bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting Fibroblast Growth Factor Receptor Signaling Inhibits Prostate Cancer Progression
Authors: Feng Shu , Shao Longjiang , Yu Wendong , Gavine Paul , Ittmann Michael 
Published: May 2012

Abstract
Purpose: Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1–3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo.
Experimental Design: Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model.
Results: AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal–regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors.
Conclusions: Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer. Clin Cancer Res; 18(14); 3880–8. ©2012 AACR.
Rapid Angiogenesis Onset after Discontinuation of Sunitinib Treatment of Renal Cell Carcinoma Patients
Authors: Griffioen Arjan W. , Mans Laurie A. , de Graaf Annemarie M.A. , Nowak-Sliwinska Patrycja , de Hoog Céline L.M.M. , de Jong Trees A.M. , Vyth-Dreese Florry A. , van Beijnum Judy R. , Bex Axel , Jonasch Eric 
Published: May 2012

Abstract
Purpose: To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy.
Experimental Design: Phase II trials of VEGF pathway–targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy. Primary tumor tissues were obtained and assessed for angiogenesis parameters. Results were compared with similar analyses on untreated tumors.
Results: Sunitinib or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor. Also, an increase in vascular pericyte coverage was found in sunitinib-pretreated tumors, consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues, among which VEGFR-1 and VEGFR-2, angiopoietin-1 and angiopoietin-2 and platelet-derived growth factor-B. In addition, apoptosis in tumor and endothelial cells was induced. Interestingly, in sunitinib-pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab-pretreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment.
Conclusion: This study describes, for the first time, the angiostatic response in human primary renal cancers at the tissue level upon treatment with VEGF-targeted therapy. Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation. The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors. Clin Cancer Res; 18(14); 3961–71. ©2012 AACR.
Making Sense of MEK1 Mutations in Intrinsic and Acquired BRAF Inhibitor Resistance
Authors: Paraiso Kim H. T. , Smalley Keiran S. M. 
Published: May 2012

Abstract
In this issue of Cancer Discovery, Shi and colleagues add further insight into the role of exon 3 MEK1 mutations in BRAF inhibitor resistance by demonstrating the presence of P124SMEK1 and I111SMEK1 mutations concurrently with V600E/KBRAF mutations at baseline in 16% of melanoma specimens. Although the presence of P124SMEK1 or I111SMEK1 mutations did not predict for resistance, and these alleles were not selected for upon BRAF inhibition, other exon 3 MEK1 mutations, such as C121S, did convey resistance, suggesting a role for defined exon 3 MEK1 mutations in acquired BRAF inhibitor resistance. Cancer Discov; 2(5); 390–2. ©2012 AACR.
Commentary on Shi et al., p. 414.
Circulating Endothelial Progenitors and Tumor Resistance to Vascular-Targeting Therapies
Authors: De Palma Michele , Nucera Silvia 
Published: May 2012

Abstract
Acute mobilization of circulating endothelial progenitors has been implicated in tumor resistance to vascular-disrupting agents. In the current issue of Cancer Discovery, Taylor and colleagues provide novel insight into the kinetics of endothelial progenitor mobilization by vascular-disrupting agents in both mouse tumor models and cancer patients. Cancer Discov; 2(5); 395–7. ©2012 AACR.
Commentary on Taylor et al., p. 434.
Occupy EGFR
Authors: Park Jin H. , Lemmon Mark A. 
Published: May 2012

Abstract
Erlotinib and gefitinib inhibit the growth of non–small cell lung cancer tumors that harbor activating epidermal growth factor receptor (EGFR) mutations but are ineffective against EGFR variants found in glioblastoma. New studies by Barkovich and colleagues and Vivanco and colleagues show that these drugs only occupy the active sites of glioblastoma-derived EGFR mutants to a limited extent and fail to inhibit the activated receptor. Other EGFR inhibitors that target distinct receptor conformations are more effective in the treatment of glioblastoma. These studies reveal distinct drug selectivities for different EGFR mutations and show that an analysis of binding-site occupancy should be considered as a biomarker for inhibitor efficacy in targeting EGFR. Cancer Discov; 2(5); 398–400. ©2012 AACR.
Commentary on Barkovich et al., p. 450 and Vivanco et al., p. 458.
Prediction of Arrhythmic Events in Ischemic and Dilated Cardiomyopathy Patients Referred for Implantable Cardiac Defibrillator
Authors: Gao Peng , Yee Raymond , Gula Lorne , Krahn Andrew D. , Skanes Allan , Leong-Sit Peter , Klein George J. , Stirrat John , Fine Nowell , Pallaveshi Luljeta , Wisenberg Gerald , Thompson Terry R. , Prato Frank , Drangova Maria , White James A. 
Published: May 2012

