bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cotargeting MAPK and PI3K Signaling with Concurrent Radiotherapy as a Strategy for the Treatment of Pancreatic Cancer
Authors: Williams Terence M. , Flecha Athena R. , Keller Paul , Ram Ashwin , Karnak David , Galbán Stefanie , Galbán Craig J. , Ross Brian D. , Lawrence Theodore S. , Rehemtulla Alnawaz , Sebolt-Leopold Judith 
Published: March 2012

Abstract
There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MAP kinase kinase (MEK or MAP2K) inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the mitogen-activated protein kinase (MAPK) and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MIA-PaCa2 xenografts. Phosphorylated levels of extracellular signal–regulated kinase (ERK)-1/2 and Akt were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor–induced radiosensitization was observed in vitro and in vivo. The further addition of an Akt inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as determined by increased radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models, and the effects can be enhanced by combination with an Akt inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with Akt inhibition. Mol Cancer Ther; 11(5); 1193–202. ©2012 AACR.
Global Longitudinal Strain Predicts Long-Term Survival in Patients With Chronic Ischemic Cardiomyopathy
Authors: Bertini Matteo , Ng Arnold C.T. , Antoni M. Louisa , Nucifora Gaetano , Ewe See H. , Auger Dominique , Marsan Nina Ajmone , Schalij Martin J. , Bax Jeroen J. , Delgado Victoria 
Published: March 2012

Background—
Left ventricular (LV) global longitudinal strain (GLS) is a measure of the active shortening of the LV in the longitudinal direction, which can be assessed with speckle-tracking echocardiography. The aims of this evaluation were to validate the prognostic value of GLS as a new index of LV systolic function in a large cohort of patients with chronic ischemic cardiomyopathy and to determine the incremental value of GLS to predict long-term outcome over other strong and well-established prognostic factors.

Methods and Results—

A total of 1060 patients underwent baseline clinical evaluation and transthoracic echocardiography. Median age was 66.9 years (interquartile range, 58.4, 74.2 years); 739 (70%) were men. The median follow-up duration for the entire patient population was 31 months. During the follow-up, 270 patients died and 309 patients reached the combined end point (all-cause mortality and heart failure hospitalization). Compared with survivors, patients who died (270, [25%]) had larger LV volumes (
P
<0.05), lower LV ejection fraction (
P
=0.004), higher wall motion score index (
P
=0.001), and greater impairment of LV GLS (
P
<0.001). After dichotomizing the population on the basis of the median value of LV GLS (−11.5%), patients with an LV GLS ≤−11.5% had superior outcome compared with patients with an LV GLS >−11.5% (log-rank χ
2
, 13.86 and 14.16 for all-cause mortality and combined end point, respectively,
P
<0.001 for both). On multivariate analysis, GLS was independently related to all-cause mortality (hazard ratio per 5% increase, 1.69; 95% confidence interval, 1.33–2.15;
P
<0.001) and combined end point (1.64; 95% confidence interval, 1.32–2.04;
P
<0.001).

Conclusions—
The assessment of LV GLS with speckle-tracking echocardiography is significantly related to long-term outcome in patients with chronic ischemic cardiomyopathy.
A periodized model for exercise improves the intra-hospital evolution of patients after myocardial revascularization: a pilot randomized controlled trial
Authors: de Macedo Rafael Michel , Neto José Rocha Faria , Costantini Costantino O , Olandoski Marcia , Casali Dayane , de Macedo Ana Carolina Brandt , Muller Andrea , Costantini Costantino R , do Amaral Vivian Ferreria , de Carvalho Katheryne Athayde Teixeira , Guarita-Souza Luiz César 
Published: March 2012

