bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ron Kinase Transphosphorylation SustainsMETOncogene Addiction
Authors: Benvenuti Silvia , Lazzari Luca , Arnesano Addolorata , Li Chiavi Giulia , Gentile Alessandra , Comoglio Paolo M. 
Published: January 2011

AbstractReceptors for the scatter factors HGF and MSP that are encoded by the MET and RON oncogenes are key players in invasive growth. Receptor cross-talk between Met and Ron occurs. Amplification of the MET oncogene results in kinase activation, deregulated expression of an invasive growth phenotype, and addiction to MET oncogene signaling (i.e., dependency on sustained Met signaling for survival and proliferation). Here we show that cancer cells addicted to MET also display constitutive activation of the Ron kinase. In human cancer cell lines coexpressing the 2 oncogenes, Ron is specifically transphosphorylated by activated Met. In contrast, Ron phosphorylation is not triggered in cells harboring constitutively active kinase receptors other than Met, including Egfr or Her2. Furthermore, Ron phosphorylation is suppressed by Met-specific kinase inhibitors (PHA-665752 or JNJ-38877605). Last, Ron phosphorylation is quenched by reducing cell surface expression of Met proteins by antibody-induced shedding. In MET-addicted cancer cells, short hairpin RNA–mediated silencing of RON expression resulted in decreased proliferation and clonogenic activity in vitro and tumorigenicity in vivo. Our findings establish that oncogene addiction to MET involves Ron transactivation, pointing to Ron kinase as a target for combinatorial cancer therapy. Cancer Res; 71(5); 1945–55. ©2011 AACR.
E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models
Authors: Bello Ezia , Colella Gennaro , Scarlato Valentina , Oliva Paolo , Berndt Alexander , Valbusa Giovanni , Serra Sonia Colombo , D'Incalci Maurizio , Cavalletti Ennio , Giavazzi Raffaella , Damia Giovanna , Camboni Gabriella 
Published: January 2011

Abstract
Tumor angiogenesis is a degenerate process regulated by a complex network of proangiogenic factors. Existing antiangiogenic drugs used in clinic are characterized by selectivity for specific factors. Antiangiogenic properties might be improved in drugs that target multiple factors and thereby address the inherent mechanistic degeneracy in angiogenesis. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) family members and their cognate receptors are key players in promoting tumor angiogenesis. Here we report the pharmacologic profile of E-3810, a novel dual inhibitor of the VEGF and FGF receptors. E-3810 potently and selectively inhibited VEGF receptor (VEGFR)-1, -2, and -3 and FGF receptor (FGFR)-1 and -2 kinases in the nanomolar range. Ligand-dependent phosphorylation of VEGFR-2 and FGFR-1 was suppressed along with human vascular endothelial cell growth at nanomolar concentrations. In contrast, E-3810 lacked cytotoxic effects on cancer cell lines under millimolar concentrations. In a variety of tumor xenograft models, including early- or late-stage subcutaneous and orthotopic models, E-3810 exhibited striking antitumor properties at well-tolerated oral doses administered daily. We found that E-3810 remained active in tumors rendered nonresponsive to the general kinase inhibitor sunitinib resulting from a previous cycle of sunitinib treatment. In Matrigel plug assays performed in nude mice, E-3810 inhibited basic FGF–induced angiogenesis and reduced blood vessel density as assessed by histologic analysis. Dynamic contrast-enhanced magnetic resonance imaging analysis confirmed that E-3810 reduced the distribution of angiogenesis-sensitive contrast agents after only 5 days of treatment. Taken together, our findings identify E-3810 as a potent antiangiogenic small molecule with a favorable pharmacokinetic profile and broad spectrum antitumor activity, providing a strong rationale for its clinical evaluation. Cancer Res; 71(4); 1396–405. ©2011 AACR.
Significance and Mechanism of Lymph Node Metastasis in Cancer Progression
Authors: Kawada Kenji , Taketo Makoto M. 
Published: January 2011

