bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thiouracil Cross-Linking Mass Spectrometry: a Cell-Based Method To Identify Host Factors Involved in Viral Amplification
Authors: Lenarcic Erik M. , Landry Dori M. , Greco Todd M. , Cristea Ileana M. , Thompson Sunnie R. 
Published: June 2013

ABSTRACT
Eukaryotic RNA viruses are known to utilize host factors; however, the identity of these factors and their role in the virus life cycle remain largely undefined. Here, we report a method to identify proteins bound to the viral RNA during amplification in cell culture: thiouracil cross-linking mass spectrometry (TUX-MS). TUX-MS relies on incorporation of a zero-distance cross-linker into the viral RNA during infection. Proteins bound to viral RNA are cross-linked prior to cell lysis, purified, and identified using mass spectrometry. Using the TUX-MS method, an unbiased screen for poliovirus (PV) host factors was conducted. All host and viral proteins that are known to interact with the poliovirus RNA were identified. In addition, TUX-MS identified an additional 66 host proteins that have not been previously described in poliovirus amplification. From these candidates, eight were selected and validated. Furthermore, we demonstrate that small interfering RNA (siRNA)-mediated knockdown of two of these uncharacterized host factors results in either a decrease in copy number of positive-stranded RNA or a decrease in PV translation. These data demonstrate that TUX-MS is a robust, unbiased method to identify previously unknown host cell factors that influence virus growth. This method is broadly applicable to a range of RNA viruses, such as flaviviruses, alphaviruses, picornaviruses, bunyaviruses, and coronaviruses.
Mutational Analysis of the Pseudomonas aeruginosa Myovirus ϕKZ Morphogenetic Protease gp175
Authors: Thomas Julie A. , Black Lindsay W. 
Published: June 2013

ABSTRACT

Pseudomonas aeruginosa
myovirus ϕKZ has a 270-kb genome within a T=27 icosahedral capsid that contains a large, unusual, and structurally well-defined protein cylindrical inner body (IB) spanning its interior. Proteolysis forms a pivotal stage in ϕKZ head and IB morphogenesis, with the protease gp175 cleaving at least 19 of 49 different head proteins, including the major capsid protein and five major structural IB proteins. Here we show that the purified mature form of gp175 is active and cleaves purified IB structural proteins gp93 and gp89. Expression vector synthesis and purification of the zymogen/precursor yielded an active, mature-length protease, showing independent C-terminal gp175 self-cleavage autoactivation. Mutation of either the predicted catalytic serine or histidine inactivated mature gp175, supporting its classification as a serine protease and representing the first such direct biochemical demonstration with purified protease and substrate proteins for any phage protease. These mutations also blocked self-cleavage of the precursor while allowing intermolecular gp175 processing. To confirm the cleavage specificity of gp175, we mutated three cleavage sites in gp93, which blocked proteolysis at these sites. The N-terminal propeptide of gp93 was shown to undergo more extensive proteolysis than previously identified. We found that proteolysis in gp93 progressed from the N to C terminus, while blocking cleavage sites slowed but did not eliminate downstream proteolysis. These findings were shown by informatics to be relevant to the head morphogenesis of numbers of other related IB-containing giant phages as well as to T4 and herpesviruses, which have homologous proteases.
Phase II Study of Everolimus in Patients with Metastatic Colorectal Adenocarcinoma Previously Treated with Bevacizumab-, Fluoropyrimidine-, Oxaliplatin-, and Irinotecan-Based Regimens
Authors: Ng Kimmie , Tabernero Josep , Hwang Jimmy , Bajetta Emilio , Sharma Sunil , Del Prete Salvatore A. , Arrowsmith Edward R. , Ryan David P. , Sedova Michaela , Jin Jin , Malek Kamel , Fuchs Charles S. 
Published: June 2013

Abstract
Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is seen in 40% to 60% of patients with colorectal cancer. Everolimus, an oral inhibitor of mTOR, showed efficacy in patients with metastatic colorectal cancers in phase I studies.
Experimental Design: In sequential phase II studies assessing two dosing schedules, patients with metastatic colorectal cancers refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/wk (n = 99) or 10 mg/d (n = 100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses.
Results: Seventy-one patients were included in the per-protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 and 4.9 months and 1.8 and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = 0.008) and lower DCR (P = 0.035) compared with those with wild-type KRAS in exploratory biomarker analyses.
Conclusions: Everolimus 70 mg/wk or 10 mg/d was well tolerated but did not confer meaningful efficacy in heavily pretreated patients with metastatic colorectal cancers. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway. Clin Cancer Res; 19(14); 3987–95. ©2013 AACR.
Developing a Common Language for Tumor Response to Immunotherapy: Immune-Related Response Criteria Using Unidimensional Measurements
Authors: Nishino Mizuki , Giobbie-Hurder Anita , Gargano Maria , Suda Margaret , Ramaiya Nikhil H. , Hodi F. Stephen 
Published: June 2013

