bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Mutations in the ATR Pathway Define Agent-Specific Requirements for Cancer Cell Growth and Survival
Authors: Wilsker Deborah , Chung Jon H. , Pradilla Ivan , Petermann Eva , Helleday Thomas , Bunz Fred 
Published: November 2011

Abstract
Many anticancer agents induce DNA strand breaks or cause the accumulation of DNA replication intermediates. The protein encoded by ataxia-telangiectasia mutated and Rad 3-related (ATR) generates signals in response to these altered DNA structures and activates cellular survival responses. Accordingly, ATR has drawn increased attention as a potential target for novel therapeutic strategies designed to potentiate the effects of existing drugs. In this study, we use a unique panel of genetically modified human cancer cells to unambiguously test the roles of upstream and downstream components of the ATR pathway in the responses to common therapeutic agents. Upstream, the S-phase–specific cyclin-dependent kinase (Cdk) 2 was required for robust activation of ATR in response to diverse chemotherapeutic agents. While Cdk2-mediated ATR activation promoted cell survival after treatment with many drugs, signaling from ATR directly to the checkpoint kinase Chk1 was required for survival responses to only a subset of the drugs tested. These results show that specifically inhibiting the Cdk2/ATR/Chk1 pathway via distinct regulators can differentially sensitize cancer cells to a wide range of therapeutic agents. Mol Cancer Ther; 11(1); 98–107. ©2011 AACR.
Effective Targeting of Hedgehog Signaling in a Medulloblastoma Model with PF-5274857, a Potent and Selective Smoothened Antagonist That Penetrates the Blood–Brain Barrier
Authors: Rohner Allison , Spilker Mary E. , Lam Justine L. , Pascual Bernadette , Bartkowski Darian , Li Qing John , Yang Amy H. , Stevens Greg , Xu Meirong , Wells Peter A. , Planken Simon , Nair Sajiv , Sun Shaoxian 
Published: November 2011

Abstract
Inhibition of the Smoothened (Smo) represents a promising therapeutic strategy for treating malignant tumors that are dependent on the Hedgehog (Hh) signaling pathway. PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a Ki of 4.6 ± 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC50 of 2.7 ± 1.4 nmol/L in cells. This Smo antagonist showed robust antitumor activity in a mouse model of medulloblastoma with an in vivo IC50 of 8.9 ± 2.6 nmol/L. The downregulation of Gli1 is closely linked to the tumor growth inhibition in patched+/− medulloblastoma mice. Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched+/− medulloblastoma tumor models yielded similar tumor and skin Gli1 IC50 values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels. In addition, PF-5274857 was found to effectively penetrate the blood–brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. The brain permeability of PF-5274857 was also confirmed and quantified in nontumor-bearing preclinical species with an intact blood–brain barrier. PF-5274857 was orally available and metabolically stable in vivo. These findings suggest that PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway. Mol Cancer Ther; 11(1); 57–65. ©2011 AACR.
Vascular Disruption in Combination with mTOR Inhibition in Renal Cell Carcinoma
Authors: Ellis Leigh , Shah Preeti , Hammers Hans , Lehet Kristin , Sotomayor Paula , Azabdaftari Gissou , Seshadri Mukund , Pili Roberto 
Published: November 2011

Abstract
Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted. Mol Cancer Ther; 11(2); 383–92. ©2011 AACR.
Aspirin in the Chemoprevention of Colorectal Neoplasia: An Overview
Authors: Chan Andrew T. , Arber Nadir , Burn John , Chia Whay Kuang , Elwood Peter , Hull Mark A. , Logan Richard F. , Rothwell Peter M. , Schrör Karsten , Baron John A. 
Published: November 2011