Objective: To compare models of the postoperative hospital treatment phase after myocardial revascularization. Design: A pilot randomized controlled trial. Setting: Hospital patients in a hospital setting. Subjects: Thirty-two patients with indications for myocardial revascularization were included between January 2008 and December 2009, with a left ventricular ejection fraction (LVEF) ≥50%, 1-second forced expiratory volume (FEV1) ≥60 and forced vital capacity (FVC) ≥60% of predicted value. Interventions: Patients were randomly placed into two groups: one performed prescribed exercises according to the model proposed by the American College of Sports Medicine (ACSM) and the other according to a periodized model. Main measures: Partial pressure of O2 ( Po2) and arterial O2 saturation ( Sao2), percentage of predicted FVC and total distance on the six-minute walking test (6MWT). Results: Twenty-seven patients were re-evaluated upon release from the hospital (ACSM = 14 and PP = 13). Five patients extubated for more than 6 hours in the postoperative period were excluded from the sample. In the preoperative period the variables Po2, Sao2, % FVC and 6MWT were similar. In the postoperative period, a reduction was observed for all parameters in both groups. Upon comparison of the groups, a difference was observed in Po2 (ACSM = 68.0 ± 4.3 vs. PP = 75.9 ± 4.8 mmHg; P < 0.001), Sao2 (ACSM = 93.5 ± 1.4 vs. PP = 94.8 ± 1.2%; P = 0.018) and 6MWT (ACSM = 339.3 ± 41.7 vs. PP = 393.8 ± 25.7 m; P < 0.001). There was no difference in % FVC. Conclusion: Patients after myocardial revascularization following a periodized model of exercise presented a better intra-hospital evolution when compared to those using the ACSM model.
Interest Rate Risk of Stock Prices in Nigeria
Authors: Udegbunam Raphael I. , Oaikhenan Hassan E. 
Published: March 2012

The article empirically examines the response of stock prices in the Nigerian Stock Market to interest rate risk, using the Duration and Convexity model. A simple non-linear stock price model that incorporates measure of interest rate duration and convexity and a vector containing a battery of other control variables is specified and estimated using annual secondary data that covered the 1981–2006 sample period. The empirical results largely corroborate the hypothesis of interest rate sensitivity of stock prices in the Nigerian Stock Market. Specifically, we find both measures of interest rate duration and convexity to exert strong but opposite effects on stock prices in Nigeria. The empirical evidence shows that the net effect of interest rate changes on stock prices is negative, an indication that stock prices fall with increases in stock risk. The results provide empirical support for the duration and convexity hypothesis of the existence of a non-linear relationship between interest rate risk and stock prices in Nigeria. JEL Classification: G1, G12
Association of 3-Dimensional Cartilage and Bone Structure with Articular Cartilage Properties in and Adjacent to Autologous Osteochondral Grafts after 6 and 12 Months in a Goat Model
Authors: Chan Elaine F. , Liu I-Ling , Semler Eric J. , Aberman Harold M. , Simon Timothy M. , Chen Albert C. , Truncale Kate G. , Sah Robert L. 
Published: March 2012

Objective: The articular cartilage of autologous osteochondral grafts is typically different in structure and function from local host cartilage and thereby presents a remodeling challenge. The hypothesis of this study was that properties of the articular cartilage of trochlear autografts and adjacent femoral condyle are associated with the 3-dimensional (3-D) geometrical match between grafted and contralateral joints at 6 and 12 months after surgery. Design: Autografts were transferred unilaterally from the lateral trochlea (LT) to the medial femoral condyle (MFC) in adult Spanish goats. Operated and contralateral nonoperated joints were harvested at 6 and 12 months and analyzed by indentation testing, micro–computed tomography, and histology to compare 1) histological indices of repair, 2) 3-D structure (articular surface deviation, bone-cartilage interface deviation, cartilage thickness), 3) indentation stiffness, and 4) correlations between stiffness and 3-D structure. Results: Cartilage deterioration was present in grafts at 6 months and more severe at 12 months. Cartilage thickness and normalized stiffness of the operated MFC were lower than the nonoperated MFC within the graft and proximal adjacent host regions. Operated MFC articular surfaces were recessed relative to the nonoperated MFC and exhibited lower cartilage stiffness with increasing recession. Sites with large bone-cartilage interface deviations, both proud and recessed, were associated with recessed articular surfaces and low cartilage stiffness. Conclusion: The effectiveness of cartilage repair by osteochondral grafting is associated with the match of 3-D cartilage and bone geometry to the native osteochondral structure.
Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function
Authors: Westerberg Lisa S. , Dahlberg Carin , Baptista Marisa , Moran Christopher J. , Detre Cynthia , Keszei Marton , Eston Michelle A. , Alt Frederick W. , Terhorst Cox , Notarangelo Luigi D. , Snapper Scott B. 
Published: March 2012

