bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer
Authors: Kinross Kathryn M. , Brown Daniel V. , Kleinschmidt Margarete , Jackson Susan , Christensen James , Cullinane Carleen , Hicks Rodney J. , Johnstone Ricky W. , McArthur Grant A. 
Published: June 2011

Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is commonly dysregulated in human cancer, making it an attractive target for novel anticancer therapeutics. We have used a mouse model of ovarian cancer generated by KrasG12D activation and Pten deletion in the ovarian surface epithelium for the preclinical assessment of a novel PI3K/mTOR inhibitor PF-04691502. To enable higher throughput studies, we developed an orthotopic primary transplant model from these mice and evaluated therapeutic response to PF-04691502 using small-animal ultrasound and FDG-PET imaging. PF-04691502 inhibited tumor growth at 7 days by 72% ± 9. FDG-PET imaging revealed that PF-04691502 reduced glucose metabolism dramatically, suggesting FDG-PET may be exploited as an imaging biomarker of target inhibition by PF-04691502. Tissue biomarkers of PI3K/mTOR pathway activity, p-AKT (S473), and p-RPS6 (S240/244), were also dramatically inhibited following PF-04691502 treatment. However, as a single agent, PF-04691502 did not induce tumor regression and the long-term efficacy was limited, with tumor proliferation continuing in the presence of drug treatment. We hypothesized that tumor progression was because of concomitant activation of the mitogen-activated protein kinase pathway downstream of KrasG12D expression promoting cell survival and that the therapeutic effect of PF-04691502 would be enhanced by combinatory inhibition of MEK using PD-0325901. This combination induced striking tumor regression, apoptosis associated with upregulation of Bim and downregulation of Mcl-1, and greatly improved duration of survival. These data suggest that contemporaneous MEK inhibition enhances the cytotoxicity associated with abrogation of PI3K/mTOR signaling, converting tumor growth inhibition to tumor regression in a mouse model of ovarian cancer driven by PTEN loss and mutant K-Ras. Mol Cancer Ther; 10(8); 1440–9. ©2011 AACR.
Clonal Structure of Carcinogen-Induced Intestinal Tumors in Mice
Authors: Thliveris Andrew T. , Clipson Linda , White Alanna , Waggoner Jesse , Plesh Lauren , Skinner Bridget L. , Zahm Christopher D. , Sullivan Ruth , Dove William F. , Newton Michael A. , Halberg Richard B. 
Published: June 2011

Abstract
Previous studies have shown that intestinal tumors from ApcMin/+ (Min) mice and familial adenomatous polyposis (FAP) patients are often polyclonal. We sought to determine whether polyclonality is unique to tumors arising from hereditary predispositions or, instead, is a common feature of intestinal tumorigenesis in other pathways to tumorigenesis. Ethylnitrosourea-induced intestinal tumors from mice wild type at the Apc locus and chimeric for the Rosa26 lineage marker were analyzed. Many were overtly polyclonal, being composed of a mixture of Rosa26+ and Rosa26− neoplastic cells. Statistical analyses revealed that polyclonality could be explained by interactions between two initiated clones separated by a very short distance. The frequency of overtly polyclonal tumors and the range of interactions estimated in this model are similar to those observed when analyzing familial tumors from Min mice. Thus, polyclonality does not depend on the familial pathway to tumorigenesis. Interactions between two initiated clones might provide a selective advantage during the early stages of intestinal tumorigenesis. Cancer Prev Res; 4(6); 916–23. ©2011 AACR.
Cancer Interception
Authors: Blackburn Elizabeth H. 
Published: June 2011

Abstract
A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden. Cancer Prev Res; 4(6); 787–92. ©2011 AACR.
Altered Histology Provides a Positive Clinical Signal in the Bronchial Epithelium
Authors: Szabo Eva 
Published: June 2011

