bluuebunny/crossref_metadata_2025_split huggingface dataset:
GDC-0980 Is a Novel Class I PI3K/mTOR Kinase Inhibitor with Robust Activity in Cancer Models Driven by the PI3K Pathway
Authors: Wallin Jeffrey J. , Edgar Kyle A. , Guan Jane , Berry Megan , Prior Wei Wei , Lee Leslie , Lesnick John D. , Lewis Cristina , Nonomiya Jim , Pang Jodie , Salphati Laurent , Olivero Alan G. , Sutherlin Daniel P. , O'Brien Carol , Spoerke Jill M. , Patel Sonal , Lensun Letitia , Kassees Robert , Ross Leanne , Lackner Mark R. , Sampath Deepak , Belvin Marcia , Friedman Lori S. 
Published: October 2011

Abstract
Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene, loss or mutation of phosphatase and tensin homolog (PTEN), and deregulation of mammalian target of rapamycin (mTOR) complexes. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K and mTOR are promising therapeutic targets for cancer. We discovered GDC-0980, a selective, potent, orally bioavailable inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2) with excellent pharmacokinetic and pharmaceutical properties. GDC-0980 potently inhibits signal transduction downstream of both PI3K and mTOR, as measured by pharmacodynamic (PD) biomarkers, thereby acting upon two key pathway nodes to produce the strongest attainable inhibition of signaling in the pathway. Correspondingly, GDC-0980 was potent across a broad panel of cancer cell lines, with the greatest potency in breast, prostate, and lung cancers and less activity in melanoma and pancreatic cancers, consistent with KRAS and BRAF acting as resistance markers. Treatment of cancer cell lines with GDC-0980 resulted in G1 cell-cycle arrest, and in contrast to mTOR inhibitors, GDC-0980 induced apoptosis in certain cancer cell lines, including those with direct pathway activation via PI3K and PTEN. Low doses of GDC-0980 potently inhibited tumor growth in xenograft models including those with activated PI3K, loss of LKB1 or PTEN, and elicited an exposure-related decrease in PD biomarkers. These preclinical data show that GDC-0980 is a potent and effective dual PI3K/mTOR inhibitor with promise for the clinic. Mol Cancer Ther; 10(12); 2426–36. ©2011 AACR.
Endoplasmic Reticulum Stress and Glycogen Synthase Kinase-3β Activation in Apolipoprotein E–Deficient Mouse Models of Accelerated Atherosclerosis
Authors: McAlpine Cameron S. , Bowes Anna J. , Khan Mohammad I. , Shi Yuanyuan , Werstuck Geoff H. 
Published: October 2011

Objective—

The goal of this study was to examine the role of endoplasmic reticulum (ER) stress signaling and the contribution of glycogen synthase kinase (GSK)-3β activation in hyperglycemic, hyperhomocysteinemic, and high-fat–fed apolipoprotein E–deficient (apoE
−/−
) mouse models of accelerated atherosclerosis.

Methods and Results—

Female apoE
−/−
mice received multiple low-dose injections of streptozotocin (40 μg/kg) to induce hyperglycemia, methionine-supplemented drinking water (0.5% wt/vol) to induce hyperhomocysteinemia, or a high-fat (21% milk fat+0.2% cholesterol) diet to induce relative dyslipidemia. A subset of mice from each group was supplemented with sodium valproate (625 mg/kg), a compound with GSK3 inhibitory activity. At 15 and 24 weeks of age, markers of ER stress, lipid accumulation, GSK3β phosphorylation, and GSK3β activity were analyzed in liver and aorta. Atherosclerotic lesions were examined and quantified. Hyperglycemia, hyperhomocysteinemia, and high-fat diet significantly enhanced GSK3β activity and also increased hepatic steatosis and atherosclerotic lesion volume compared with controls. Valproate supplementation blocked GSK3β activation and attenuated the development of atherosclerosis and the accumulation of hepatic lipids in each of the models examined. The mechanism by which GSK3β activity is regulated in these models likely involves alterations in phosphorylation at serine 9 and tyrosine 216.