Abstract
Purpose: Immune-related response criteria (irRC) was developed to adequately assess tumor response to immunotherapy. The irRC are based on bidimensional measurements, as opposed to unidimensional measurements defined by Response Evaluation Criteria in Solid Tumors, which has been widely used in solid tumors. We aimed to compare response assessment by bidimensional versus unidimensional irRC in patients with advanced melanoma treated with ipilimumab.
Experimental Design: Fifty-seven patients with advanced melanoma treated with ipilimumab in a phase II, expanded access trial were studied. Bidimensional tumor measurement records prospectively conducted during the trial were reviewed to generate a second set of measurements using unidimensional, longest diameter measurements. The percent changes of measurements at follow-up, best overall response, and time-to-progression (TTP) were compared between bidimensional and unidimensional irRC. Interobserver variability for bidimensional and unidimensional measurements was assessed in 25 randomly selected patients.
Results: The percent changes at follow-up scans were highly concordant between the 2 criteria (Spearman r: 0.953–0.965, first to fourth follow-up). The best immune-related response was highly concordant between the 2 criteria (κw = 0.881). TTP was similar between the bidimensional and unidimensional assessments (progression-free at 6 months: 70% vs. 81%, respectively). The unidimensional measurements were more reproducible than bidimensional measurements, with the 95% limits of agreement of (−16.1%, 5.8%) versus (−31.3%, 19.7%), respectively.
Conclusion: irRC using the unidimensional measurements provided highly concordant response assessment compared with the bidimensional irRC, with less measurement variability. The use of unidimensional irRC is proposed to assess response to immunotherapy in solid tumors, given its simplicity, higher reproducibility, and high concordance with the bidimensional irRC. Clin Cancer Res; 19(14); 3936–43. ©2013 AACR.
Dual PI3K/mTOR Inhibitors: Does p53 Modulate Response?
Authors: Ekshyyan Oleksandr , Anandharaj Arunkumar , Nathan Cherie-Ann O. 
Published: June 2013

Abstract
Head and neck squamous cell carcinomas have multiple genetic alterations that can influence clinical response to treatment. It is important to evaluate how distinct alterations affect response to targeted agents to identify a subset of patients who can benefit from therapy, improving survival and decreasing toxicity. Clin Cancer Res; 19(14); 3719–21. ©2013 AACR.
Breast Cancer Metastasis Suppressor-1 Promoter Methylation in Primary Breast Tumors and Corresponding Circulating Tumor Cells
Authors: Chimonidou Maria , Kallergi Galatea , Georgoulias Vassilis , Welch Danny R. , Lianidou Evi S. 
Published: June 2013

Abstract
Breast cancer metastasis suppressor-1 (BRMS1) differentially regulates the expression of multiple genes, leading to metastasis suppression without affecting orthotopic tumor growth. For the first time, BRMS1 promoter methylation was evaluated as a prognostic biomarker in primary breast tumors and a subset of corresponding circulating tumor cells (CTC). Formalin-fixed paraffin embedded samples were analyzed for BRMS1 methylation status using methylation-specific PCR in a human specimen cohort consisting of noncancerous tissues, benign fibroadenomas, and primary breast tumors, including some with adjacent noncancerous tissues. Peripheral blood mononuclear cells from a large subset of these patients were fixed in cytospins and analyzed. In addition, BRMS1 expression in cytospins was examined by double-immunofluorescence using anti-BRMS1 and pan-cytokeratin antibodies. BRMS1 promoter methylation was not detected in noncancerous breast tissues or benign fibroadenomas; however, methylation was observed in more than a third of primary breast tumors. Critically, BRMS1 promoter methylation in primary tumors was significantly associated with reduced disease-free survival with a trend toward reduced overall survival. Similarly, a third of cytospin samples were positive for the presence of CTCs, and the total number of detected CTCs was 41. Although a large fraction of CTCs were negative or maintained low expression of BRMS1, promoter methylation was observed in a small fraction of samples, implying that BRMS1 expression in CTCs was either downregulated or heterogeneous. In summary, these data define BRMS1 promoter methylation in primary breast tumors and associated CTCs.
Implications: This study indicates that BRMS1 promoter methylation status has biomarker potential in breast cancer. Mol Cancer Res; 11(10); 1248–57. ©2013 AACR.
Parallel RNA Interference Screens Identify EGFR Activation as an Escape Mechanism in FGFR3-Mutant Cancer
Authors: Herrera-Abreu Maria Teresa , Pearson Alex , Campbell James , Shnyder Steve D. , Knowles Margaret A. , Ashworth Alan , Turner Nicholas C. 
Published: June 2013