Abstract
The history of lung cancer chemoprevention trials has been uniformly disappointing in that the large phase III studies showed no effect or harm in actively smoking participants, and smaller phase II studies have also been negative. In this issue of the journal (beginning on page 793), Keith and colleagues report their randomized, placebo-controlled trial of the oral prostacyclin analogue iloprost, the first trial to show an improvement in bronchial histology (i.e., regression), which occurred in former, but not current, smokers with sputum atypia. This Perspective discusses the strength of the clinical signal provided by this observation and its implications for further drug development. Cancer Prev Res; 4(6); 775–8. ©2011 AACR.
Response Gene to Complement 32 Promotes Vascular Lesion Formation Through Stimulation of Smooth Muscle Cell Proliferation and Migration
Authors: Wang Jia-Ning , Shi Ning , Xie Wei-Bing , Guo Xia , Chen Shi-You 
Published: June 2011

Objective—
The objectives of this study were to determine the role of response gene to complement 32 (RGC-32) in vascular lesion formation after experimental angioplasty and to explore the underlying mechanisms.

Methods and Results—

Using a rat carotid artery balloon-injury model, we documented for the first time that neointima formation was closely associated with a significantly increased expression of RGC-32 protein. Short hairpin RNA knockdown of RGC-32 via adenovirus-mediated gene delivery dramatically inhibited the lesion formation by 62% as compared with control groups 14 days after injury. Conversely, RGC-32 overexpression significantly promoted the neointima formation by 33%. Gain- and loss-of-function studies in primary culture of rat aortic smooth muscle cells (RASMCs) indicated that RGC-32 is essential for both the proliferation and migration of RASMCs. RGC-32 induced RASMC proliferation by enhancing p34
CDC2
activity. RGC-32 stimulated the migration of RASMC by inducing focal adhesion contact and stress fiber formation. These effects were caused by the enhanced rho kinase II-α activity due to RGC-32-induced downregulation of Rad GTPase.

Conclusion—
RGC-32 plays an important role in vascular lesion formation following vascular injury. Increased RGC-32 expression in vascular injury appears to be a novel mechanism underlying the migration and proliferation of vascular smooth muscle cells. Therefore, targeting RGC-32 is a potential therapeutic strategy for the prevention of vascular remodeling in proliferative vascular diseases.
A Cost–Utility Analysis of Mechanical Thrombectomy as an Adjunct to Intravenous Tissue-Type Plasminogen Activator for Acute Large-Vessel Ischemic Stroke
Authors: Kim Anthony S. , Nguyen-Huynh Mai , Johnston S. Claiborne 
Published: June 2011

Background and Purpose—
Mechanical thrombectomy has the potential to improve recanalization rates and outcomes for patients with ischemic stroke, but potential gains could be offset by procedural complications and costs. We evaluated the cost and utility of combined intravenous (IV) tissue-type plasminogen activator (tPA) and mechanical thrombectomy compared to IV tPA alone for acute large-vessel ischemic stroke.

Methods—
We constructed a decision tree for a hypothetical 68-year-old with a large-vessel ischemic stroke who is eligible for IV tPA. The interventional strategy was IV tPA, a cerebral angiogram, and mechanical thrombectomy and thrombolysis if indicated. Recanalization, hemorrhage complications, and outcomes for the interventional strategy were from the Multi-MERCI study. The medical strategy was IV tPA using inputs from a comprehensive systematic review. Costs were estimated from Medicare reimbursements. We modeled lifetime costs and utilities for disability using a Markov model and Monte-Carlo multivariable sensitivity analysis.

Results—
For the baseline scenario, the recanalization rate was 72.9% for the interventional strategy and 46.2% for the medical strategy. For the interventional strategy, the symptomatic hemorrhage rate was 8.6% with recanalization and 15.4% without. For the medical strategy, the corresponding rates were 3.6% and 13.3%, respectively. The interventional strategy was cost-effective in 97.6% of simulations (incremental cost-effectiveness ratio $16 001/quality-adjusted life year; 95% CI, $2736–$39 232).