Abstract
Considerable evidence supports the effectiveness of aspirin for chemoprevention of colorectal cancer (CRC) in addition to its well-established benefits in the prevention of vascular disease. Epidemiologic studies have consistently observed an inverse association between aspirin use and risk of CRC. A recent pooled analysis of a long-term posttrial follow-up of nearly 14,000 patients from four randomized, cardiovascular disease prevention trials showed that daily aspirin treatment for about five years was associated with a 34% reduction in 20-year CRC mortality. A separate metaanalysis of nearly 3,000 patients with a history of colorectal adenoma or cancer in four randomized adenoma prevention trials showed that aspirin reduced the occurrence of advanced adenomas by 28% and any adenoma by 17%. Aspirin has also been shown to be beneficial in a clinical trial of patients with Lynch syndrome, a hereditary CRC syndrome; in those treated with aspirin for at least two years, there was a 50% or more reduction in the risk of CRC commencing five years after randomization and after aspirin had been discontinued. A few observational studies have shown an increase in survival among patients with CRC who use aspirin. Taken together, these findings strengthen the case for consideration of long-term aspirin use in CRC prevention. Despite these compelling data, there is a lack of consensus about the balance of risks and benefits associated with long-term aspirin use, particularly in low-risk populations. The optimal dose to use for cancer prevention and the precise mechanism underlying aspirin's anticancer effect require further investigation. Cancer Prev Res; 5(2); 164–78. ©2011 AACR.
Frequent and Widespread Vascular Abnormalities in Human Signal Transducer and Activator of Transcription 3 Deficiency
Authors: Chandesris Marie-Olivia , Azarine Arshid , Ong Kim-Thanh , Taleb Soraya , Boutouyrie Pierre , Mousseaux Elie , Romain Mélissa , Bozec Erwan , Laurent Stéphane , Boddaert Nathalie , Thumerelle Caroline , Tillie-Leblond Isabelle , Hoarau Cyrille , Lebranchu Yvon , Aladjidi Nathalie , Tron François , Barlogis Vincent , Body Gérard , Munzer Marine , Jaussaud Roland , Suarez Felipe , Clément Olivier , Hermine Olivier , Tedgui Alain , Lortholary Olivier , Picard Capucine , Mallat Ziad , Fischer Alain 
Published: November 2011

Background—
Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described.

Methods and Results—
We prospectively screened 21 adult STAT3-deficient patients (median age, 26 years; range, 17–44 years) for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking–based imaging specifically for the carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models.

Conclusions—
Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.
Pak1 as a Novel Therapeutic Target for Antihypertrophic Treatment in the Heart
Authors: Liu Wei , Zi Min , Naumann Ronald , Ulm Susanne , Jin Jiawei , Taglieri Domenico M. , Prehar Sukhpal , Gui Junhong , Tsui Hoyee , Xiao Rui-Ping , Neyses Ludwig , Solaro R. John , Ke Yunbo , Cartwright Elizabeth J. , Lei Ming , Wang Xin 
Published: November 2011

Background—
Stress-induced hypertrophic remodeling is a critical pathogenetic process leading to heart failure. Although many signal transduction cascades are demonstrated as important regulators to facilitate the induction of cardiac hypertrophy, the signaling pathways for suppressing hypertrophic remodeling remain largely unexplored. In this study, we identified p21-activated kinase 1 (Pak1) as a novel signaling regulator that antagonizes cardiac hypertrophy.

Methods and Results—

Hypertrophic stress applied to primary neonatal rat cardiomyocytes (NRCMs) or murine hearts caused the activation of Pak1. Analysis of NRCMs expressing constitutively active Pak1 or in which Pak1 was silenced disclosed that Pak1 played an antihypertrophic role. To investigate the in vivo role of Pak1 in the heart, we generated mice with a cardiomyocyte-specific deletion of Pak1 (Pak1
cko
). When subjected to 2 weeks of pressure overload, Pak1
cko
mice developed greater cardiac hypertrophy with attendant blunting of JNK activation compared with controls, and these knockout mice underwent the transition into heart failure when prolonged stress was applied. Chronic angiotensin II infusion also caused increased cardiac hypertrophy in Pak1
cko
mice. Moreover, we discovered that the Pak1 activator FTY720, a sphingosine-like analog, was able to prevent pressure overload-induced hypertrophy in wild-type mice without compromising their cardiac functions. Meanwhile, FTY720 failed to exert such an effect on Pak1
cko
mice, suggesting that the antihypertrophic effect of FTY720 likely acts through Pak1 activation.

Conclusions—
These results, for the first time, establish Pak1 as a novel antihypertrophic regulator and suggest that it may be a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.
Predictive Value of the High-Sensitivity Troponin T Assay and the Simplified Pulmonary Embolism Severity Index in Hemodynamically Stable Patients With Acute Pulmonary Embolism
Authors: Lankeit Mareike , Jiménez David , Kostrubiec Maciej , Dellas Claudia , Hasenfuss Gerd , Pruszczyk Piotr , Konstantinides Stavros 
Published: November 2011

Background—
The new, high-sensitivity troponin T (hsTnT) assay may improve risk stratification of normotensive patients with acute pulmonary embolism (PE). We externally validated the prognostic value of hsTnT, and of the simplified Pulmonary Embolism Severity Index (sPESI), in a large multicenter cohort.