Background—
Scar signal quantification using late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) identifies patients at higher risk of future events, both in ischemic cardiomyopathy (ICM) and nonischemic dilated cardiomyopathy (DCM). However, the ability of scar signal burden to predict events in such patient groups at the time of referral for implantable cardioverter-defibrillator (ICD) has not been well explored. This study evaluates the predictive use of multiple scar quantification measures in ICM and DCM patients being referred for ICD.

Methods and Results—

One hundred twenty-four consecutive patients referred for ICD therapy (59 with ICM and 65 with DCM) underwent a standardized LGE-CMR protocol with blinded, multithreshold scar signal quantification and, for those with ICM, peri-infarct signal quantification. Patients were followed prospectively for the primary combined outcome of appropriate ICD therapy, survived cardiac arrest, or sudden cardiac death. At a mean follow-up of 632 ± 262 days, 18 patients (15%) had suffered the primary outcome. Total scar was significantly higher among those suffering a primary outcome, a relationship maintained within each cardiomyopathy cohort (
P
<0.01 for all comparisons). Total scar was the strongest independent predictor of the primary outcome and demonstrated a negative predictive value of 86%. In the ICM subcohort, peri-infarct signal showed only a nonsignificant trend toward elevation among those having a primary end point.

Conclusions—
Myocardial scar quantification by LGE-CMR predicts arrhythmic events in patients being evaluated for ICD eligibility irrespective of cardiomyopathy etiology.
Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack
Authors: James Stefan K. , Storey Robert F. , Khurmi Nardev S. , Husted Steen , Keltai Matyas , Mahaffey Kenneth W. , Maya Juan , Morais Joao , Lopes Renato D. , Nicolau Jose C. , Pais Prem , Raev Dimitar , Lopez-Sendon Jose L. , Stevens Susanna R. , Becker Richard C. 
Published: May 2012

Background—
Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages.

Methods and Results—

We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66–1.13; interaction
P
=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42–0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71–1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively).

Conclusions—
Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.

Clinical Trial Registration—

URL:
http://www.clinicatrials.gov
. Unique identifier: NCT00391872.
Upstream-Propagating Wave Modes in Moist and Dry Flow over Topography
Authors: Keller Teddie L. , Rotunno Richard , Steiner Matthias , Sharman Robert D. 
Published: May 2012

Abstract
Previous studies have observed upstream-propagating modes in two-dimensional numerical simulations of idealized flow over topography with moist, nearly neutral conditions in the troposphere, topped by a stable stratosphere. The generation and propagation mechanisms for these modes were attributed to localized and dramatic changes in stability induced by the desaturation of the flow impinging on the mountain. In the present paper it is shown that these modes are transient upstream-propagating gravity waves, which are a fundamental feature of both moist and dry flow over topography of a two-layer troposphere–stratosphere atmospheric profile impulsively started from rest. The mode selection and propagation speeds of these transient waves are highly dependent on the tropospheric stability, as well as the wind speed and tropopause depth. In the moist case these modes appear to propagate according to an effective static stability that is intermediate to the normal dry stability and the lower moist stability. Comparisons with the linear, time-dependent, hydrostatic analytic solution show that these modes are similar to the transients observed in flow of a constant wind and stability layer over topography with a rigid upper boundary.
Validating IASI Temperature and Moisture Sounding Retrievals over East Asia Using Radiosonde Observations
Authors: Kwon Eun-Han , Sohn B. J. , Smith William L. , Li Jun 
Published: May 2012

