bluuebunny/crossref_metadata_2025_split huggingface dataset:
Asenapine: A Review of Acute and Extension Phase Data in Bipolar Disorder
Authors: McIntyre Roger S. 
Published: October 2010

SUMMARYThe second generation atypical antipsychotic, asenapine (Saphris), was approved by the US FDA (August 2009) for the acute treatment of manic or mixed episodes with or without psychotic features associated with bipolar I disorder in adults as well as the acute treatment of schizophrenia. Asenapine exhibits a high affinity for and antagonism at several serotonergic (5‐HT2A‐C, 5HT5A, 5HT6, 5HT7), dopaminergic (D2, D3), alpha‐adrenergic (α1 and α2), and histaminergic (H1, H2) receptor subtypes. Asenapine is the first atypical antipsychotic formulated as a fast‐dissolving, rapidly absorbed sublingual tablet. Asenapine was evaluated in adults with bipolar I disorder, manic or mixed episodes with or without psychotic features. Two identically designed 3‐week registration trials confirmed the efficacy of asenapine relative to placebo in studies that included olanzapine as an active control. The placebo‐subtracted rate of EPS (excluding akathisia) is 5% whereas the placebo‐subtracted rate of akathisia was 2%. The placebo‐subtracted rate of clinically significant weight gain (≥7%) with asenapine was approximately 5% during the 3‐week acute mania trials. A 9‐ extension trial indicated that 19% of asenapine patients will experience clinically significant weight gain. Clinically significant metabolic abnormalities were not observed during the acute and/or extension trials. Asenapine can be associated with somnolence (asenapine 24%, placebo 6%) and does not appear to be associated with clinically significant changes in vital signs, laboratory parameters, or electrocardiographic changes. Bipolar depression and recurrence prevention studies are required to fully characterize this novel agent's position in the treatment of bipolar disorder.
On the discrete logarithm problem in elliptic curves
Authors: Diem Claus 
Published: October 2010

AbstractWe study the elliptic curve discrete logarithm problem over finite extension fields. We show that for any sequences of prime powers (qi)i∈ℕand natural numbers (ni)i∈ℕwithni⟶∞andni/log (qi)⟶0 fori⟶∞, the elliptic curve discrete logarithm problem restricted to curves over the fields 𝔽qniican be solved in subexponential expected time (qnii)o(1). We also show that there exists a sequence of prime powers (qi)i∈ℕsuch that the problem restricted to curves over 𝔽qican be solved in an expected time ofe𝒪(log (qi)2/3).
Serum ferritin values in primary care: are high values overlooked?
Authors: Ogilvie Catherine , Fitzsimons Kathyrn , Fitzsimons Edward J 
Published: October 2010

ObjectiveTo examine serum ferritin values in iron-replete patients in primary care and determine the action taken on those patients with very high values (>1000 μg/l).MethodsSerum ferritin values from 4170 consecutive patients in primary care were examined. All measurements had been made at the request of the general practitioner.ResultsFerritin values in males reached a steady state by 30 years and did not increase thereafter. Values above 300 μg/l were found in 17% of all males. Female values rose progressively with age. Less than 10% of women <50 years had values >100 μg/l. By the age of 70 years, 8% had values >300 μg/l. Ferritin values >1000 μg/l were found in 59 patients. This rise was neither explained nor investigated in 32 cases.ConclusionRaised ferritin values are frequently found in samples submitted from primary care and most so in adult males. The authors also conclude that general practitioners require more guidance from haematologists in the management of patients with very high values.
Expression of Snail in Upper Urinary Tract Urothelial Carcinoma: Prognostic Significance and Implications for Tumor Invasion
Authors: Kosaka Takeo , Kikuchi Eiji , Mikami Shuji , Miyajima Akira , Shirotake Suguru , Ishida Masaru , Okada Yasunori , Oya Mototsugu 
Published: October 2010