Methods and Results—

We prospectively examined 526 normotensive patients with acute PE; of those, 31 (5.9%) had an adverse 30-day outcome. The predefined hsTnT cutoff value of 14 pg/mL was associated with a high prognostic sensitivity and negative predictive value, comparable to those of the sPESI. Both hsTnT ≥14 pg/mL (OR, 4.97 [95% CI, 1.71–14.43];
P
=0.003) and sPESI ≥1 point(s) (OR, 9.51 [2.24–40.29];
P
=0.002) emerged, besides renal insufficiency (OR, 2.97 [1.42–6.22];
P
=0.004), as predictors of early death or complications; in a multivariable model, they remained independent predictors of outcome (
P
=0.044 and 0.012, respectively). A total of 127 patients (24.1%) were identified as low risk by a sPESI of 0 and hsTnT <14 pg/mL; none of them had an adverse 30-day outcome. During 6-month follow-up, 52 patients (9.9%) died. Kaplan-Meier analysis illustrated that patients with hsTnT ≥14 pg/mL (
P
=0.001) and those with sPESI ≥1 (
P
<0.001) had a decreased probability of 6-month survival. Patients with sPESI of 0 and hsTnT <14 pg/mL at baseline had a 42% reduction in the risk of dying (hazard ratio, 0.58 [0.01–0.42];
P
=0.005).

Conclusions—
The hsTnT assay and the sPESI improve risk stratification of acute PE. Combination of both modalities may yield additive prognostic information and particularly identify possible candidates for out-of-hospital treatment.
Efficacy and Safety of Celivarone, With Amiodarone as Calibrator, in Patients With an Implantable Cardioverter-Defibrillator for Prevention of Implantable Cardioverter-Defibrillator Interventions or Death
Authors: Kowey Peter R. , Crijns Harry J.G.M. , Aliot Etienne M. , Capucci Alessandro , Kulakowski Piotr , Radzik David , Roy Denis , Connolly Stuart J. , Hohnloser Stefan H. 
Published: November 2011

Background—
Celivarone is a new antiarrhythmic agent developed for the treatment of ventricular arrhythmias. This study investigated the efficacy and safety of celivarone in preventing implantable cardioverter-defibrillator (ICD) interventions or death.

Methods and Results—
Celivarone (50, 100, or 300 mg/d) was assessed compared with placebo in this randomized, double-blind, placebo-controlled, parallel-group study. Amiodarone (200 mg/d after loading dose of 600 mg/d for 10 days) was used as a calibrator. A total of 486 patients with a left ventricular ejection fraction ≤40% and at least 1 ICD intervention for ventricular tachycardia or ventricular fibrillation in the previous month or ICD implantation in the previous month for documented ventricular tachycardia/ventricular fibrillation were randomized. Median treatment duration was 9 months. The primary efficacy end point was occurrence of ventricular tachycardia/ventricular fibrillation–triggered ICD interventions (shocks or antitachycardia pacing) or sudden death. The proportion of patients experiencing an appropriate ICD intervention or sudden death was 61.5% in the placebo group; 67.0%, 58.8%, and 54.9% in the celivarone 50-, 100-, and 300-mg groups, respectively; and 45.3% in the amiodarone group. Hazard ratios versus placebo for the primary end point ranged from 0.860 for celivarone 300 mg to 1.199 for celivarone 50 mg. None of the comparisons versus placebo were statistically significant. Celivarone had an acceptable safety profile.

Conclusions—
Celivarone was not effective for the prevention of ICD interventions or sudden death.

Clinical Trial Registration—

http://www.clinicaltrials.gov
. Unique identifier: NCT00993382.
Skill of 2-m Temperature Seasonal Forecasts over Europe in ECMWF and RegCM Models
Authors: Patarčić Mirta , Branković Čedo 
Published: November 2011

Various measures of forecast quality are analyzed for 2-m temperature seasonal forecasts over Europe from global and regional model ensembles for winter and summer seasons during the period 1991 to 2001. The 50-km Regional Climate Model (RegCM3) is used to dynamically downscale nine-member ensembles of ECMWF global experimental seasonal forecasts. Three sets of RegCM3 experiments with different soil moisture initializations are performed: the RegCM3 default initial soil moisture, initial soil moisture taken from ECMWF seasonal forecasts, and initial soil moisture obtained from RegCM3 ECMWF interim Re-Analysis (ERA-Interim)-driven integrations (RegCM3 climatology). Both deterministic and probabilistic skill metrics are estimated. The better-resolved spatial scales in near-surface temperature by RegCM3 do not necessarily lead to the improved regional model skill in the regions where systematic errors are large. The impact of initial soil moisture on RegCM3 forecast skill is seen in summer in the southern part of the integration domain. When regional model soil moisture was initialized from ECMWF seasonal forecasts, systematic errors were reduced and deterministic skill was enhanced relative to the other RegCM3 experiments. The Brier skill score for rare cold anomalies in this experiment is comparable to that of the global model, whereas in other experiments it is significantly smaller than in global model. There is no major impact of soil moisture initialization on forecast skill in winter. However, some significant improvements in RegCM3 probabilistic skill scores for positive anomalies in winter are found in the central part of the domain where RegCM3 systematic errors are smaller than in global model.
Large-Scale Characteristics and Probability of Rapidly Intensifying Tropical Cyclones in the Western North Pacific Basin
Authors: Shu Shoujuan , Ming Jie , Chi Peng 
Published: November 2011