Abstract
Temperature and moisture profiles retrieved from Infrared Atmospheric Sounding Interferometer (IASI) data are evaluated using collocated radiosonde data from September 2008 to August 2009 over East Asia. The level-2 products used in this study were provided by the National Oceanic and Atmospheric Administration/National Environmental Satellite, Data, and Information Service. By using radiosonde observations as a reference, the bias and root-mean-square error (RMSE) of the temperature and water vapor profiles are obtained to examine the performance of the IASI retrievals depending on surface types and the degree of atmospheric moisture. Overall, retrievals over the land or under drier atmospheric conditions show degraded performance for both the temperature and the moisture, especially for the boundary layer temperature. It is further shown that the vertical distributions of the RMSEs and the biases of the IASI retrievals resemble the variability pattern of the radiosonde observations from the mean profiles. These retrieval aspects are thought to be related to the surface emissivity effect on the IASI retrieval and the difficulties of accounting for large atmospheric variability in the retrieval process. Although the retrieval performance appears to degrade under cloudy conditions, cloudy- and clear-sky retrievals show similar statistical behaviors varying with surface type and atmospheric moisture. Furthermore, the similar statistical behaviors between first guess and final retrievals suggest that error characteristics inherent to the first guess were not sufficiently resolved by the physical retrieval process, leaving a need to improve the first guess for the better retrieval.
The Effect of Hormonal Oral Contraception on Acquisition of Peak Bone Mineral Density of Adolescents and Young Women
Authors: Ziglar Susan , Hunter Tracy S. 
Published: May 2012

Maximizing bone mass in youth is touted as the best strategy to offset the natural losses of aging and the menopausal transition. Not achieving maximum peak bone mineral density (BMD) is an independent risk factor for osteoporosis and thus a public health concern. Adolescence is a critical time of bone mineralization mediated by endogenous estradiol. Research has shown that the highest velocity of bone mass accrual occurs 1 year before menarche and after the first 3 years. Low-peak attainment of BMD in young women is associated with contributing factors such as diets low in calcium, eating disorders, lack of exercise, smoking, and low estrogen states. Oral contraceptives (OCs) suppress endogenous estradiol production by suppressing the hypothalamic–pituitary–ovarian axis. Thus, OCs, by replacing endogenous estradiol with ethinyl estradiol (EE), establish and maintain new hormone levels. The early initiation and the use of very low dose of EE raises the possibility that bone mass accrual at a critical time of bone mineralization in young women or adolescents may be jeopardized. This review examines the studies of BMD in adolescents and young women that use combination hormonal contraception. Some studies had inherent limitations, such as small trial, poor control of confounders, failure to exclude women with prior use of hormonal contraceptives, or prior pregnancy from control groups. The vast majority of reviewed studies showed OCs containing 20 to 30 µg of EE interfere with acquisition of peak BMD. Limited numbers of studies examine the effects of OCs containing 35 µg on adolescents and young adults. Additionally, studies are needed evaluating the progestin component of OCs as their differing androgenic properties may affect bone mineralization as well.
Bivalved Fiberglass Cast Compared With Plaster Splint Immobilization for Initial Management of Ankle Fracture-Dislocations
Authors: Baker Jeffrey R. , Patel Shail N. , Teichman Adam J. , Bochat Summer E.S. , Fleischer Adam E. , Knight Jessica M. 
Published: May 2012

The initial management of ankle fracture-dislocations is the crucial step in the treatment of these emergent traumatic injuries. A stepwise approach is necessary to properly evaluate, diagnose, and treat ankle fracture-dislocations. The goal of initial management is to evaluate the vascular status of the extremity and then restore proper alignment of the talus underneath the tibia. A retrospective review was performed on 40 patients, who presented to a community-based hospital emergency room, treated by the foot and ankle service for ankle fracture-dislocation. An analysis of patient demographics, injury pattern/classification, number of reduction attempts, and immobilization method was performed and evaluated. This analysis was correlated with a review of the literature to develop an algorithm for the initial management of ankle fracture-dislocations recommending the use of a bivalved below-the-knee fiberglass cast for maintained stabilization post reduction. Level of Evidence: Therapeutic Level IV
Intraclonal heterogeneity and distinct molecular mechanisms characterize the development of t(4;14) and t(11;14) myeloma
Authors: Walker Brian A. , Wardell Christopher P. , Melchor Lorenzo , Hulkki Sanna , Potter Nicola E. , Johnson David C. , Fenwick Kerry , Kozarewa Iwanka , Gonzalez David , Lord Christopher J. , Ashworth Alan , Davies Faith E. , Morgan Gareth J. 
Published: May 2012