AbstractPurpose: There are few molecular markers known to predict upper urinary tract urothelial carcinomas (UTUC) prognosis. Snail, which contributes to epithelial–mesenchymal transition (EMT), has been documented in cancer progression, but not clear yet in UTUC. We therefore addressed the expression and biological significance of Snail in UTUC.Experimental Design: To elucidate the biological significance of Snail in UTUC, we examined the immunohistochemical expression of snail in UTUC and analyzed its clinical significance in 150 patients with UTUC. Biological effects of Snail in EMT and invasion were evaluated by using small interfering RNA (siRNA) specific for Snail in urothelial carcinoma cell lines and the Matrigel invasion assay.Results: Nuclear Snail staining was very weak in superficial UTUC. In contrast, strong Snail staining was observed in many of the nucleus of invasive UTUC. Snail expression was significantly higher in the high tumor stage, high grade, and in tumors showing lymphovascular invasion (LVI). Multivariate Cox regression analysis revealed that elevated Snail expression was a significant and an independent prognostic predictor of recurrence-free survival and cancer-specific survival. Patients with positive LVI and high Snail expression showed the worse outcome. Targeting of Snail mRNA expression in UMUC-3 cells with Snail-specific siRNA downregulated the mRNA expression of Snail, Vimentin, MMP2, and MMP9. Furthermore, the cells with siRNA for Snail showed decreased invasion activity in comparison with the cells transfected with a nontargeting siRNA.Conclusion: Snail-induced EMT represents a clinically relevant mechanism of UTUC progression and an attractive target for the treatment of patients with UTUC. Clin Cancer Res; 16(23); 5814–23. ©2010 AACR.
A First-in-Human Study of Conatumumab in Adult Patients with Advanced Solid Tumors
Authors: Herbst Roy S. , Kurzrock Razelle , Hong David S. , Valdivieso Manuel , Hsu Cheng-Pang , Goyal Lovely , Juan Gloria , Hwang Yuying C. , Wong Susan , Hill John S. , Friberg Greg , LoRusso Patricia M. 
Published: October 2010

Abstract
Purpose: To determine the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of conatumumab, an investigational, fully human monoclonal agonist antibody against human death receptor 5, in patients with advanced solid tumors.
Experimental Design: In the dose-escalation phase, patients received escalating intravenous doses of conatumumab (0.3, 1, 3, 10, or 20 mg/kg, 3–9 per cohort) every 2 weeks. In the dose-expansion phase, 10 patients with colorectal cancer (CRC) and 7 with non–small cell lung cancer (NSCLC) received 20 mg/kg of conatumumab every 2 weeks.
Results: Thirty-seven patients received 1 or more doses of conatumumab. Conatumumab seemed to be well tolerated; there were no dose-limiting toxicities. Of adverse events possibly related to treatment, only 3 patients (8%) had a grade 3 event (fatigue and/or elevated lipase), and no anticonatumumab antibodies were detected. An MTD was not reached. Conatumumab exhibited dose linear kinetics from 3 to 20 mg/kg, with a mean terminal half-life of 13 to 19 days. One patient with NSCLC (0.3 mg/kg) had a confirmed partial response (PR) at week 32 (38% reduction in tumor size), with further reduction (48%) by week 96; this patient remains on conatumumab after 4.2 years with a sustained PR. Fourteen patients had a best response of stable disease, 2 for 32 weeks or more. One patient with CRC (0.3 mg/kg) and stable disease for 24 weeks had a 24% reduction in tumor size by RECIST (Response Evaluation Criteria in Solid Tumors) and a 35% reduction in the sum of standardized uptake values of all lesions measured by [18F]fluorodeoxyglucose positron emission tomographic scan. Changes in tumor levels of activated caspase-3 did not appear to be associated with tumor response.
Conclusions: Conatumumab can be administered safely up to the target dose of 20 mg/kg every 2 weeks. Clin Cancer Res; 16(23); 5883–91. ©2010 AACR.
Context-Dependent Bidirectional Regulation of the MutS Homolog 2 by Transforming Growth Factor β Contributes to Chemoresistance in Breast Cancer Cells
Authors: Yu Yang , Wang Yujun , Ren Xiubao , Tsuyada Akihiro , Li Arthur , Liu Liguang James , Wang Shizhen Emily 
Published: October 2010