Abstract
The Wiskott-Aldrich syndrome protein (WASP) is a key cytoskeletal regulator of hematopoietic cells. Although WASP-knockout (WKO) mice have aberrant B-cell cytoskeletal responses, B-cell development is relatively normal. We hypothesized that N-WASP, a ubiquitously expressed homolog of WASP, may serve some redundant functions with WASP in B cells. In the present study, we generated mice lacking WASP and N-WASP in B cells (conditional double knockout [cDKO] B cells) and show that cDKO mice had decreased numbers of follicular and marginal zone B cells in the spleen. Receptor-induced activation of cDKO B cells led to normal proliferation but a marked reduction of spreading compared with wild-type and WKO B cells. Whereas WKO B cells showed decreased migration in vitro and homing in vivo compared with wild-type cells, cDKO B cells showed an even more pronounced decrease in the migratory response in vivo. After injection of 2,4,6-trinitrophenol (TNP)–Ficoll, cDKO B cells had reduced antigen uptake in the splenic marginal zone. Despite high basal serum IgM, cDKO mice mounted a reduced immune response to the T cell–independent antigen TNP-Ficoll and to the T cell–dependent antigen TNP–keyhole limpet hemocyanin. Our results reveal that the combined activity of WASP and N-WASP is required for peripheral B-cell development and function.
Reordering based integrative expression profiling for microarray classification
Authors: Wu Xiaogang , Huang Hui , Sonachalam Madhankumar , Reinhard Sina , Shen Jeffrey , Pandey Ragini , Chen Jake Y 
Published: March 2012

Abstract

Background
Current network-based microarray analysis uses the information of interactions among concerned genes/gene products, but still considers each gene expression individually. We propose an organized knowledge-supervised approach - Integrative eXpression Profiling (IXP), to improve microarray classification accuracy, and help discover groups of genes that have been too weak to detect individually by traditional ways. To implement IXP, ant colony optimization reordering (ACOR) algorithm is used to group functionally related genes in an ordered way.

Results
Using Alzheimer's disease (AD) as an example, we demonstrate how to apply ACOR-based IXP approach into microarray classifications. Using a microarray dataset - GSE1297 with 31 samples as training set, the result for the blinded classification on another microarray dataset - GSE5281 with 151 samples, shows that our approach can improve accuracy from 74.83% to 82.78%. A recently-published 1372-probe signature for AD can only achieve 61.59% accuracy in the same condition. The ACOR-based IXP approach also has better performance than the IXP approach based on classic network ranking, graph clustering, and random-ordering methods in an overall classification performance comparison.

Conclusions
The ACOR-based IXP approach can serve as a knowledge-supervised feature transformation approach to increase classification accuracy dramatically, by transforming each gene expression profile to an integrated expression files as features inputting into standard classifiers. The IXP approach integrates both gene expression information and organized knowledge - disease gene/protein network topology information, which is represented as both network node weights (local topological properties) and network node orders (global topological characteristics).
Computational and experimental analyses of retrotransposon-associated minisatellite DNAs in the soybean genome
Authors: Mogil Lauren S , Slowikowski Kamil , Laten Howard M 
Published: March 2012

Abstract

Background
Retrotransposons are mobile DNA elements that spread through genomes via the action of element-encoded reverse transcriptases. They are ubiquitous constituents of most eukaryotic genomes, especially those of higher plants. The pericentromeric regions of soybean (Glycine max) chromosomes contain >3,200 intact copies of the Gmr9/GmOgre retrotransposon. Between the 3' end of the coding region and the long terminal repeat, this retrotransposon family contains a polymorphic minisatellite region composed of five distinct, interleaved minisatellite families. To better understand the possible role and origin of retrotransposon-associated minisatellites, a computational project to map and physically characterize all members of these families in the G. max genome, irrespective of their association with Gmr9, was undertaken.

Methods
A computational pipeline was developed to map and analyze the organization and distribution of five Gmr9-associated minisatellites throughout the soybean genome. Polymerase chain reaction amplifications were used to experimentally assess the computational outputs.

Results
A total of 63,841 copies of Gmr9-associated minisatellites were recovered from the assembled G. max genome. Ninety percent were associated with Gmr9, an additional 9% with other annotated retrotransposons, and 1% with uncharacterized repetitive DNAs. Monomers were tandemly interleaved and repeated up to 149 times per locus.