Conclusions—
Based on observational data, the combination of IV tPA and mechanical thrombectomy for large-vessel ischemic stroke appears to be cost-effective compared to IV tPA alone. These findings require additional validation with randomized trial data.
Severity of Intraventricular Extension Correlates With Level of Admission Glucose After Intracerebral Hemorrhage
Authors: Appelboom Geoffrey , Piazza Matthew A. , Hwang Brian Y. , Carpenter Amanda , Bruce Samuel S. , Mayer Stephan , Connolly E. Sander 
Published: June 2011

Background and Purpose—
Hyperglycemia after spontaneous intracerebral hemorrhage (ICH) is associated with poor outcome, but the pathophysiology of ICH-induced glucose dysregulation remains unclear. We sought to identify clinical and radiographic parameters of ICH that are associated with admission hyperglycemia.

Methods—
Patients admitted to the Columbia University Medical Center Neurological Intensive Care Unit with spontaneous ICH between January 2009 and September 2010 were prospectively enrolled in the ICH Outcomes Project. Clinical, radiographic, and laboratory data were collected prospectively. Receiver operating characteristic analysis was used to identify the glucose level with optimal sensitivity and specificity for in-hospital mortality. Logistic and linear regression analyses were used to identify independent predictors of outcome measures where appropriate.

Results—

One hundred four patients admitted during the study period were included in the analysis. Mean admission glucose level was 8.23±3.15 mmol/L (3.83 to 18.89 mmol/L) and 23.2% had a history of diabetes mellitus. Admission glucose was significantly associated with discharge (
P
=0.003) and 3-month mortality (
P
=0.002). Critical hyperglycemia defined at 10 mmol/L independently predicted discharge mortality (
P
=0.027; OR, 4.381; 95% CI, 1.186 to 16.174) and 3-month mortality (
P
=0.011; OR, 10.95; 95% CI, 1.886 to 62.41). Admission intraventricular extension score (
P
=0.038; OR, 1.117; 95% CI, 1.043 to 1.197) and diabetes mellitus (
P
=0.002; OR, 5.530; 95% CI, 1.833 to 16.689) were independent predictors of critical hyperglycemia. The intraventricular extension score (B=0.115,
P
=0.001) linearly correlated with admission glucose level (
R
=0.612,
P
=0.001) after adjusting for other clinical variables.

Conclusions—
Admission hyperglycemia after spontaneous ICH is associated with poor outcome and potentially related to the presence and severity of intraventricular extension.
Impact of White Matter Lesions on Physical Functioning and Fall Risk in Older People
Authors: Zheng Jacqueline J.J. , Delbaere Kim , Close Jacqueline C.T. , Sachdev Perminder S. , Lord Stephen R. 
Published: June 2011

Background and Purpose—
White matter lesions (WMLs) are common findings on neuroimaging in older people. This review systematically evaluates the published literature on the associations between WMLs and balance, gait, mobility, and falls in older people.

Methods—
Studies were identified with searches of the MEDLINE databases. Articles reporting associations between WMLs and balance, gait, mobility, and falls in older people in cross-sectional and longitudinal studies were included.

Results—
Thirty-one articles reporting data from 19 studies met the inclusion criteria. There were consistent findings from both cross-sectional and longitudinal studies indicating greater WML volumes are associated with impaired balance, slower gait, and reduced mobility. Most studies addressing regional WML distributions have reported that WMHs in the frontal lobe and periventricular regions show the strongest relationships with balance, gait, and mobility impairments. In relation to falls, a threshold effect was apparent in that only those with severe WML volumes were found to be at increased risk of falling.

