bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonal Evolution, Genomic Drivers, and Effects of Therapy in Chronic Lymphocytic Leukemia
Authors: Ouillette Peter , Saiya-Cork Kamlai , Seymour Erlene , Li Cheng , Shedden Kerby , Malek Sami N. 
Published: April 2013

Abstract
Purpose: The identification of gene mutations and structural genomic aberrations that are critically involved in chronic lymphocytic leukemia (CLL) pathogenesis is still evolving. One may postulate that genomic driver lesions with effects on CLL cell proliferation, apoptosis thresholds, or chemotherapy resistance should increase in frequency over time when measured sequentially in a large CLL cohort.
Experimental Design: We sequentially sampled a large well-characterized CLL cohort at a mean of 4 years between samplings and measured acquired copy number aberrations (aCNA) and LOH using single-nucleotide polymorphism (SNP) 6.0 array profiling and the mutational state of TP53, NOTCH1, and SF3B1 using Sanger sequencing. The paired analysis included 156 patients, of whom 114 remained untreated and 42 received intercurrent therapies, predominantly potent chemoimmunotherapy, during the sampling interval.
Results: We identify a strong effect of intercurrent therapies on the frequency of acquisition of aCNAs in CLL. Importantly, the spectrum of acquired genomic changes was largely similar in patients who did or did not receive intercurrent therapies; therefore, various genomic changes that become part of the dominant clones are often already present in CLL cell populations before therapy. Furthermore, we provide evidence that therapy of CLL with preexisting TP53 mutations results in outgrowth of genomically very complex clones, which dominate at relapse.
Conclusions: Using complementary technologies directed at the detection of genomic events that are present in substantial proportions of the clinically relevant CLL disease bulk, we capture aspects of genomic evolution in CLL over time, including increases in the frequency of genomic complexity, specific recurrent aCNAs, and TP53 mutations. Clin Cancer Res; 19(11); 2893–904. ©2013 AACR.
Zoledronic Acid Reverses the Epithelial–Mesenchymal Transition and Inhibits Self-Renewal of Breast Cancer Cells through Inactivation of NF-κB
Authors: Schech Amanda J. , Kazi Armina A. , Gilani Rabia A. , Brodie Angela H. 
Published: April 2013

Abstract
Zoledronic acid, a third-generation bisphosphonate, has been shown to reduce cell migration, invasion, and metastasis. However, the effects of zoledronic acid on the epithelial–mesenchymal transition (EMT), a cellular process essential to the metastatic cascade, remain unclear. Therefore, the effects of zoledronic acid on EMT, using triple-negative breast cancer (TNBC) cells as a model system, were examined in more detail. Zoledronic acid treatment decreased the expression of mesenchymal markers, N-cadherin, Twist, and Snail, and subsequently upregulated expression of E-cadherin. Zoledronic acid also inhibited cell viability, induced cell-cycle arrest, and decreased the proliferative capacity of TNBC, suggesting that zoledronic acid inhibits viability through reduction of cell proliferation. As EMT has been linked to acquisition of a self-renewal phenotype, the effects of zoledronic acid on self-renewal in TNBC were also studied. Treatment with zoledronic acid decreased expression of self-renewal proteins, BMI-1 and Oct-4, and both prevented and eliminated mammosphere formation. To understand the mechanism of these results, the effect of zoledronic acid on established EMT regulator NF-κB was investigated. Zoledronic acid inhibited phosphorylation of RelA, the active subunit of NF-κB, at serine 536 and modulated RelA subcellular localization. Treatment with zoledronic acid reduced RelA binding to the Twist promoter, providing a direct link between inactivation of NF-κB signaling and loss of EMT transcription factor gene expression. Binding of Twist to the BMI-1 promoter was also decreased, correlating modulation of EMT to decreased self-renewal. On the basis of these results, it is proposed that through inactivation of NF-κB, zoledronic acid reverses EMT, which leads to a decrease in self-renewal. Mol Cancer Ther; 12(7); 1356–66. ©2013 AACR.
Identification and Characterization of a Small-Molecule Inhibitor of Wnt Signaling in Glioblastoma Cells
Authors: De Robertis Alessandra , Valensin Silvia , Rossi Marco , Tunici Patrizia , Verani Margherita , De Rosa Antonella , Giordano Cinzia , Varrone Maurizio , Nencini Arianna , Pratelli Carmela , Benicchi Tiziana , Bakker Annette , Hill Jeffrey , Sangthongpitag Kanda , Pendharkar Vishal , Liu Boping , Mee Ng Fui , Wen Then Siew , Jing Tai Shi , Cheong Seong-Moon , He Xi , Caricasole Andrea , Salerno Massimiliano 
Published: April 2013