Conclusion—
These findings support the existence of a common mechanism of accelerated atherosclerosis involving ER stress signaling through activation of GSK3β. Furthermore, our results suggest that atherosclerosis can be attenuated by modulating GSK3β phosphorylation.
Effects of Augmented Exercise Therapy on Outcome of Gait and Gait-Related Activities in the First 6 Months After Stroke
Authors: Veerbeek Janne M. , Koolstra Muriel , Ket Johannes C.F. , van Wegen Erwin E.H. , Kwakkel Gert 
Published: October 2011

Background and Purpose—
The purpose of this study was to determine the effects of augmented exercise therapy on gait, gait-related activities, and (basic and extended) activities of daily living within the first 6 months poststroke.

Methods—
A systematic literature search in electronic databases from 1990 until October 2010 was performed. Randomized controlled trials were included in which the experimental group spent augmented time in lower-limb exercise therapy compared with the control group. Outcomes were gait, gait-related activities, and (extended) activities of daily living. Results from individual studies were pooled by calculating the summary effect sizes. Subgroup analyses were applied for a treatment contrast of ≥16 hours, timing poststroke, type of control intervention, and methodological quality.

Results—
Fourteen (N=725) of 4966 identified studies were included. Pooling resulted in small to moderate significant summary effect sizes in favor of augmented exercise therapy for walking ability, comfortable and maximum walking speed, and extended activities of daily living. No significant effects were found for basic activities of daily living. Subgroup analysis did not show a significant effect modification.

Conclusions—
Dose–response trials in stroke rehabilitation are heterogeneous. The present meta-analysis suggests that increased time spent on exercise of gait and gait-related activities in the first 6 months poststroke results in significant small to moderate effects in terms of walking ability, walking speed, and extended activities of daily living. High-quality dose–response exercise therapy trials are needed with identical treatment goals but incremental levels of intensity.
Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran
Authors: Zhou Wei , Schwarting Sönke , Illanes Sergio , Liesz Arthur , Middelhoff Moritz , Zorn Markus , Bendszus Martin , Heiland Sabine , van Ryn Joanne , Veltkamp Roland 
Published: October 2011

Background and Purpose—
Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth.

Methods—
In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 μL), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later.

Results—
DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent.

Conclusions—
The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.
Cardiac Cycle-Related Volume Change in Unruptured Cerebral Aneurysms
Authors: Kuroda Junko , Kinoshita Manabu , Tanaka Hisashi , Nishida Takeo , Nakamura Hajime , Watanabe Yoshiyuki , Tomiyama Noriyuki , Fujinaka Toshiyuki , Yoshimine Toshiki 
Published: October 2011

Background and Purpose—
The hemodynamic factors of aneurysms were recently evaluated using computational fluid dynamics in a static vessel model in an effort to understand the mechanisms of initiation and rupture of aneurysms. However, few reports have evaluated the dynamic wall motion of aneurysms due to the cardiac cycle. The objective of this study was to quantify cardiac cycle-related volume changes in aneurysms using 4-dimensional CT angiography.

Methods—
Four-dimensional CT angiography was performed in 18 patients. Image data of 1 cardiac cycle were divided into 10 phases and the volume of the aneurysm was then quantified in each phase. These data were also compared with intracranial vessels of normal appearance.

Results—

The observed cardiac cycle-related volume changes were in good agreement with the sizes of the aneurysms and normal vessels. The cardiac cycle-related volume changes of the intracranial aneurysms and intracranial normal arteries were 5.40%±4.17% and 4.20±2.04%, respectively, but these did not differ statistically (
P
=0.12).