Abstract
The effect of local therapy, such as surgical lymph node (LN) dissection and radiotherapy, on the survival of cancer patients has been debated for decades. Several lines of recent clinical evidence support that LN metastasis plays significant roles in systemic dissemination of cancer cells, although the effects of surgical LN dissection on survival was downplayed historically because of controversial data. Molecular studies of LN metastasis suggest that the microenvironment within LNs, including chemokines and lymphangiogenesis, can mediate the metastatic spread to the sentinel LNs, and beyond. It has been shown that chemokine receptor CXCR3 is involved in LN metastasis, and its inhibition may improve patient prognosis. Although it remains to be determined whether local therapy is best pursued through LN dissection or through a combination of resection with radiation, prevention of regional metastases is an important goal in the treatment of cancer patients to achieve a better survival. Cancer Res; 71(4); 1214–8. ©2011 AACR.
Carotid Intima-Media Thickness in Psoriatic Arthritis
Authors: Di Minno Matteo Nicola Dario , Iervolino Salvatore , Peluso Rosario , Scarpa Raffaele , Di Minno Giovanni 
Published: January 2011

Objective—
Subjects with psoriatic arthritis (PsA) have an abnormally high prevalence of vascular risk factors (VRFs) and are predisposed to vascular mortality. Tumor necrosis factor (TNF)-α, a major determinant of inflammation, is involved in atherosclerosis. Ultrasonographic carotid intima-media thickness (C-IMT) evaluation allows for subclinical atherosclerosis detection.

Methods and Results—

Two hundred twenty-four PsA patients (120 on TNF-α blockers and 104 on traditional disease-modifying antirheumatic drugs [DMARDs]) underwent a C-IMT ultrasound assessment. As many as 305 matched subjects without any inflammatory/rheumatologic disease served as controls. The C-IMT of PsA subjects without VRFs was higher (
P
<0.0001) than that of controls, the C-IMT of PsA subjects with ≥1 VRF(s) was lower (
P
<0.0001) than that of controls, and the C-IMT was lower (
P
<0.0001) in those on TNF-α blockers than in those on DMARDs. Carotid plaques were detected in 15.8% of those on TNF-α blockers and in 40.4% of those on DMARDs (
P
<0.0001). Treatment duration inversely (β=−0.317,
P
<0.0001) predicted C-IMT in PsA subjects on TNF-α blockers but not in those on DMARDs (
P
=0.313).

Conclusion—
Among PsA individuals, the C-IMT is higher in subjects on DMARDs than in those on TNF-α blockers. The reduction of inflammation may hamper the cascade that causes the raised vascular risk in PsA patients.
Dimethylarginine Dimethylaminohydrolase 1 Modulates Endothelial Cell Growth Through Nitric Oxide and Akt
Authors: Zhang Ping , Hu Xinli , Xu Xin , Chen Yingjie , Bache Robert J. 
Published: January 2011

Objective—
Dimethylarginine dimethylaminohydrolase 1 (DDAH1) modulates NO production by degrading the endogenous nitric oxide (NO) synthase (NOS) inhibitors asymmetrical dimethylarginine (ADMA) and L-NG-monomethyl arginine (L-NMMA). This study examined whether, in addition to degrading ADMA, DDAH1 exerts ADMA-independent effects that influence endothelial function.

Methods and Results—

Using selective gene silencing of DDAH1 with small interfering RNA and overexpression of DDAH1 in human umbilical vein endothelial cells, we found that DDAH1 acts to promote endothelial cell proliferation, migration, and tube formation by Akt phosphorylation, as well as through the traditional role of degrading ADMA. Incubation of human umbilical vein endothelial cells with the NOS inhibitors
l
-NG-nitro-arginine methyl ester (L-NAME) or ADMA, the soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3–2)quinoxalin-1-one, or the cGMP analog 8-(4-Chlorophenylthio)-cGMP had no effect on phosphorylated (p)-Akt
Ser473
, indicating that the increase in p-Akt
Ser473
produced by DDAH1 was independent of the NO-cGMP signaling pathway. DDAH1 formed a protein complex with Ras, and DDAH1 overexpression increased Ras activity. The Ras inhibitor manumycin-A or dominant-negative Ras significantly attenuated the DDAH1-induced increase in p-Akt
Ser473
. Furthermore, DDAH1 knockout impaired endothelial sprouting from cultured aortic rings, and overexpression of constitutively active Akt or DDAH1 rescued endothelial sprouting in the aortic rings from these mice.

