/Argives, interior/exterior, public/personal, words/symbols, and one/many. The dramatic function is to project conflict, particularly, to allow the verbal duels created by Eteocles and his scout to represent for the audience the duels that take place at the gates. Although antithesis is a common feature of archaic style, Aeschylean antithesis shows arresting similarities with Empedoclean usage where contraries are unified in the process of creating and preserving the cosmos/Thebes. Likeneikosandphilia, Eteocles and Polynices, hostile by nature, are in the end shown to be one.
Sensitivities and Mechanisms of the Zonal Mean Atmospheric Circulation Response to Tropical Warming
Authors: Sun Lantao , Chen Gang , Lu Jian 
Published: March 2013

Abstract
Although El Niño and global warming are both characterized by warming in the tropical upper troposphere, the latitudinal changes of the Hadley cell edge and midlatitude eddy-driven jet are opposite in sign. Using an idealized dry atmospheric model, the zonal mean circulation changes are investigated with respect to different patterns of tropical warming. Generally speaking, an equatorward shift in circulation takes place in the presence of enhanced tropical temperature gradient or narrow tropical warming, similar to the changes associated with El Niño events. In contrast, the zonal mean atmospheric circulations expand or shift poleward in response to upper-tropospheric warming or broad tropical warming, resembling the changes under future global warming.
The mechanisms underlying these opposite changes in circulation are investigated by comparing the dry dynamical responses to a narrow tropical warming and a broad warming as analogs for El Niño and global warming. When running the idealized model in a zonally symmetric configuration in which the eddy feedback is disabled, both the narrow and broad warmings give rise to an equatorward shift of the subtropical jet. The eddy adjustment is further examined using large ensembles of transient response to a sudden switch-on of the forcing. For both narrow and broad tropical warmings, the jets move equatorward initially. In the subsequent adjustment, the initial equatorward shift is further enhanced and sustained by the low-level baroclinicity under the narrow tropical warming, whereas the initial equatorward shift transitions to a poleward shift associated with altered irreversible mixing of potential vorticity in the upper troposphere in the case of broad warming.
On the Usage of Spectral and Broadband Satellite Instrument Measurements to Differentiate Climate Models with Different Cloud Feedback Strengths
Authors: Feldman Daniel R. , Coleman Daniel M. , Collins William D. 
Published: March 2013

Abstract
Top-of-atmosphere radiometric signals associated with different high- and low-cloud–radiative feedbacks have been examined through the use of an observing system simulation experiment (OSSE). The OSSE simulates variations in the spectrally resolved and spectrally integrated signals that are due to a range of plausible feedbacks of the climate system when forced with CO2 concentrations that increase at 1% yr−1. This initial version of the OSSE is based on the Community Climate System Model, version 3 (CCSM3), and exploits the fact that CCSM3 exhibits different cloud feedback strengths for different model horizontal resolutions. In addition to the conventional broadband shortwave albedos and outgoing longwave fluxes, a dataset of shortwave spectral reflectance and longwave spectral radiance has been created. These data have been analyzed to determine simulated satellite instrument signals of poorly constrained cloud feedbacks for three plausible realizations of Earth's climate system produced by CCSM3. These data have been analyzed to estimate the observational record length of albedo, outgoing longwave radiation, shortwave reflectance, or longwave radiance required to differentiate these dissimilar Earth system realizations. Shortwave spectral measurements in visible and near-infrared water vapor overtone lines are best suited to differentiate model results, and a 33% difference in shortwave–cloud feedbacks can be detected with 20 years of continuous measurements. Nevertheless, at most latitudes and with most wavelengths, the difference detection time is more than 30 years. This suggests that observing systems of sufficiently stable calibration would be useful in addressing the contribution of low clouds to the spread of climate sensitivities currently exhibited by the models that report to the Intergovernmental Panel on Climate Change (IPCC).
Evolving Land–Atmosphere Interactions over North America from CMIP5 Simulations
Authors: Dirmeyer Paul A. , Jin Yan , Singh Bohar , Yan Xiaoqin 
Published: March 2013

Abstract
Long-term changes in land–atmosphere interactions during spring and summer are examined over North America. A suite of models from phase 5 of the Coupled Model Intercomparison Project simulating preindustrial, historical, and severe future climate change scenarios are examined for changes in soil moisture, surface fluxes, atmospheric boundary layer characteristics, and metrics of land–atmosphere coupling.
Simulations of changes from preindustrial to modern conditions show warming brings stronger surface fluxes at high latitudes, while subtropical regions of North America respond with drier conditions. There is a clear anthropogenic aerosol response in midlatitudes that reduces surface radiation and heat fluxes, leading to shallower boundary layers and lower cloud base. Over the Great Plains, the signal does not reflect a purely radiatively forced response, showing evidence that the expansion of agriculture may have offset the aerosol impacts on the surface energy and water cycle.
Future changes show soils are projected to dry across North America, even though precipitation increases north of a line that retreats poleward from spring to summer. Latent heat flux also has a north–south dipole of change, increasing north and decreasing south of a line that also moves northward with the changing season. Metrics of land–atmosphere feedback increase over most of the continent but are strongest where latent heat flux increases in the same location and season where precipitation decreases. Combined with broadly elevated cloud bases and deeper boundary layers, land–atmosphere interactions are projected to become more important in the future with possible consequences for seasonal climate prediction.