Abstract
Activation of fibroblast growth factor receptors (FGFR) is a common oncogenic event. Little is known about the determinants of sensitivity to FGFR inhibition and how these may vary between different oncogenic FGFRs. Using parallel RNA interference (RNAi) genetic screens, we show that the EGF receptor (EGFR) limits sensitivity to FGFR inhibition in FGFR3-mutant and -translocated cell lines, but not in other FGFR-driven cell lines. We also identify two distinct mechanisms through which EGFR limits sensitivity. In partially FGFR3-dependent lines, inhibition of FGFR3 results in transient downregulation of mitogen-activated protein kinase signaling that is rescued by rapid upregulation of EGFR signaling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signaling via repression of FGFR3, with EGFR inhibition rescued by delayed upregulation of FGFR3 expression. Importantly, combinations of FGFR and EGFR inhibitors overcome these resistance mechanisms in vitro and in vivo. Our results illustrate the power of parallel RNAi screens in identifying common resistance mechanisms to targeted therapies.
Significance: Our data identify a novel therapeutic approach to the treatment of FGFR3-mutant cancer, emphasizing the potential of combination approaches targeting both FGFR3 and EGFR. Our data extend the role of EGFR in mediating resistance to inhibitors targeting a mutant oncogene, showing that EGFR signaling can repress mutant FGFR3 to induce intrinsic resistance to FGFR targeting. Cancer Discov; 3(9); 1058–71. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 953
Extending the Convergence of Canonical WNT Signaling and Classic Cancer Pathways for Treatment of Malignant Peripheral Nerve Sheath Tumors
Authors: Reilly Karlyne M. 
Published: June 2013

Abstract
Summary: Malignant peripheral nerve sheath tumors (MPNST) are incurable tumors of the Schwann cell lineage that progress unpredictably from benign plexiform neurofibromas. In this issue of Cancer Discovery, Watson and colleagues use an insertional mutagenesis screen combined with network analysis to identify the canonical WNT signaling pathway as an important potential biomarker of tumor progression and target for combination therapy in MPNSTs. Cancer Discov; 3(6); 610–2. ©2013 AACR.
See related article by Watson et al., p. 674
Scavenger Receptor-AI–Targeted Iron Oxide Nanoparticles for In Vivo MRI Detection of Atherosclerotic Lesions
Authors: Segers Filip M.E. , den Adel Brigit , Bot Ilze , van der Graaf Linda M. , van der Veer Eric P. , Gonzalez Walter , Raynal Isabelle , de Winther Menno , Wodzig Will K. , Poelmann Robert E. , van Berkel Theo J.C. , van der Weerd Louise , Biessen Erik A.L. 
Published: June 2013

Objective—
In search of molecular imaging modalities for specific detection of inflammatory atherosclerotic plaques, we explored the potential of targeting scavenger receptor-AI (SR-AI), which is highly expressed by lesional macrophages and linked to effective internalization machinery.

Approach and Results—

Ultrasmall superparamagnetic iron oxide particles were conjugated to a peptidic SR-AI ligand (0.371 mol Fe/L and 0.018 mol PP1/L). In vitro incubation of human or murine macrophages with SR-AI–targeted USPIO led to significantly higher iron uptake in vitro than with nontargeted USPIO, as judged by quantitative atomic absorption spectroscopy and Perl’s staining. Incremental uptake was strictly mediated by SRs. SR-AI–targeted USPIO displayed accelerated plasma decay and a 3.5-fold increase (
P
=0.01) in atherosclerotic plaque accumulation on intravenous injection into apolipoprotein E–deficient mice compared with nontargeted USPIO. In addition, atherosclerotic humanized LDLr
−/−
chimeras with leukocyte expression of human SR-AI showed a significant improvement in contrast-to-noise ratio (2.7-fold;
P
=0.003) in the atherosclerotic aortic arch plaques 24 hours after injection of SR-AI–targeted USPIO compared with chimeras with leukocyte SR-AI deficiency.