AbstractThe TGF-β, a tumor suppressive cytokine in normal cells, is abused in cancer to promote the malignancy. In this study, we reported that TGF-β downregulated the mutS homolog 2 (MSH2), a central component of the DNA mismatch repair (MMR) system, in HER2-transformed MCF10A mammary epithelial cells and in breast cancer (BC) cells. This was mediated by a TGF-β–induced micro RNA (miRNA), miR-21, which targeted the 3′ untranslated region of MSH2 mRNA and downregulated its expression. A negative correlation between the expression of TGF-β1 and MSH2 was also detected in primary breast tumors. In contrast, TGF-β upregulated MSH2 in nontransformed cells through Smad-mediated, p53-dependent promoter activation, which was absent in BC cells with impaired p53 function. Although this upregulating mechanism also existed in MCF10A/HER2 and p53-proficient BC cells, both basal and TGF-β–induced MSH2 promoter activities were significantly lower than those in MCF10A. Moreover, the basal and TGF-β–induced miR-21 levels were markedly higher in transformed cells, suggesting that the preset levels of miR-21 and MSH2 promoter activity, which is affected by the p53 status, determine the outputs of the bidirectional regulation of MSH2 by TGF-β in a certain cellular context. We further found that by downregulating MSH2, TGF-β contributed to resistance to DNA-damaging chemotherapy agents in cancer cells. Our results indicated a regulatory antagonism between promoter activation and miRNA-mediated posttranscriptional inhibition underlying a dual effect of TGF-β on the DNA repair machinery, which may influence the genomic stability in a context-dependent manner and contribute to chemoresistance in cancer. Mol Cancer Res; 8(12); 1633–42. ©2010 AACR.
NF-E2–Related Factor 2 Promotes Atherosclerosis by Effects on Plasma Lipoproteins and Cholesterol Transport That Overshadow Antioxidant Protection
Authors: Barajas Berenice , Che Nam , Yin Fen , Rowshanrad Amir , Orozco Luz D. , Gong Ke Wei , Wang Xuping , Castellani Lawrence W. , Reue Karen , Lusis Aldons J. , Araujo Jesus A. 
Published: October 2010

Objective—
To test the hypothesis that NF-E2–related factor 2 (Nrf2) expression plays an antiatherogenic role by its vascular antioxidant and anti-inflammatory properties.

Methods and Results—

Nrf2 is an important transcription factor that regulates the expression of phase 2 detoxifying enzymes and antioxidant genes. Its expression in vascular cells appears to be an important factor in the protection against vascular oxidative stress and inflammation. We developed Nrf2 heterozygous (HET) and homozygous knockout (KO) mice on an apolipoprotein (apo) E–null background by sequential breeding, resulting in Nrf2
−/−
, apoE
−/−
(KO), Nrf2
−/+
, apoE
−/−
(HET) and Nrf2
+/+
, and apoE
−/−
wild-type littermates. KO mice exhibited decreased levels of antioxidant genes with evidence of increased reactive oxygen species generation compared with wild-type controls. Surprisingly, KO males exhibited 47% and 53% reductions in the degree of aortic atherosclerosis compared with HET or wild-type littermates, respectively. Decreased atherosclerosis in KO mice correlated with lower plasma total cholesterol in a sex-dependent manner. KO mice also had a decreased hepatic cholesterol content and a lower expression of lipogenic genes, suggesting that hepatic lipogenesis could be reduced. In addition, KO mice exhibited atherosclerotic plaques characterized by a lesser macrophage component and decreased foam cell formation in an in vitro lipid-loading assay. This was associated with a lower rate of cholesterol influx, mediated in part by decreased expression of the scavenger receptor CD36.

Conclusion—
Nrf2 expression unexpectedly promotes atherosclerotic lesion formation in a sex-dependent manner, most likely by a combination of systemic metabolic and local vascular effects.
Matrix Metalloproteinase Activation Predicts Amelioration of Remodeling After Dietary Modification in Injured Arteries
Authors: Tavakoli Sina , Razavian Mahmoud , Zhang Jiasheng , Nie Lei , Marfatia Ravi , Dobrucki Lawrence W. , Sinusas Albert J. , Robinson Simon , Edwards D. Scott , Sadeghi Mehran M. 
Published: October 2010

Objective—
To establish and validate early noninvasive imaging of matrix metalloproteinase (MMP) activation for monitoring the progression of vascular remodeling and response to dietary modification.

Methods and Results—

Apolipoprotein E
−/−
mice that were fed a high-fat diet underwent left common carotid artery wire injury. One week after surgery, a group of animals were withdrawn from the high-fat diet. The other group of animals continued that diet throughout the study. Micro single-photon emission computed tomographic (microSPECT)/CT imaging with RP805 (a
99m
Tc-labeled tracer targeting activated MMPs) was repeatedly performed at 2 and 4 weeks after surgery. Histological analysis at 4 weeks showed significant left carotid neointima formation, monocyte/macrophage infiltration, and upregulation of several MMPs, which were ameliorated by withdrawal from the high-fat diet. In vivo microSPECT/CT images visualized significant RP805 uptake, reflecting MMP activation, in the injured carotid arteries. MMP activation was reduced as early as 1 week after withdrawal from the high-fat diet and significantly correlated with neointimal area at 4 weeks after surgery.