Conclusions—
The findings of this systematic review indicate that WMLs are common and are significantly associated with impaired balance, gait, mobility, and falls in older people. In many studies, however, impaired mobility and increased fall risk are only evident in people who have the most severe degree of WMLs.
Reliability and Validity of Bilateral Ankle Accelerometer Algorithms for Activity Recognition and Walking Speed After Stroke
Authors: Dobkin Bruce H. , Xu Xiaoyu , Batalin Maxim , Thomas Seth , Kaiser William 
Published: June 2011

Background and Purpose—
Outcome measures of mobility for large stroke trials are limited to timed walks for short distances in a laboratory, step counters and ordinal scales of disability and quality of life. Continuous monitoring and outcome measurements of the type and quantity of activity in the community would provide direct data about daily performance, including compliance with exercise and skills practice during routine care and clinical trials.

Methods—
Twelve adults with impaired ambulation from hemiparetic stroke and 6 healthy controls wore triaxial accelerometers on their ankles. Walking speed for repeated outdoor walks was determined by machine-learning algorithms and compared to a stopwatch calculation of speed for distances not known to the algorithm. The reliability of recognizing walking, exercise, and cycling by the algorithms was compared to activity logs.

Results—

A high correlation was found between stopwatch-measured outdoor walking speed and algorithm-calculated speed (Pearson coefficient, 0.98;
P
=0.001) and for repeated measures of algorithm-derived walking speed (
P
=0.01). Bouts of walking >5 steps, variations in walking speed, cycling, stair climbing, and leg exercises were correctly identified during a day in the community. Compared to healthy subjects, those with stroke were, as expected, more sedentary and slower, and their gait revealed high paretic-to-unaffected leg swing ratios.

Conclusions—
Test–retest reliability and concurrent and construct validity are high for activity pattern-recognition Bayesian algorithms developed from inertial sensors. This ratio scale data can provide real-world monitoring and outcome measurements of lower extremity activities and walking speed for stroke and rehabilitation studies.
Isentropic Slopes, Downgradient Eddy Fluxes, and the Extratropical Atmospheric Circulation Response to Tropical Tropospheric Heating
Authors: Butler Amy H. , Thompson David W. J. , Birner Thomas 
Published: June 2011

Abstract
Climate change experiments run on Intergovernmental Panel on Climate Change (IPCC)–class numerical models consistently suggest that increasing concentrations of greenhouse gases will lead to a poleward shift of the midlatitude jets and their associated eddy fluxes of heat and potential vorticity (PV). Experiments run on idealized models suggest that the poleward contraction of the jets can be traced to the effects of increased latent heating and thus locally enhanced warming in the tropical troposphere. Here the authors provide new insights into the dynamics of the circulation response to tropical tropospheric heating using transient experiments in an idealized general circulation model.
It is argued that the response of the midlatitude jets to tropical heating is driven fundamentally by 1) the projection of the heating onto the meridional slope of the lower tropospheric isentropic surfaces, and 2) a diffusive model of the eddy fluxes of heat and PV. In the lower and middle troposphere, regions where the meridional slope of the isentropes (i.e., the baroclinicity) is increased are marked by anomalously poleward eddy fluxes of heat, and vice versa. Near the tropopause, regions where the meridional gradients in PV are increased are characterized by anomalously equatorward eddy fluxes of PV, and vice versa. The barotropic component of the response is shown to be closely approximated by the changes in the lower-level heat fluxes. As such, the changes in the eddy fluxes of momentum near the tropopause appear to be driven primarily by the changes in wave generation in the lower troposphere.
Ice in Clouds Experiment—Layer Clouds. Part I: Ice Growth Rates Derived from Lenticular Wave Cloud Penetrations
Authors: Heymsfield Andrew J. , Field Paul R. , Bailey Matt , Rogers Dave , Stith Jeffrey , Twohy Cynthia , Wang Zhien , Haimov Samuel 
Published: June 2011