Abstract
Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive and highly invasive phenotype of these tumors makes them among the most anatomically damaging human cancers with a median survival of less than 1 year. Although canonical Wnt pathway activation in cancers has been historically linked to the presence of mutations involving key components of the pathway (APC, β-catenin, or Axin proteins), an increasing number of studies suggest that elevated Wnt signaling in GBM is initiated by several alternative mechanisms that are involved in different steps of the disease. Therefore, inhibition of Wnt signaling may represent a therapeutically relevant approach for GBM treatment. After the selection of a GBM cell model responsive to Wnt inhibition, we set out to develop a screening approach for the identification of compounds capable of modulating canonical Wnt signaling and associated proliferative responses in GBM cells. Here, we show that the small molecule SEN461 inhibits the canonical Wnt signaling pathway in GBM cells, with relevant effects at both molecular and phenotypic levels in vitro and in vivo. These include SEN461-induced Axin stabilization, increased β-catenin phosphorylation/degradation, and inhibition of anchorage-independent growth of human GBM cell lines and patient-derived primary tumor cells in vitro. Moreover, in vivo administration of SEN461 antagonized Wnt signaling in Xenopus embryos and reduced tumor growth in a GBM xenograft model. These data represent the first demonstration that small-molecule–mediated inhibition of Wnt signaling may be a potential approach for GBM therapeutics. Mol Cancer Ther; 12(7); 1180–9. ©2013 AACR.
Frequent Mutation of the PI3K Pathway in Head and Neck Cancer Defines Predictive Biomarkers
Authors: Lui Vivian W.Y. , Hedberg Matthew L. , Li Hua , Vangara Bhavana S. , Pendleton Kelsey , Zeng Yan , Lu Yiling , Zhang Qiuhong , Du Yu , Gilbert Breean R. , Freilino Maria , Sauerwein Sam , Peyser Noah D. , Xiao Dong , Diergaarde Brenda , Wang Lin , Chiosea Simion , Seethala Raja , Johnson Jonas T. , Kim Seungwon , Duvvuri Umamaheswar , Ferris Robert L. , Romkes Marjorie , Nukui Tomoko , Kwok-Shing Ng Patrick , Garraway Levi A. , Hammerman Peter S. , Mills Gordon B. , Grandis Jennifer R. 
Published: April 2013

Abstract
Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway–mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA–wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.
Significance: Treatment options for HNSCC are limited, in part, because of an incomplete understanding of the targetable mutations that “drive” tumor growth. Here, we define a subgroup of HNSCC harboring activating mutations of genes in the PI3K pathway where targeting the pathway shows antitumor efficacy. These results suggest that PI3K pathway mutation assessment may be used to guide HNSCC therapy. Cancer Discov; 3(7); 761–9. ©2013 AACR.
See related commentary by Iglesias-Bartolome et al., p. 722
This article is highlighted in the In This Issue feature, p. 705
Societal Trust and Geography
Authors: Le Stephen H. T. 
Published: April 2013