Abstract
We have used whole exome sequencing to compare a group of presentation t(4;14) with t(11;14) cases of myeloma to define the mutational landscape. Each case was characterized by a median of 24.5 exonic nonsynonymous single-nucleotide variations, and there was a consistently higher number of mutations in the t(4;14) group, but this number did not reach statistical significance. We show that the transition and transversion rates in the 2 subgroups are similar, suggesting that there was no specific mechanism leading to mutation differentiating the 2 groups. Only 3% of mutations were seen in both groups, and recurrently mutated genes include NRAS, KRAS, BRAF, and DIS3 as well as DNAH5, a member of the axonemal dynein family. The pattern of mutation in each group was distinct, with the t(4;14) group being characterized by deregulation of chromatin organization, actin filament, and microfilament movement. Recurrent RAS pathway mutations identified subclonal heterogeneity at a mutational level in both groups, with mutations being present as either dominant or minor subclones. The presence of subclonal diversity was confirmed at a single-cell level using other tumor-acquired mutations. These results are consistent with a distinct molecular pathogenesis underlying each subgroup and have important impacts on targeted treatment strategies. The Medical Research Council Myeloma IX trial is registered under ISRCTN68454111.
GeVaDSs – decision support system for novel Genetic Vaccine development process
Authors: Blazewicz Jacek , Borowski Marcin , Chaara Wahiba , Kedziora Pawel , Klatzmann David , Lukasiak Piotr , Six Adrien , Wojciechowski Pawel 
Published: May 2012

AbstractBackgroundThe lack of a uniform way for qualitative and quantitative evaluation of vaccine candidates under development led us to set up a standardized scheme for vaccine efficacy and safety evaluation. We developed and implemented molecular and immunology methods, and designed support tools for immunization data storage and analyses. Such collection can create a unique opportunity for immunologists to analyse data delivered from their laboratories.ResultsWe designed and implemented GeVaDSs (Genetic Vaccine Decision Support system) an interactive system for efficient storage, integration, retrieval and representation of data. Moreover, GeVaDSs allows for relevant association and interpretation of data, and thus for knowledge-based generation of testable hypotheses of vaccine responses.ConclusionsGeVaDSs has been tested by several laboratories in Europe, and proved its usefulness in vaccine analysis. Case study of its application is presented in the additional files. The system is available at:http://gevads.cs.put.poznan.pl/preview/(login: viewer, password: password).
Improving ancient DNA read mapping against modern reference genomes
Authors: Schubert Mikkel , Ginolhac Aurelien , Lindgreen Stinus , Thompson John F , AL-Rasheid Khaled AS , Willerslev Eske , Krogh Anders , Orlando Ludovic 
Published: May 2012

Abstract

Background
Next-Generation Sequencing has revolutionized our approach to ancient DNA (aDNA) research, by providing complete genomic sequences of ancient individuals and extinct species. However, the recovery of genetic material from long-dead organisms is still complicated by a number of issues, including post-mortem DNA damage and high levels of environmental contamination. Together with error profiles specific to the type of sequencing platforms used, these specificities could limit our ability to map sequencing reads against modern reference genomes and therefore limit our ability to identify endogenous ancient reads, reducing the efficiency of shotgun sequencing aDNA.

Results
In this study, we compare different computational methods for improving the accuracy and sensitivity of aDNA sequence identification, based on shotgun sequencing reads recovered from Pleistocene horse extracts using Illumina GAIIx and Helicos Heliscope platforms. We show that the performance of the Burrows Wheeler Aligner (BWA), that has been developed for mapping of undamaged sequencing reads using platforms with low rates of indel-types of sequencing errors, can be employed at acceptable run-times by modifying default parameters in a platform-specific manner. We also examine if trimming likely damaged positions at read ends can increase the recovery of genuine aDNA fragments and if accurate identification of human contamination can be achieved using a strategy previously suggested based on best hit filtering. We show that combining our different mapping and filtering approaches can increase the number of high-quality endogenous hits recovered by up to 33%.

Conclusions
We have shown that Illumina and Helicos sequences recovered from aDNA extracts could not be aligned to modern reference genomes with the same efficiency unless mapping parameters are optimized for the specific types of errors generated by these platforms and by post-mortem DNA damage. Our findings have important implications for future aDNA research, as we define mapping guidelines that improve our ability to identify genuine aDNA sequences, which in turn could improve the genotyping accuracy of ancient specimens. Our framework provides a significant improvement to the standard procedures used for characterizing ancient genomes, which is challenged by contamination and often low amounts of DNA material.