Conclusions—
Collectively, our data provide several lines of evidence that SR-AI–targeted molecular imaging of USPIO-based contrast agents holds great promise for in situ detection of inflammatory plaques in manifest atherosclerosis.
High‐sensitivity C‐reactive Protein is a Predictive Factor of Adiposity in Children: Results of the Identification and prevention of Dietary‐ and lifestyle‐induced health Effects in Children and InfantS (IDEFICS) Study
Authors: Nappo Annunziata , Iacoviello Licia , Fraterman Arno , Gonzalez‐Gil Esther M. , Hadjigeorgiou Charis , Marild Staffan , Molnar Denes , Moreno Luis A. , Peplies Jenny , Sioen Isabel , Veidebaum Toomas , Siani Alfonso , Russo Paola 
Published: June 2013

Background

Whereas cross‐sectional studies have shown that obesity is associated with increased C‐reactive protein (
CRP
) levels in children, little is known about the impact of low‐grade inflammation on body mass changes during growth.

Methods and Results

We assessed cross‐sectionally and longitudinally the association of high‐sensitivity (hs)‐
CRP
levels with overweight/obesity and related cardiometabolic risk factors in the Identification and prevention of Dietary‐ and lifestyle‐induced health Effects in Children and InfantS (
IDEFICS
) cohort. 16 224 children from 8 European countries (2 to 9 years) were recruited during the baseline survey (T0). After the exclusion of 7187 children because of missing hs‐
CRP
measurements and 2421 because of drug use during the previous week, the analysis was performed on 6616 children (Boys=3347; Girls=3269; age=6.3±1.7 years). Of them, 4110 were reexamined 2 years later (T1). Anthropometric variables, blood pressure, hs‐
CRP
, blood lipids, glucose and insulin were measured. The population at T0 was divided into 3 categories, according to the baseline hs‐
CRP
levels. Higher hs‐
CRP
levels were associated with significantly higher prevalence of overweight/obesity, body mass index (
BMI
) z‐score and central adiposity indices (
P
values all <0.0001), and with higher blood pressure and lower
HDL
‐cholesterol levels. Over the 2‐year follow‐up, higher baseline hs‐
CRP
levels were associated with a significant increase in
BMI
z‐score (
P
<0.001) and significantly higher risk of incident overweight/obesity.

Conclusions

Higher hs‐
CRP
levels are associated to higher body mass and overweight/obesity risk in a large population of European children. Children with higher baseline levels of hs‐
CRP
had a greater increase in
BMI
z‐score and central adiposity over time and were at higher risk of developing overweight/obesity during growth.
Size Ratio Can Highly Predict Rupture Risk in Intracranial Small (<5 mm) Aneurysms
Authors: Kashiwazaki Daina , Kuroda Satoshi 
Published: June 2013

Background and Purpose—
Management strategies for unruptured intracranial aneurysms (UIAs) are controversial. This study aimed to identify surrogate parameters that highly predict the rupture risk of small (<5 mm) UIAs.

Methods—
Radiological data were collected from 854 patients with aneurysmal subarachnoid hemorrhages who were enrolled in the Sapporo SAH Study. They had a total of 854 ruptured intracranial aneurysms and 180 UIAs. The size, aneurysm-to-vessel size ratio, and distribution were precisely compared between ruptured intracranial aneurysms and UIAs.

Results—

For all aneurysms, the size was significantly larger in ruptured intracranial aneurysms (7.0±1.3 mm) than in the UIAs (3.7±1.2 mm;
P
<0.001). Size ratio was also significantly higher in ruptured intracranial aneurysms (4.3±1.9) than in the UIAs (2.2±1.6;
P
<0.001). Multivariate logistic analysis showed that size and size ratio were correlated with aneurysm rupture. However, in small aneurysms, multivariate logistic regression revealed that only size ratio was associated with ruptured aneurysms (
P
=0.008; odds ratio, 9.1). There were no significant differences in size or aneurysm location. A receiver operating characteristic analysis was performed for size ratio in small aneurysms, and the threshold separating ruptured and unruptured groups was 3.12 and the area under the curve was 0.801.