Societal trust is widely believed to be a fundamental component of prosperous societies, but geographical determinants of societal trust have not been examined in depth. This study examines hypothesized pathways between geography and societal trust. Strongest support is found for the hypothesis that higher geographical latitude leads to lower disease prevalence, lower income inequality, and less ethnic and less linguistic heterogeneity. Lower disease prevalence, lower income inequality, and less ethnic and less linguistic heterogeneity in turn appear to determine the viability of a “virtuous circle” of mutually reinforcing societal characteristics, including greater wealth, greater life expectancy, greater political rights, greater civil liberties, greater societal trust, less religiosity, and less corruption.
LIM kinase-1 selectively promotes glycoprotein Ib-IX–mediated TXA2 synthesis, platelet activation, and thrombosis
Authors: Estevez Brian , Stojanovic-Terpo Aleksandra , Delaney M. Keegan , O’Brien Kelly A. , Berndt Michael C. , Ruan Changgeng , Du Xiaoping 
Published: April 2013

Key Points
Role for LIMK1 in GPIb-IX–dependent cPLA2 activation, TXA2 synthesis, and platelet activation independent of its role in actin polymerization. LIMK1 is important in arterial thrombosis in vivo but appears to be dispensable for hemostasis, suggesting a new antithrombotic target.
Genomic selection of purebred animals for crossbred performance in the presence of dominant gene action
Authors: Zeng Jian , Toosi Ali , Fernando Rohan L , Dekkers Jack CM , Garrick Dorian J 
Published: April 2013

Abstract

Background
Genomic selection is an appealing method to select purebreds for crossbred performance. In the case of crossbred records, single nucleotide polymorphism (SNP) effects can be estimated using an additive model or a breed-specific allele model. In most studies, additive gene action is assumed. However, dominance is the likely genetic basis of heterosis. Advantages of incorporating dominance in genomic selection were investigated in a two-way crossbreeding program for a trait with different magnitudes of dominance. Training was carried out only once in the simulation.

Results
When the dominance variance and heterosis were large and overdominance was present, a dominance model including both additive and dominance SNP effects gave substantially greater cumulative response to selection than the additive model. Extra response was the result of an increase in heterosis but at a cost of reduced purebred performance. When the dominance variance and heterosis were realistic but with overdominance, the advantage of the dominance model decreased but was still significant. When overdominance was absent, the dominance model was slightly favored over the additive model, but the difference in response between the models increased as the number of quantitative trait loci increased. This reveals the importance of exploiting dominance even in the absence of overdominance. When there was no dominance, response to selection for the dominance model was as high as for the additive model, indicating robustness of the dominance model. The breed-specific allele model was inferior to the dominance model in all cases and to the additive model except when the dominance variance and heterosis were large and with overdominance. However, the advantage of the dominance model over the breed-specific allele model may decrease as differences in linkage disequilibrium between the breeds increase. Retraining is expected to reduce the advantage of the dominance model over the alternatives, because in general, the advantage becomes important only after five or six generations post-training.

Conclusion
Under dominance and without retraining, genomic selection based on the dominance model is superior to the additive model and the breed-specific allele model to maximize crossbred performance through purebred selection.
Quality control, analysis and secure sharing of Luminex® immunoassay data using the open source LabKey Server platform
Authors: Eckels Josh , Nathe Cory , Nelson Elizabeth K , Shoemaker Sara G , Nostrand Elizabeth Van , Yates Nicole L , Ashley Vicki C , Harris Linda J , Bollenbeck Mark , Fong Youyi , Tomaras Georgia D , Piehler Britt 
Published: April 2013

Abstract

Background
Immunoassays that employ multiplexed bead arrays produce high information content per sample. Such assays are now frequently used to evaluate humoral responses in clinical trials. Integrated software is needed for the analysis, quality control, and secure sharing of the high volume of data produced by such multiplexed assays. Software that facilitates data exchange and provides flexibility to perform customized analyses (including multiple curve fits and visualizations of assay performance over time) could increase scientists’ capacity to use these immunoassays to evaluate human clinical trials.