Conclusion—
DDAH1 exerts a unique role in activating Akt that affects endothelial function independently of degrading endogenous NOS inhibitors.
Oxidative Stress–Induced Degradation of Thioredoxin-1 and Apoptosis Is Inhibited by Thioredoxin-1–Actin Interaction in Endothelial Cells
Authors: Zschauer Tim-Christian , Kunze Kerstin , Jakob Sascha , Haendeler Judith , Altschmied Joachim 
Published: January 2011

Objective—
Thioredoxin-1 (Trx-1), one important antioxidative enzyme in endothelial cells, is required for apoptosis inhibition. Apoptosis induction is dependent on cytoskeletal changes, which depend on actin rearrangements. Therefore, we wanted to elucidate whether a physical interaction exists between Trx-1 and actin and what the functional consequences are.

Methods and Results—

Combined immunoprecipitation/mass spectrometry identified actin as a new binding partner for Trx-1. A separate pool of Trx-1 forms a complex with apoptosis signaling kinase 1. Actin is required for stress fiber formation; thus, the interaction of actin with Trx-1 might interfere with this process. Stress fiber formation, which is directly linked to the phosphorylation of focal adhesion kinase (FAK), occurs as early as 1 hour after H
2
O
2
treatment. It is inhibited by Trx-1 overexpression, treatment with exogenous Trx-1, or inhibition of FAK. Prolonged incubation with H
2
O
2
induced stress fiber formation, reduced Trx-1 protein levels, and increased apoptosis. All these processes were inhibited by preincubation with the FAK inhibitor PF573228. On the contrary, incubation with PF573228 1 hour after H
2
O
2
treatment did not block stress fiber formation, degradation of Trx-1, or apoptosis.

Conclusion—
These data demonstrate that the actin–Trx-1 complex protects Trx-1 from degradation and, thus, endothelial cells from apoptosis. Reciprocally, Trx-1 prevents stress fiber formation.
Microinfarct Pathology, Dementia, and Cognitive Systems
Authors: Arvanitakis Zoe , Leurgans Sue E. , Barnes Lisa L. , Bennett David A. , Schneider Julie A. 
Published: January 2011

Background and Purpose—
Little is known about the role of microinfarcts in dementia and cognition. We examined microinfarcts and dementia, global cognition, and 5 cognitive systems in community-dwelling older persons.

Methods—
Four hundred twenty-five subjects enrolled in the Religious Orders Study underwent annual clinical evaluations, including 19 neuropsychological tests and assessment for dementia, and brain autopsy (39% men; mean age at death, 87; Mini-Mental State Examination score, 21). Neuropathologic examination documented the presence, number, and location of chronic microinfarcts on 6-μm hematoxylin–eosin-stained sections from cortical and subcortical regions. Multiple regression analyses adjusted for age at death, sex, education, macroscopic infarcts, Alzheimer disease pathology, and Lewy bodies.

Results—

Microinfarcts were present in 129 of 425 (30%) persons (54 cortical, 80 subcortical, 49 multiple); 58 of 129 (45%) of persons with microinfarcts did not exhibit macroscopic infarcts. Persons with microinfarcts had increased odds of dementia (OR, 1.77; 95% CI, 1.07–2.92), especially those persons with multiple cortical microinfarcts. Microinfarcts were also associated with lower average global cognition (estimate, −0.287; SE, 0.113;
P
=0.012), particularly for persons with multiple cortical microinfarcts. Microinfarcts were specifically associated with lower episodic memory (estimate, −0.279; SE, 0.138;
P
=0.044), semantic memory (estimate, −0.391; SE, 0.130;
P
=0.003), and perceptual speed (estimate, −0.400; SE, 0.117;
P
<0.001). In addition, single, multiple, and cortical microinfarcts were associated with worse semantic memory and perceptual speed (all
P
<0.028). Neither macroscopic infarcts nor AD pathology modified these associations (all
P
>0.154).