Conclusion—
MMP activation predicts the progression of vascular remodeling and can track the effect of dietary modification after vascular injury.
Increased Serum N-Terminal Pro–B-Type Natriuretic Peptide Levels in Patients With Medial Arterial Calcification and Poorly Compressible Leg Arteries
Authors: Jouni Hayan , Rodeheffer Richard J. , Kullo Iftikhar J. 
Published: October 2010

Objective—
To determine whether serum levels of N-terminal (NT) pro–B-type natriuretic peptide (pro-BNP) are higher in patients with poorly compressible arteries (PCA) than in patients with peripheral artery disease (PAD) and control subjects without PCA or PAD.

Methods and Results—

Medial arterial calcification in the lower extremities results in PCA and may be associated with increased arterial stiffness and hemodynamic/myocardial stress. PCA was defined as having an ankle-brachial index >1.4 or an ankle blood pressure >255 mm Hg, whereas PAD was defined as having an ankle-brachial index ≤0.9. Study participants with PCA (n=100; aged 71±10 years; 70% men) and age- and sex-matched patients with PAD (n=300) were recruited from the noninvasive vascular laboratory. Age- and sex-matched controls (n=300) were identified from a community-based cohort and had no history of PAD. NT pro-BNP levels were approximately 2.5-fold higher in patients with PCA than in patients with PAD and approximately 4-fold higher than in age- and sex-matched controls. In multivariable regression analyses that adjusted for age, sex, smoking, hypertension, history of coronary heart disease/stroke, systolic blood pressure, and serum creatinine, NT pro-BNP levels remained significantly higher in patients with PCA than in patients with PAD and controls (
P
<0.001).

Conclusion—
Patients with medial arterial calcification and PCA have higher serum levels of NT pro-BNP than patients with PAD and controls, which is suggestive of an adverse hemodynamic milieu and increased risk for adverse cardiovascular outcomes.
Understanding Chinese Diplomatic Transformation: A Multi-Actors’ Perspective
Authors: Changhe Su 
Published: October 2010

AbstractThere is growing interest in the role of sub-central actors in Chinese diplomatic evolution. This study explores Chinese diplomatic transformation from the perspective of so-called ‘multi-actors’. It begins with a discussion about the interaction of domestic and international politics, a context where Chinese diplomacy has transformed, and then identifies the roles of local governments, governmental agencies, NGOs and enterprises in China’s changing diplomatic system. The article suggests that these new groups of actors (referred to here as multi-actors) have become important factors to be reckoned with in the Chinese diplomatic system, although their roles are still limited compared with the central government. The article concludes that the establishment of a well-organized diplomatic system, which can be used to coordinate different actors and address transnational issues, will be an enduring challenge for the undergoing reform of the Chinese diplomatic system.
Impact of the Urban Heat Island Effect on Precipitation over a Complex Geographic Environment in Northern Taiwan
Authors: Lin Chuan-Yao , Chen Wan-Chin , Chang Pao-Liang , Sheng Yang-Fan 
Published: October 2010

Abstract
To evaluate the impacts of the urban heat island (UHI) effect on precipitation over a complex geographic environment in northern Taiwan, the next-generation mesoscale model, the Weather Research and Forecasting (WRF) model, coupled with the Noah land surface model and urban canopy model (UCM), was used to study this issue. Based on a better land use classification derived from Moderate Resolution Imaging Spectroradiometer (MODIS) satellite data (the MODIS case), it has significantly improved simulation results for the accumulation rainfall pattern as compared with the original U.S. Geological Survey (USGS) 25-category land use classification (the USGS case). The precipitation system was found to develop later but stronger in the urban (MODIS) case than in the nonurban (USGS) case. In comparison with the observation by radar, simulation results predicted reasonably well; not only was the rainfall system enhanced downwind of the city over the mountainous area, but it also occurred at the upwind plain area in the MODIS case. The simulation results suggested that the correct land use classification is crucial for urban heat island modeling study. The UHI effect plays an important role in perturbing thermal and dynamic processes; it affects the location of thunderstorms and precipitation over the complex geographic environment in northern Taiwan.
Constraints on Climate Sensitivity from Radiation Patterns in Climate Models
Authors: Huber Markus , Mahlstein Irina , Wild Martin , Fasullo John , Knutti Reto 
Published: October 2010