Conclusions—
We successfully quantified the volume change in intracranial aneurysms and intracranial normal arteries in human subjects. The data may indicate that cardiac cycle-related volume changes do not differ between unruptured aneurysms and normal intracranial arteries, suggesting that the global integrity of an unruptured aneurysmal wall is not different from that of normal intracranial arteries.
Carotid Plaque Vulnerability
Authors: Cicha Iwona , Wörner Anja , Urschel Katharina , Beronov Kamen , Goppelt-Struebe Margarete , Verhoeven Eric , Daniel Werner G. , Garlichs Christoph D. 
Published: October 2011

Background and Purpose—
Rupture of atherosclerotic plaques is one of the main causes of ischemic strokes. The aim of this study was to investigate carotid plaque vulnerability markers in relation to blood flow direction and the mechanisms leading to plaque rupture at the upstream side of carotid stenoses.

Methods—
Frequency and location of rupture, endothelial erosion, neovascularization, and hemorrhage were determined in longitudinal sections of 80 human carotid specimens. Plaques were immunohistochemically analyzed for markers of vulnerability. Plaque geometry was measured to reconstruct shape profiles of ruptured versus stable plaques and to perform computational fluid dynamics analyses.

Results—
In 86% of ruptured plaques, rupture was observed upstream. In this region, neovascularization and hemorrhage were increased, along with increased immunoreactivity of vascular endothelial and connective tissue growth factor, whereas endothelial erosion was more frequent downstream. Proteolytic enzymes, mast cell chymase and cathepsin L, and the proapoptotic protein Bax showed significantly higher expression upstream as compared with the downstream shoulder of atherosclerotic lesions. Comparison of geometric profiles for ruptured and stable plaques showed increased longitudinal asymmetry of fibrous cap and lipid core thickness in ruptured plaques. The specific geometry of plaques ruptured upstream induced increased levels of shear stress and increased pressure drop between the upstream and the downstream plaque shoulders.

Conclusions—
Vulnerability of the upstream plaque region is associated with enhanced neovascularization, hemorrhage, and cap thinning induced by proteolytic and proapoptotic mechanisms. These processes are reflected in structural plaque characteristics, analyses of which could improve the efficacy of vascular diagnostics and prevention.
A New Support System Using a Mobile Device (Smartphone) for Diagnostic Image Display and Treatment of Stroke
Authors: Takao Hiroyuki , Murayama Yuichi , Ishibashi Toshihiro , Karagiozov Kostadin L. , Abe Toshiaki 
Published: October 2011

Background and Purpose—
With the increasing demand for rapid diagnosis and treatment of stroke, the telemedicine role of coordinating timely the efforts of the stroke team became important. We developed a system for rapidly exchanging diagnostic images and clinical and management information.

Methods—
A system was created on the basis of communicating patient data and images between hospital systems and participating staff members in and out of the hospital through their standard, currently used handheld communication devices. The system is able to transfer clinical data, CT, MR, angiographic, intraoperative images, and expert opinion in real time.

Results—
A pilot application of the system in our hospital showed successful information transfer, allowing medical staff to discuss patients' diagnosis and management using a Twitter system.

Conclusions—
The system (i-Stroke) may become a useful tool for acute patient management in the field of neurology and neurosurgery.
Mortality of Cerebral Venous–Sinus Thrombosis in a Large National Sample
Authors: Haghighi Afshin Borhani , Edgell Randall C. , Cruz-Flores Salvador , Feen Eli , Piriyawat Paisith , Vora Nirav , Callison R. Charles , Alshekhlee Amer 
Published: October 2011

Background and Purpose—
The purpose of this study was to evaluate the mortality rates associated with cerebral venous–sinus thrombosis in a large national sample.

Methods—
A cohort of patients with cerebral venous–sinus thrombosis was identified from the National Inpatient Sample database for the years 2000 to 2007. According to the International Classification of Diseases, 9th Revision, Clinical Modification codes, cerebral venous–sinus thrombosis is categorized into pyogenic and nonpyogenic groups. Multivariate logistic regression analysis was used to assess covariates associated with hospital mortality.