Abstract
Lenticular wave clouds are used as a natural laboratory to estimate the linear and mass growth rates of ice particles at temperatures from −20° to −32°C and to characterize the apparent rate of ice nucleation at water saturation at a nearly constant temperature. Data are acquired from 139 liquid cloud penetrations flown approximately along or against the wind direction. A mean linear ice growth rate of about 1.4 μm s−1, relatively independent of particle size (in the range 100–400 μm) and temperature is deduced. Using the particle size distributions measured along the wind direction, the rate of increase in the ice water content (IWC) is calculated from the measured particle size distributions using theory and from those distributions by assuming different ice particle densities; the IWC is too small to be measured. Very low ice effective densities, &lt;0.1 g cm−3, are needed to account for the observed rate of increase in the IWC and the unexpectedly high linear growth rate.
Using data from multiple penetrations through a narrow (along wind) and thin wave cloud with relatively flat airflow streamlines, growth rate calculations are used to estimate where the ice particles originate and whether the ice is nucleated in a narrow band or over an extended period of time. The calculations are consistent with the expectation that the ice formation occurs near the leading cloud edge, presumably through a condensation–freezing process. The observed ice concentration increase along the wind is more likely due to a variation in ice growth rates than to prolonged ice nucleation.
Spectrally Invariant Approximation within Atmospheric Radiative Transfer
Authors: Marshak A. , Knyazikhin Y. , Chiu J. C. , Wiscombe W. J. 
Published: June 2011

Abstract
Certain algebraic combinations of single scattering albedo and solar radiation reflected from, or transmitted through, vegetation canopies do not vary with wavelength. These “spectrally invariant relationships” are the consequence of wavelength independence of the extinction coefficient and scattering phase function in vegetation. In general, this wavelength independence does not hold in the atmosphere, but in cloud-dominated atmospheres the total extinction and total scattering phase function vary only weakly with wavelength. This paper identifies the atmospheric conditions under which the spectrally invariant approximation can accurately describe the extinction and scattering properties of cloudy atmospheres. The validity of the assumptions and the accuracy of the approximation are tested with 1D radiative transfer calculations using publicly available radiative transfer models: Discrete Ordinate Radiative Transfer (DISORT) and Santa Barbara DISORT Atmospheric Radiative Transfer (SBDART). It is shown for cloudy atmospheres with cloud optical depth above 3, and for spectral intervals that exclude strong water vapor absorption, that the spectrally invariant relationships found in vegetation canopy radiative transfer are valid to better than 5%. The physics behind this phenomenon, its mathematical basis, and possible applications to remote sensing and climate are discussed.
Evaluation of WRF Parameterizations for Climate Studies over Southern Spain Using a Multistep Regionalization
Authors: Argüeso Daniel , Hidalgo-Muñoz José M. , Gámiz-Fortis Sonia R. , Esteban-Parra María Jesús , Dudhia Jimy , Castro-Díez Yolanda 
Published: June 2011

Abstract
This paper evaluates the Weather Research and Forecasting model (WRF) sensitivity to eight different combinations of cumulus, microphysics, and planetary boundary layer (PBL) parameterization schemes over a topographically complex region in southern Spain (Andalusia) for the period 1990–99. The WRF configuration consisted of a 10-km-resolution domain nested in a coarser domain driven by 40-yr European Centre for Medium-Range Weather Forecasts Re-Analysis (ERA-40) data, with spectral nudging above the PBL employed over the latter domain. The model outputs have been compared at different time scales with an observational dataset that comprises 438 rain gauges and 152 temperature stations with records of both daily maximum and minimum temperatures. To reduce the “representation error,” the validation with observations has been performed using a multistep regionalization that distinguishes five precipitation regions and four temperature regions.
The analysis proves that both cumulus and PBL schemes have a crucial impact on the description of precipitation in Andalusia, whereas no noticeable differences between microphysics options were appreciated. Temperature is described similarly by all the configurations, except for the PBL choice affecting minimum values.
WRF provides a definite improvement over ERA-40 in the climate description in terms of frequency, spatial distribution, and intensity of extreme events. It also captures more accurately the annual cycle and reduces the biases and the RMSE for monthly precipitation, whereas only a minor enhancement of these features was obtained for monthly-mean maximum and minimum temperatures. The results indicate that WRF is able to correctly reproduce Andalusian climate and produces useful added-value information for climate studies.