Results
The HIV Vaccine Trials Network and the Statistical Center for HIV/AIDS Research and Prevention collaborated with LabKey Software to enhance the open source LabKey Server platform to facilitate workflows for multiplexed bead assays. This system now supports the management, analysis, quality control, and secure sharing of data from multiplexed immunoassays that leverage Luminex xMAP® technology. These assays may be custom or kit-based. Newly added features enable labs to: (i) import run data from spreadsheets output by Bio-Plex Manager™ software; (ii) customize data processing, curve fits, and algorithms through scripts written in common languages, such as R; (iii) select script-defined calculation options through a graphical user interface; (iv) collect custom metadata for each titration, analyte, run and batch of runs; (v) calculate dose-response curves for titrations; (vi) interpolate unknown concentrations from curves for titrated standards; (vii) flag run data for exclusion from analysis; (viii) track quality control metrics across runs using Levey-Jennings plots; and (ix) automatically flag outliers based on expected values. Existing system features allow researchers to analyze, integrate, visualize, export and securely share their data, as well as to construct custom user interfaces and workflows.

Conclusions
Unlike other tools tailored for Luminex immunoassays, LabKey Server allows labs to customize their Luminex analyses using scripting while still presenting users with a single, graphical interface for processing and analyzing data. The LabKey Server system also stands out among Luminex tools for enabling smooth, secure transfer of data, quality control information, and analyses between collaborators. LabKey Server and its Luminex features are freely available as open source software at http://www.labkey.com under the Apache 2.0 license.
Deletions within COL11A1in Type 2 stickler syndrome detected by multiplex ligation-dependent probe amplification (MLPA)
Authors: Vijzelaar Raymon , Waller Sarah , Errami Abdellatif , Donaldson Alan , Lourenco Teresa , Rodrigues Marcia , McConnell Vivienne , Fincham Gregory , Snead Martin , Richards Allan 
Published: April 2013

Abstract

Background

COL11A1 is a large complex gene around 250 kb in length and consisting of 68 exons. Pathogenic mutations in the gene can result in Stickler syndrome, Marshall syndrome or Fibrochondrogenesis. Many of the mutations resulting in either Stickler or Marshall syndrome alter splice sites and result in exon skipping, which because of the exon structure of collagen genes usually leaves the message in-frame. The mutant protein then exerts a dominant negative effect as it co-assembles with other collagen gene products. To date only one large deletion of 40 kb in the COL11A1, which was detected by RT-PCR, has been characterized. However, commonly used screening protocols, utilizing genomic amplification and exon sequencing, are unlikely to detect such large deletions. Consequently the frequency of this type of mutation is unknown.

Case presentations
We have used Multiplex Ligation-Dependent Probe Amplification (MLPA) in conjunction with exon amplification and sequencing, to analyze patients with clinical features of Stickler syndrome, and have detected six novel deletions that were not found by exon sequencing alone.

Conclusion
Exon deletions appear to represent a significant proportion of type 2 Stickler syndrome. This observation was previously unknown and so diagnostic screening of COL11A1 should include assays capable of detecting both large and small deletions, in addition to exon sequencing.
Changes in the MALT1-A20-NF-κB expression pattern may be related to T cell dysfunction in AML
Authors: Shi Li , Chen Shaohua , Lu Yuhong , Wang Xu , Xu Ling , Zhang Fan , Yang Lijian , Wu Xiuli , Li Bo , Li Yangqiu 
Published: April 2013