Abstract
The estimated range of climate sensitivity, the equilibrium warming resulting from a doubling of the atmospheric carbon dioxide concentration, has not decreased substantially in past decades. New statistical methods for estimating the climate sensitivity have been proposed and provide a better quantification of relative probabilities of climate sensitivity within the almost canonical range of 2–4.5 K; however, large uncertainties remain, in particular for the upper bound. Simple indices of spatial radiation patterns are used here to establish a relationship between an observable radiative quantity and the equilibrium climate sensitivity. The indices are computed for the Coupled Model Intercomparison Project phase 3 (CMIP3) multimodel dataset and offer a possibility to constrain climate sensitivity by considering radiation patterns in the climate system. High correlations between the indices and climate sensitivity are found, for example, in the cloud radiative forcing of the incoming longwave surface radiation and in the clear-sky component of the incoming surface shortwave flux, the net shortwave surface budget, and the atmospheric shortwave attenuation variable β. The climate sensitivity was estimated from the mean of the indices during the years 1990–99 for the CMIP3 models. The surface radiative flux dataset from the Clouds and the Earth’s Radiant Energy System (CERES) together with its top-of-atmosphere Energy Balanced and Filled equivalent (CERES EBAF) are used as a reference observational dataset, resulting in a best estimate for climate sensitivity of 3.3 K with a likely range of 2.7–4.0 K. A comparison with other satellite and reanalysis datasets show similar likely ranges and best estimates of 1.7–3.8 (3.3 K) [Earth Radiation Budget Experiment (ERBE)], 2.9–3.7 (3.3 K) [International Satellite Cloud Climatology Project radiative surface flux data (ISCCP-FD)], 2.8–4.1 (3.5 K) [NASA’s Modern Era Retrospective-Analysis for Research and Application (MERRA)], 3.0–4.2 (3.6 K) [Japanese 25-yr Reanalysis (JRA-25)], 2.7–3.9 (3.4 K) [European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-Interim)], 3.0–4.0 (3.5 K) [ERA-40], and 3.1–4.7 (3.6 K) for the NCEP reanalysis. For each individual reference dataset, the results suggest that values for the sensitivity below 1.7 K are not likely to be consistent with observed radiation patterns given the structure of current climate models. For the aggregation of the reference datasets, the climate sensitivity is not likely to be below 2.9 K within the framework of this study, whereas values exceeding 4.5 K cannot be excluded from this analysis. While these ranges cannot be interpreted properly in terms of probability, they are consistent with other estimates of climate sensitivity and reaffirm that the current climatology provides a strong constraint on the lower bound of climate sensitivity even in a set of structurally different models.
Hysteresis Behavior of the Atlantic Ocean Circulation Identified in Observational Data
Authors: Dima Mihai , Lohmann Gerrit 
Published: October 2010

Abstract
On the basis of the multidecadal component of a Fram Strait sea ice export reconstruction and on a sea surface temperature proxy for changes in the ocean circulation, a bifurcation diagram for two cycles of the Atlantic Ocean multidecadal oscillation is constructed. It suggests a hysteresis behavior that is consistent with nonlinear convective adjustment to changes in deep-water formation in the North Atlantic and with the meridional overturning circulation bistability associated with two distinct configurations of the North Atlantic subpolar gyre, simulated in response to idealized carbon dioxide increase. The nonlinear dynamics of the Atlantic Ocean circulation emphasized here on the basis of observational data adds to the hysteresis behavior shown in theoretical and numerical studies.
On the Persistence of Cold-Season SST Anomalies Associated with the Annular Modes
Authors: Ciasto Laura M. , Alexander Michael A. , Deser Clara , England Matthew H. 
Published: October 2010

Abstract
In this study, a simple stochastic climate model is used to examine the impact of the ocean mixed layer depth, surface turbulent energy fluxes, and Ekman currents on the persistence of cold-season extratropical sea surface temperature (SST) anomalies associated with variability in the annular modes of atmospheric circulation in both hemispheres. Observational analysis reveals that during the cold season, SST anomalies associated with the southern annular mode (SSTSAM) persist considerably longer than those associated with the northern annular mode (SSTNAM). Using the simple model, it is shown that the persistence of the cold-season SSTSAM is consistent with the simple stochastic climate paradigm in which the atmospheric forcing is approximated as white noise, and the persistence of SST anomalies can be largely determined by the thermal inertia of the ocean mixed layer. In the North Atlantic, however, the simple climate model overestimates the persistence of the cold-season SSTNAM. It is thought that this overestimate occurs because the NAM-related heat flux forcing cannot be described purely as white noise but must also include a feedback from the underlying SST anomalies.