Results—
Among 3488 patients, the overall mortality rate was 4.39%, which was nonsignificantly higher among the pyogenic group (4.55% versus 3.52%; OR, 0.76; 95% CI, 0.47–1.23). In the pyogenic cerebral venous–sinus thrombosis group, hematologic disorders were the most frequent predisposing condition (16.2%); whereas systemic malignancy followed by hematologic disorders were most common in the nonpyogenic group (14.08% and 10.04%, respectively). Predictors of mortality included age, intracerebral hemorrhage as well as the predisposing conditions of hematologic disorders, systemic malignancy, and central nervous system infection.

Conclusions—
Compared with arterial stroke, CVST harbors a relatively low mortality rate. Death is determined by age, the presence of intracerebral hemorrhage, and certain predisposing conditions.
Dynamics of Interdecadal Climate Variability: A Historical Perspective*
Authors: Liu Zhengyu 
Published: October 2011

Abstract
The emerging interest in decadal climate prediction highlights the importance of understanding the mechanisms of decadal to interdecadal climate variability. The purpose of this paper is to provide a review of our understanding of interdecadal climate variability in the Pacific and Atlantic Oceans. In particular, the dynamics of interdecadal variability in both oceans will be discussed in a unified framework and in light of historical development. General mechanisms responsible for interdecadal variability, including the role of ocean dynamics, are reviewed first. A hierarchy of increasingly complex paradigms is used to explain variability. This hierarchy ranges from a simple red noise model to a complex stochastically driven coupled ocean–atmosphere mode. The review suggests that stochastic forcing is the major driving mechanism for almost all interdecadal variability, while ocean–atmosphere feedback plays a relatively minor role. Interdecadal variability can be generated independently in the tropics or extratropics, and in the Pacific or Atlantic. In the Pacific, decadal–interdecadal variability is associated with changes in the wind-driven upper-ocean circulation. In the North Atlantic, some of the multidecadal variability is associated with changes in the Atlantic meridional overturning circulation (AMOC). In both the Pacific and Atlantic, the time scale of interdecadal variability seems to be determined mainly by Rossby wave propagation in the extratropics; in the Atlantic, the time scale could also be determined by the advection of the returning branch of AMOC in the Atlantic. One significant advancement of the last two decades is the recognition of the stochastic forcing as the dominant generation mechanism for almost all interdecadal variability. Finally, outstanding issues regarding the cause of interdecadal climate variability are discussed. The mechanism that determines the time scale of each interdecadal mode remains one of the key issues not understood. It is suggested that much further understanding can be gained in the future by performing specifically designed sensitivity experiments in coupled ocean–atmosphere general circulation models, by further analysis of observations and cross-model comparisons, and by combining mechanistic studies with decadal prediction studies.
Trends in Daily Solar Radiation and Precipitation Coefficients of Variation since 1984
Authors: Medvigy David , Beaulieu Claudie 
Published: October 2011

Abstract
This study investigates the possibility of changes in daily scale solar radiation and precipitation variability. Coefficients of variation (CVs) were computed for the daily downward surface solar radiation product from the International Satellite Cloud Climatology Project and the daily precipitation product from the Global Precipitation Climatology Project. Regression analysis was used to identify trends in CVs. Statistically significant changes in solar radiation variability were found for 35% of the globe, and particularly large increases were found for tropical Africa and the Maritime Continent. These increases in solar radiation variability were correlated with increases in precipitation variability and increases in deep convective cloud amount. The changes in high-frequency climate variability identified here have consequences for any process depending nonlinearly on climate, including solar energy production and terrestrial ecosystem photosynthesis. To assess these consequences, additional work is needed to understand how high-frequency climate variability will change in the coming decades.
The Impacts of Taiwan Topography on the Predictability of Typhoon Morakot’s Record-Breaking Rainfall: A High-Resolution Ensemble Simulation
Authors: Fang Xingqin , Kuo Ying-Hwa , Wang Anyu 
Published: October 2011