Conclusions—
Microinfarcts are common, and persons with multiple cortical microinfarcts have higher odds of dementia. Microinfarcts are also associated with lower cognition, specifically perceptual speed and semantic and episodic memory.
Impacts of Urban Processes and Urbanization on Summer Precipitation: A Case Study of Heavy Rainfall in Beijing on 1 August 2006
Authors: Miao Shiguang , Chen Fei , Li Qingchun , Fan Shuiyong 
Published: January 2011

AbstractFinescale simulations (with 500-m grid spacing) using the Weather Research and Forecasting Model (WRF) were used to investigate impacts of urban processes and urbanization on a localized, summer, heavy rainfall in Beijing. Evaluation using radar and gauge data shows that this configuration of WRF with three-dimensional variational data assimilation of local weather and GPS precipitable water data can simulate this event generally well. Additional WRF simulations were conducted to test the sensitivity of simulation of this storm to different urban processes and urban land-use scenarios. The results confirm that the city does play an important role in determining storm movement and rainfall amount. Comparison of cases with and without the presence of the city of Beijing with respect to the approaching storm shows that the urban effect seems to lead to the breaking of the squall line into convective cells over the urban area. The change of precipitation amount depends on the degree of urbanization (i.e., the change over time in the extent of Beijing city). Model results show that an early urbanization prior to 1980 decreases the maximum rainfall, whereas further urbanization in Beijing is conducive to bifurcating the path of rainfall. According to sensitivity results with a single-layer urban canopy model, the thermal transport (sensible and latent heating) induced by the presence of an urban area apparently is more important than associated momentum transport, with latent and sensible heating apparently having equally important roles in the modification of simulated precipitation. Urban surfaces tend to cause the rainfall to be more locally concentrated. High-rise urban cores may bifurcate the path of rainfall as well as increase the area percentage of heavy rainfall.
Ocean–Atmosphere Influences on Low-Frequency Warm-Season Drought Variability in the Gulf Coast and Southeastern United States
Authors: Ortegren Jason T. , Knapp Paul A. , Maxwell Justin T. , Tyminski William P. , Soulé Peter T. 
Published: January 2011

AbstractFrom the 344 state climate divisions in the conterminous United States, nine distinct regions of warm-season drought variability are identified using principal component analysis. The drought metric used is the Palmer hydrological drought index for the period 1895–2008. The focus of this paper is multidecadal drought variability in the Southeast (SEUS) and eastern Gulf South (EGS) regions of the United States, areas in which the low-frequency forcing mechanisms of warm-season drought are still poorly understood. Low-frequency drought variability in the SEUS and EGS is associated with smoothed indexed time series of major ocean–atmosphere circulation features, including two indices of spatiotemporal variability in the North Atlantic subtropical anticyclone (Bermuda high). Long-term warm-season drought conditions are significantly out of phase between the two regions. Multidecadal regimes of above- and below-average moisture in the SEUS and EGS are closely associated with slow variability in sea surface temperatures in the North Atlantic Ocean and with the summer mean position and mean strength of the Bermuda high. Multivariate linear regression indicates that 82%–92% of the low-frequency variability in warm-season moisture is explained by two of the three leading principal components of low-frequency variability in the climate indices. The findings are important for water resource managers and water-intensive industries in the SEUS and EGS. The associations identified in the paper are valuable for enhanced drought preparedness and forecasting in the study area and potentially for global models of coupled ocean–atmosphere variability.
Using an Integrated Response-Function Method to Explore Agro-Climatic Suitability for Spring Soybean Growth in North China
Authors: He Yingbin , Yao Yanmin , Tang Huajun , Chen Youqi , Li Jianping , Yang Peng , Chen Zhongxin , Xin Xiaoping , Wang Limin , Li Dandan , Deng Hui 
Published: January 2011

AbstractTo understand agro-climatic suitability for spring soybean growth in north China, an integrated crop-response-function method was developed. This method includes crop-response functions for temperature, precipitation, and sunshine and is assessed by a weighting method based on the coefficient of determination. The results show that the most suitable area (S1) for spring soybean growth occupied approximately 21.35% of the total area of north China. Among three types of spring soybeans of early maturity, middle maturity, and late maturity, middle maturity was the most suitable variety to grow in the study area, covering nearly 1.133 × 106 km2 or about 99.75% of the total area of S1. As a result of this study, the authors suggest that breeders pay more attention to middle-maturity cultivars in north China. The findings from this study may provide useful information for policy makers issuing guidelines for agricultural production.
A New Homogenized Climate Division Precipitation Dataset for Analysis of Climate Variability and Climate Change
Authors: McRoberts D. Brent , Nielsen-Gammon John W. 
Published: January 2011