Abstract
The China Meteorological Administration (CMA) and the National Centers for Environmental Prediction (NCEP) reanalysis datasets are employed to examine the large-scale characteristics of rapidly intensifying western North Pacific tropical cyclones (TCs). The results show that of all 27 581 samples for the period 1970–2007, 85%, 65%, and 47% of all tropical depressions (TDs), tropical storms (TSs), and typhoons (TYs), respectively, intensify. Of the 1214 TCs, 18%, 70%, 30%, and 10% of all tropical cyclones, supertyphoons, severe typhoons, and typhoons, respectively, underwent rapid intensification (RI) at least once during their lifetime. Three kinds of cases—RI, slow change in intensity (SC), and rapid decay (RD)—during the period 1982–2007 are used to analyze the large-scale conditions associated with them. The comparison shows that the RI cases tend to occur farther south and east than the non-RI cases. In addition, the RI cases have a more westerly component of motion and intensify more during the preceding 12 h than do the non-RI cases. For the non-RI cases, the SC cases tend to have a lower initial intensity and a lower speed of motion than do the RD cases. Also, the RI cases are farther from their maximum potential intensity and develop in warmer water, lower vertical shear, and more easterly upper-tropospheric flow than do the non-RI cases. The probability of RI for TCs is estimated by using the rapid intensify index (RII) developed in this study for the western North Pacific basin. The verification based upon the cross validation shows that the RII is skillful relative to climatology.
Taking the pain out of waiting
Authors: Cashmore Aaron W , Noller Jennifer , Johnson Bronwyn , Ritchie Jan , Blinkhorn Anthony S 
Published: November 2011

Objective: The Tooth Smart Programme is a hospital-based parent-counselling programme established to stabilize existing carious lesions and prevent new caries in children. The purpose of this qualitative study was to: explore participating parents’ experiences of and views about parent counselling; identify and describe factors that influence the uptake of oral health advice; and uncover any unanticipated outcomes of parent counselling. Methods: A purposively selected group of parents were invited to participate in, face-to-face, semi-structured interviews. Interviews were audio-recorded and transcribed. Transcripts were analyzed by qualitative thematic analysis. Results: Participants liked the programme sessions occurring in a hospital dental clinic. This approach was valued because it allowed a dental assessment to accompany the preventive advice. Most felt that they had been successful in increasing the frequency and quality of their child’s tooth-brushing. Some reported that increased brushing reduced their child’s dental pain. Conversely, most had found it hard to control their child’s snacking on sugary foods and drinks. Conclusion: Future development of programmes should consider participants’ expressed need for parent counselling to be provided in patient-centred sessions.
Biochemical evidence on the potential role of organophosphates in hepatic glucose metabolism toward insulin resistance through inflammatory signaling and free radical pathways
Authors: Mostafalou Sara , Eghbal Mohammad Ali , Nili-Ahmadabadi Amir , Baeeri Maryam , Abdollahi Mohammad 
Published: November 2011

Several studies show that organophosphate pesticides exert several effects on glucose homeostasis. The current study investigates the influence of subchronic exposure to malathion (MT) on hepatic gluconeogenesis in relation to acetyl cholinesterase (AChE) inhibition, oxidative stress and inflammatory response in the rat. MT was administered by gavage at doses of 25, 50 and 100 mg/kg for 32 days. Fasting hyperglycemia was seen in line with an increased activity of hepatic phosphoenolpyruvate carboxykinase, glucose 6-phosphatase and tumor necrosis factor α. In addition to the impaired glucose tolerance and inhibition of AChE in a dose-dependent manner, there were significant increases in hepatic lipid peroxidation, carbonyl groups and 8-deoxyguanosine as the biomarkers of reactive oxygen species–mediated damage to lipid, protein and DNA, respectively. Altered quality of the liver in glucose production especially gluconeogenesis could be a compensatory mechanism against MT toxicity or even result in tissue damage. MT-induced insulin resistance in the liver occurs through oxidative and inflammatory signaling pathways.