Abstract
In this study, the impacts of Taiwan topography on the extreme rainfall of Typhoon Morakot and the predictability of this rainfall are examined with a high-resolution (4 km) ensemble simulation using the Advanced Research core of the Weather Research and Forecasting Model (WRF-ARW). Ensemble prediction with realistic topography reproduces salient features of orographic precipitation. The 24- and 96-h accumulated rainfall amount and distribution from the ensemble mean compare reasonably well with the observed precipitation. When the terrain of Taiwan is removed, the rainfall distribution is markedly changed, suggesting the importance of the orography in determining the rainfall structure. Moreover, the peak 96-h rainfall amount is reduced to less than 20%, and the total rainfall amount over southern Taiwan is reduced to less than 60% of the experiments with Taiwan topography. Further analysis indicates that Taiwan’s topography substantially increases the variability of rainfall prediction. Analysis uncertainties as reflected in the perturbed initial state of the ensemble are amplified due to orographic influences on the typhoon circulation. As a result, significant variability occurs in the storm track, timing, and location of landfall, and storm intensities, which in turn, increases the rainfall variability. These results suggest that accurate prediction of heavy precipitation at a specific location and at high temporal resolution for an event such as Typhoon Morakot over Taiwan is extremely challenging. The forecasting of such an event would benefit from probabilistic prediction provided by a high-resolution mesoscale ensemble forecast system.
Estimating Tropical Cyclone Intensity from Infrared Image Data
Authors: Piñeros Miguel F. , Ritchie Elizabeth A. , Tyo J. Scott 
Published: October 2011

Abstract
This paper describes results from a near-real-time objective technique for estimating the intensity of tropical cyclones from satellite infrared imagery in the North Atlantic Ocean basin. The technique quantifies the level of organization or axisymmetry of the infrared cloud signature of a tropical cyclone as an indirect measurement of its maximum wind speed. The final maximum wind speed calculated by the technique is an independent estimate of tropical cyclone intensity. Seventy-eight tropical cyclones from the 2004–09 seasons are used both to train and to test independently the intensity estimation technique. Two independent tests are performed to test the ability of the technique to estimate tropical cyclone intensity accurately. The best results from these tests have a root-mean-square intensity error of between 13 and 15 kt (where 1 kt ≈ 0.5 m s−1) for the two test sets.
Acquired STAT4 deficiency as a consequence of cancer chemotherapy
Authors: Lupov Ivan P. , Voiles Larry , Han Ling , Schwartz Allysia , De La Rosa Manuel , Oza Kinnari , Pelloso David , Sahu Ravi P. , Travers Jeffrey B. , Robertson Michael J. , Chang Hua-Chen 
Published: October 2011

AbstractSignal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is activated by IL-12 signaling and promotes Th1-cell differentiation and IFN-γ production. Defective IFN-γ production because of STAT4 mRNA and protein deficiency occurs after autologous stem cell transplantation for lymphoma. In the present study, we investigated the mechanisms of STAT4 deficiency in lymphoma patients. The tumor-bearing state is not responsible, because STAT4 levels were not significantly different in PBMCs obtained from healthy control subjects compared with those from lymphoma patients before treatment. STAT4 protein levels were significantly decreased in PBMCs and T cells obtained from lymphoma patients after standard-dose chemotherapy. Furthermore, treatment of control PBMC cultures or a natural killer cell line with chemotherapy drugs in vitro also resulted in reduced STAT4 protein and diminished, IL-12–induced IFN-γ production. Translation of STAT4 protein was not impaired in chemotherapy-treated cells, whereas the STAT4 protein half-life was significantly reduced. Chemotherapy drugs promoted the ubiquitination and proteasomal degradation of STAT4. Treatment with the proteasome inhibitor bortezomib reversed chemotherapy-induced STAT4 deficiency and defective IFN-γ production. We conclude that acquired STAT4 deficiency in lymphoma patients is a consequence of treatment with chemotherapy, results that have important implications for the design of optimal immunotherapy for lymphoma.