AbstractTo elucidate the characteristics of T-cell receptor (TCR) signal transduction in T-cells from acute myeloid leukemia (AML), the mucosa-associated-lymphoid-tissue lymphoma-translocation gene 1 (MALT1), A20, NF-κB and MALT1-V1 gene expression levels in CD3+T cells sorted from the peripheral blood of patients with AML were analyzed by real-time PCR. A significantly lower MALT1 and A20 expression level was found in T cells from patients with AML compared with healthy controls (p = 0.045,p < 0.0001); however, the expression level of MALT1-V1 (variant 1) was significantly higher in the AML group than in the healthy control group (p = 0.006), and the expression level of NF-κB was increased in the AML group. In conclusion, the characteristics of the expression pattern of MALT1-A20-NF-κB and the distribution of MALT1 variants in T cells from AML were first characterized. Overall, low TCR-CD3 signaling is related to low MALT1 expression, which may related to T cell immunodeficiency, while the up-regulation of MALT1-V1 may play a role in overcoming the T cell activity by downregulating A20 in patients with AML, which may be related to a specific response to AML-associated antigens.
Routine ultrasound examination by OB/GYN residents increase the accuracy of diagnosis for emergency surgery in gynecology
Authors: Toret-Labeeuw Flavie , Huchon Cyrille , Popowski Thomas , Chantry Anne A , Dumont Alexandre , Fauconnier Arnaud 
Published: April 2013

Abstract

Introduction
Diagnostic accuracy of first-line sonographic evaluation by obstetrics/gynecology residents in determining the need for emergency surgery in women with acute pelvic pain is unknown. Aim of this study was to evaluate the diagnostic accuracy of routine ultrasound evaluation by obstetrics/gynecology residents, available 24 hours a day, in patients with acute pelvic pain.

Methods
A cross-sectional retrospective study included consecutive patients who underwent emergency laparoscopy for acute pelvic pain at a teaching hospital gynecologic emergency unit, between January 1, 2004, and December 31, 2006. The laparoscopic diagnosis was the reference standard. Gynecologic and nongynecologic conditions requiring immediate surgery to avoid severe morbidity or death were defined as surgical emergencies. In all patients, obstetrics/gynecology residents routinely performed clinical examination and standardized ultrasonography was routinely recorded. Sonograms were re-interpreted for the study, blinded to physical examination and laparoscopic findings, according to evidence-based predetermined criteria. Sensitivity, specificity, and likelihood ratios were computed for clinical data alone, sonographic data alone, and the combination of both.

Results
Emergency laparoscopy was performed in 234 patients, diagnosing 139 (59%) surgical emergencies. Clinical and sonographic examinations performed by the residents each independently predicted a need for emergency surgery. Combining both examinations was superior over each examination alone and had an acceptable false-negative rate of 1%.

Conclusions
First-line combined clinical and sonographic examination by obstetrics/gynecology residents is effective in ruling out surgical emergencies in patients with acute pelvic pain.
An agent-based framework for performance modeling of an optimistic parallel discrete event simulator
Authors: Kurve Aditya , Kotobi Khashayar , Kesidis George 
Published: April 2013

Abstract

Purpose
The performance of an optimistic parallel discrete event simulator (PDES) in terms of the total simulation execution time of an experiment depends on a large set of variables. Many of them have a complex and generally unknown relationship with the simulation execution time. In this paper, we describe an agent-based performance model of a PDES kernel that is typically used to simulate large-sized complex networks on multiple processors or machines. The agent-based paradigm greatly simplifies the modeling of system dynamics by representing a component logical process (LP) as an autonomous agent that interacts with other LPs through event queues and also interacts with its environment which comprises the processor it resides on.

Method
We model the agents representing the LPs using a “base” class of an LP agent that allows us to use a generic behavioral model of an agent that can be extended further to model more details of LP behavior. The base class focuses only on the details that most likely influence the overall simulation execution time of the experiment.

Results
We apply this framework to study a local incentive based partitioning algorithm where each LP makes an informed local decision about its assignment to a processor, resulting in a system akin to a self organizing network. The agent-based model allows us to study the overall effect of the local incentive-based cost function on the simulation execution time of the experiment which we consider to be the global performance metric.

Conclusion
This work demonstrates the utility of agent-based approach in modeling a PDES kernel in order to evaluate the effects of a large number of variable factors such as the LP graph properties, load balancing criteria and others on the total simulation execution time of an experiment.