AbstractA new homogeneous climate division monthly precipitation dataset [based on full network estimated precipitation (FNEP)] was created as an alternative to the National Climatic Data Center (NCDC) climate division dataset. These alternative climate division monthly precipitation values were estimated using an equal-weighted average of Cooperative Observer Program stations that contained serially complete time series. Missing station observations were estimated by a procedure that was optimized through testing on U.S. Historical Climate Network stations. Inhomogeneities in the NCDC dataset arise from two principal causes. The pre-1931 estimation of NCDC climate division monthly precipitation from statewide averages led to a significant time series discontinuity in several climate divisions. From 1931 to the present, NCDC climate division averages have been calculated from a subset of available station data within each climate division, and temporal changes in the location of available stations have caused artificial changes in the time series. The FNEP climate division dataset is recommended over the NCDC dataset for studies involving climate trends or long-term climate variability. According to the FNEP data, the 1895–2009 linear precipitation trend is positive across most of the United States, and trends exceed 10% per century across the southern plains and the Corn Belt. Remaining inhomogeneities from changes in gauge technology and station location may be responsible for an artificial trend of 1%–3% per century.
Observational Analysis of Sudden Tropical Cyclone Track Changes in the Vicinity of the East China Sea
Authors: Wu Liguang , Zong Huijun , Liang Jia 
Published: January 2011

Abstract
An observational analysis of observed sudden typhoon track changes is conducted with a focus on the underlying mechanism and the possible role of slowly varying low-frequency flows. Four typhoons that took a generally northwestward track prior to sharply turning northeastward in the vicinity of the East China Sea are investigated.
It is found that the sudden track changes occurred near the center of the Madden–Julian oscillation (MJO)-scale cyclonic circulation or at the bifurcation point of the steering flows at 700 hPa, and they were all associated with a well-developed quasi-biweekly oscillation (QBW)-scale gyre. Calculation of vorticity advection suggests that the peripheral ridging resulting from the interaction between the typhoons and the flows on the MJO and QBW scales can compress the typhoon circulation, leading to an area of high winds to the east or south of the typhoon center. The enhanced synoptic-scale winds shifted the typhoons northward and placed them in a northeastward orbit under the steering of the flows associated with the Pacific subtropical high. The sudden track change can be likened to the maneuvering of satellite orbit change in that the enhanced synoptic-scale winds act as a booster rocket to shift the typhoons northward to the southwesterly steering flows.
Dynamics of Midlatitude Tropopause Height in an Idealized Model
Authors: Zurita-Gotor Pablo , Vallis Geoffrey K. 
Published: January 2011

Abstract
This paper investigates the factors that determine the equilibrium state, and in particular the height and structure of the tropopause, in an idealized primitive equation model forced by Newtonian cooling in which the eddies can determine their own depth. Previous work has suggested that the midlatitude tropopause height may be understood as the intersection between a radiative and a dynamical constraint. The dynamical constraint relates to the lateral transfer of energy, which in midlatitudes is largely effected by baroclinic eddies, and its representation in terms of mean-flow properties. Various theories have been proposed and investigated for the representation of the eddy transport in terms of the mean flow, including a number of diffusive closures and the notion that the flow evolves to a state marginally supercritical to baroclinic instability. The radiative constraint expresses conservation of energy and so must be satisfied, although it need not necessarily be useful in providing a tight constraint on tropopause height.
This paper explores whether and how the marginal criticality and radiative constraints work together to produce an equilibrated flow and a tropopause that is internal to the fluid. The paper investigates whether these two constraints are consistent with simulated variations in the tropopause height and in the mean state when the external parameters of an idealized primitive equation model are changed. It is found that when the vertical redistribution of heat is important, the radiative constraint tightly constrains the tropopause height and prevents an adjustment to marginal criticality. In contrast, when the stratification adjustment is small, the radiative constraint is only loosely satisfied and there is a tendency for the flow to adjust to marginal criticality. In those cases an alternative dynamical constraint would be needed in order to close the problem and determine the eddy transport and tropopause height in terms of forcing and mean flow.