Conclusions
The computational pipeline enabled a fast, accurate, and detailed characterization of known minisatellites in a large, downloaded DNA database, and PCR amplification supported the general organization of these arrays.
Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons
Authors: Lejeune François-Xavier , Mesrob Lilia , Parmentier Frédéric , Bicep Cedric , Vazquez-Manrique Rafael P , Parker J Alex , Vert Jean-Philippe , Tourette Cendrine , Neri Christian 
Published: March 2012

Abstract

Background
A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD.

Results
Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified.

Conclusions
Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.
Ongoing monitoring of data clustering in multicenter studies
Authors: Guthrie Lauren B , Oken Emily , Sterne Jonathan AC , Gillman Matthew W , Patel Rita , Vilchuck Konstantin , Bogdanovich Natalia , Kramer Michael S , Martin Richard M 
Published: March 2012

Abstract

Background
Multicenter study designs have several advantages, but the possibility of non-random measurement error resulting from procedural differences between the centers is a special concern. While it is possible to address and correct for some measurement error through statistical analysis, proactive data monitoring is essential to ensure high-quality data collection.

Methods
In this article, we describe quality assurance efforts aimed at reducing the effect of measurement error in a recent follow-up of a large cluster-randomized controlled trial through periodic evaluation of intraclass correlation coefficients (ICCs) for continuous measurements. An ICC of 0 indicates the variance in the data is not due to variation between the centers, and thus the data are not clustered by center.

Results
Through our review of early data downloads, we identified several outcomes (including sitting height, waist circumference, and systolic blood pressure) with higher than expected ICC values. Further investigation revealed variations in the procedures used by pediatricians to measure these outcomes. We addressed these procedural inconsistencies through written clarification of the protocol and refresher training workshops with the pediatricians. Further data monitoring at subsequent downloads showed that these efforts had a beneficial effect on data quality (sitting height ICC decreased from 0.92 to 0.03, waist circumference from 0.10 to 0.07, and systolic blood pressure from 0.16 to 0.12).

Conclusions
We describe a simple but formal mechanism for identifying ongoing problems during data collection. The calculation of the ICC can easily be programmed and the mechanism has wide applicability, not just to cluster randomized controlled trials but to any study with multiple centers or with multiple observers.
HIV testing and willingness to get HIV testing at a peer-run drop-in centre for people who inject drugs in Bangkok, Thailand
Authors: Ti Lianping , Hayashi Kanna , Kaplan Karyn , Suwannawong Paisan , Fu Eric , Wood Evan , Kerr Thomas 
Published: March 2012

Abstract

Background
Regular HIV testing among people who inject drugs is an essential component of HIV prevention and treatment efforts. We explored HIV testing behaviour among a community-recruited sample of injection drug users (IDU) in Bangkok, Thailand.

Methods
Data collected through the Mitsampan Community Research Project were used to examine correlates of HIV testing behaviour among IDU and to explore reasons for not being tested. Multivariate logistic regression was used to examine factors associated with willingness to access HIV testing at the drug-user-run Mitsampan Harm Reduction Centre (MSHRC).

Results
Among the 244 IDU who participated in this study, 186 (76.2%) reported receiving HIV testing in the previous six months. Enrolment in voluntary drug treatment (odds ratio [OR] = 2.34; 95% confidence interval [CI]: 1.18 - 4.63) and the tenofovir trial (OR = 44.81; 95%CI: 13.44 - 149.45) were positively associated with having been tested, whereas MSHRC use (OR = 1.78; 95%CI: 0.96 - 3.29) was marginally associated with having been tested. 56.9% of those who had not been tested reported in engaging in HIV risk behaviour in the past six months. 181 (74.2%) participants were willing to be tested at the MSHRC if testing were offered there. In multivariate analyses, willingness to get HIV testing at the MSHRC was positively associated with ever having been to the MSHRC (adjusted odds ratio [AOR] = 2.42; 95%CI: 1.21 - 4.85) and, among females, being enrolled in voluntary drug treatment services (AOR = 9.38; 95%CI: 1.14 - 76.98).

Conclusions
More than three-quarters of IDU received HIV testing in the previous six months. However, HIV risk behaviour was common among those who had not been tested. Additionally, 74.2% of participants were willing to receive HIV testing at the MSHRC. These findings provide evidence for ongoing HIV prevention education, as well potential benefits of incorporating HIV testing for IDU within peer-led harm reduction programs.