Conclusions—
This study revealed that the size ratio, and not the absolute size, may highly predict the risk of rupture in small UIAs. Size ratio measurements are very simple and provide useful information for determining treatment and follow-up strategies for patients with small UIAs.
Large-Eddy Simulations of Trade Wind Cumuli Using Particle-Based Microphysics with Monte Carlo Coalescence
Authors: Arabas Sylwester , Shima Shin-ichiro 
Published: June 2013

Abstract
A series of simulations employing the superdroplet method (SDM) for representing aerosol, cloud, and rain microphysics in large-eddy simulations (LES) is discussed. The particle-based formulation treats all particles in the same way, subjecting them to condensational growth and evaporation, transport of the particles by the flow, gravitational settling, and collisional growth. SDM features a Monte Carlo–type numerical scheme for representing the collision and coalescence process. All processes combined cover representation of cloud condensation nuclei (CCN) activation, drizzle formation by autoconversion, accretion of cloud droplets, self-collection of raindrops, and precipitation, including aerosol wet deposition. The model setup used in the study is based on observations from the Rain in Cumulus over the Ocean (RICO) field project. Cloud and rain droplet size spectra obtained in the simulations are discussed in context of previously published analyses of aircraft observations carried out during RICO. The analysis covers height-resolved statistics of simulated cloud microphysical parameters such as droplet number concentration, effective radius, and parameters describing the width of the cloud droplet size spectrum. A reasonable agreement with measurements is found for several of the discussed parameters. The sensitivity of the results to the grid resolution of the LES, as well as to the sampling density of the probabilistic Monte Carlo–type model, is explored.
Covariance Inflation in the Ensemble Kalman Filter: A Residual Nudging Perspective and Some Implications
Authors: Luo Xiaodong , Hoteit Ibrahim 
Published: June 2013

Abstract
This article examines the influence of covariance inflation on the distance between the measured observation and the simulated (or predicted) observation with respect to the state estimate. In order for the aforementioned distance to be bounded in a certain interval, some sufficient conditions are derived, indicating that the covariance inflation factor should be bounded in a certain interval, and that the inflation bounds are related to the maximum and minimum eigenvalues of certain matrices. Implications of these analytic results are discussed, and a numerical experiment is presented to verify the validity of the analysis conducted.
A Prospective Study of Musculoskeletal Outcomes Among Manufacturing Workers
Authors: Gerr Fredric , Fethke Nathan B. , Merlino Linda , Anton Dan , Rosecrance John , Jones Michael P. , Marcus Michele , Meyers Alysha R. 
Published: June 2013

Objective: To better characterize associations between physical risk factors and upper-extremity musculoskeletal symptoms and disorders, a prospective epidemiologic study of 386 manufacturing workers was performed. Background: Methodological limitations of previous studies have resulted in inconsistent associations. Method: An individual, task-based exposure assessment strategy was used to assess upper-extremity exertion intensity, repetition, and time-in-posture categories. Participants recorded time spent performing daily work tasks on a preprinted log, which was then used to calculate time-weighted-average exposures across each week of follow-up. In addition, a weekly Strain Index (SI) risk category was assigned to each participant. Incident musculoskeletal symptoms and disorders were assessed weekly. Proportional hazards analyses were used to examine associations between exposure measures and incident hand/arm and neck/shoulder symptoms and disorders. Results: Incident symptoms and disorders were common (incident hand/arm symptoms = 58/100 person-years (PY), incident hand/arm disorders = 19/100 PY, incident neck/shoulder symptoms = 54/100 PY, incident neck/shoulder disorders = 14/100 PY). Few associations between separate estimates of physical exposure and hand/arm and neck/shoulder outcomes were observed. However, associations were observed between dichotomized SI risk category and incident hand/arm symptoms (hazard ratio [HR] = 1.73, 95% confidence interval [CI] = [0.99, 3.04]) and disorders (HR = 1.93, 95% CI = [0.85, 4.40]). Conclusion: Evidence of associations between physical risk factors and musculoskeletal outcome was strongest when exposure was estimated with the SI, in comparison to other metrics of exposure. Application: The results of this study provide evidence that physical exposures in the workplace contribute to musculoskeletal disorder incidence. Musculoskeletal disorder prevention efforts should include mitigation of these occupational risk factors.