bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial
Authors: Hegi Monika E. , Diserens Annie-Claire , Bady Pierre , Kamoshima Yuta , Kouwenhoven Mathilde C. M. , Delorenzi Mauro , Lambiv Wanyu L. , Hamou Marie-France , Matter Matthias S. , Koch Arend , Heppner Frank L. , Yonekawa Yasuhiro , Merlo Adrian , Frei Karl , Mariani Luigi , Hofer Silvia 
Published: April 2011

Abstract
Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma. Twenty-two patients selected for reoperation of recurrent glioblastoma were treated within a phase II trial for 5 days with 500 mg gefitinib before surgery followed by postoperative gefitinib until recurrence. Resected glioblastoma tissues exhibited high concentrations of gefitinib (median, 4.1 μg/g), 20 times higher than respective plasma. EGFR-pathway activity was evaluated with phosphorylation-specific assays. The EGFR was efficiently dephosphorylated in treated patients as compared to a control cohort of 12 patients. However, no significant effect on 12 pathway constituents was detected. In contrast, in vitro treatment of a glioblastoma cell line, BS-153, with endogenous EGFRwt amplification and EGFRvIII expression resulted not only in dephosphorylation of the EGFR, but also of key regulators in the pathway such as AKT. Treating established xenografts of the same cell line as an in vivo model showed dephosphorylation of the EGFR without affecting downstream signal transductors, similar to the human glioblastoma. Taken together, gefitinib reaches high concentrations in the tumor tissue and efficiently dephosphorylates its target. However, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation. Mol Cancer Ther; 10(6); 1102–12. ©2011 AACR.
Differential Roles for the Interferon-Inducible IFI16 and AIM2 Innate Immune Sensors for Cytosolic DNA in Cellular Senescence of Human Fibroblasts
Authors: Duan Xin , Ponomareva Larissa , Veeranki Sudhakar , Panchanathan Ravichandran , Dickerson Eric , Choubey Divaker 
Published: April 2011

Abstract
The IFN-inducible IFI16 and AIM2 proteins act as innate immune sensors for cytosolic double-stranded DNA (dsDNA). On sensing dsDNA, the IFI16 protein induces the expression of IFN-β whereas the AIM2 protein forms an inflammasome, which promotes the secretion of IL-1β. Given that the knockdown of IFI16 expression in human diploid fibroblasts (HDF) delays the onset of cellular senescence, we investigated the potential roles for the IFI16 and AIM2 proteins in cellular senescence. We found that increased IFI16 protein levels in old (vs. young) HDFs were associated with the induction of IFN-β. In contrast, increased levels of the AIM2 protein in the senescent (vs. old) HDFs were associated with increased production of IL-1β. The knockdown of type I IFN-α receptor subunit, which reduced the basal levels of the IFI16 but not of the AIM2, protein delayed the onset of cellular senescence. Accordingly, increased constitutive levels of IFI16 and AIM2 proteins in ataxia telangiectasia mutated (ATM) HDFs were associated with the activation of the IFN signaling and increased levels of IL-1β. The IFN-β treatment of the young HDFs, which induced the expression of IFI16 and AIM2 proteins, activated a DNA damage response and also increased basal levels of IL-1β. Interestingly, the knockdown of AIM2 expression in HDFs increased the basal levels of IFI16 protein and activated the IFN signaling. In contrast, the knockdown of the IFI16 expression in HDFs decreased the basal and dsDNA-induced activation of the IFN signaling. Collectively, our observations show differential roles for the IFI16 and AIM2 proteins in cellular senescence and associated secretory phenotype. Mol Cancer Res; 9(5); 589–602. ©2011 AACR.
Asymptotic Properties of an Autocorrelation Coefficient for Coherent Doppler Sonar
Authors: Dillon Jeremy , Zedel Len , Hay Alex E. 
Published: April 2011

Abstract
A new formula is derived for the asymptotic form of the magnitude of an autocorrelation coefficient for coherent Doppler sonar. The autocorrelation magnitude is shown to be a biased estimator in the limit of infinite ensemble length. Numerical simulation of a Gaussian random process is used to verify the asymptotic formula and to show that a bias persists for finite pulse-pair averages. Validity of the asymptotic formula is also confirmed using a high-fidelity coherent Doppler sonar simulation, and from sonar measurements in a towing tank. It is shown that the distribution of observed autocorrelation coefficients is well predicted by a Gaussian random process once the autocorrelation bias has been removed.
A Scale-Invariant Formulation of the Anticipated Potential Vorticity Method
Authors: Chen Qingshan , Gunzburger Max , Ringler Todd 
Published: April 2011

AbstractThe long-term success of climate models that operate on multiresolution grids depends on access to subgrid parameterizations that act appropriately across a wide range of spatial and temporal scales. As the first step in a series of efforts to obtain such scale-aware subgrid parameterizations, the authors focus on the anticipated potential vorticity method (APVM) on a sequence of quasi-uniform grids with varying resolutions. Through a scale analysis technique and phenomenological theories for two-dimensional turbulent flows, they derive a new formulation of the APVM that depends on a single parameter that is formally independent of the time-step size, the grid resolution, and the flow itself. Results of numerical experiments with this new formulation demonstrate that the optimal parameter of the new APVM formulation is invariant with respect to the time-step size, is insensitive to the flows, and is only weakly dependent on the grid resolution.
Operational Convective-Scale Numerical Weather Prediction with the COSMO Model: Description and Sensitivities
Authors: Baldauf Michael , Seifert Axel , Förstner Jochen , Majewski Detlev , Raschendorfer Matthias , Reinhardt Thorsten 
Published: April 2011

Abstract
Since April 2007, the numerical weather prediction model, COSMO (Consortium for Small Scale Modelling), has been used operationally in a convection-permitting configuration, named COSMO-DE, at the Deutscher Wetterdienst (DWD; German weather service). Here the authors discuss the model changes that were necessary for the convective scale, and report on the experience from the first years of operational application of the model. For COSMO-DE the ability of the numerical solver to treat small-scale structures has been improved by using a Runge–Kutta method, which allows for the use of higher-order upwind advection schemes. The one-moment cloud microphysics parameterization has been extended by a graupel class, and adaptations for describing evaporation of rain and stratiform precipitation processes were made. Comparisons with a much more sophisticated two-moment scheme showed only minor differences in most cases with the exception of strong squall-line situations. Whereas the deep convection parameterization was switched off completely, small-scale shallow convection was still parameterized by the appropriate part of the Tiedtke scheme. During the first year of operational use, convective events in synoptically driven situations were satisfactorily simulated. Also the daily cycles of summertime 10-m wind and 1-h precipitation sums were well captured. However, it became evident that the boundary layer description had to be adapted to enhance convection initiation in airmass convection situations. Here the asymptotic Blackadar length scale l∞ had proven to be a sensitive parameter.
Limitation of Economic Damages as a ‘Humanitarian Gesture’: The German Foundation ‘Remembrance, Responsibility and the Future’
Authors: Hense Anja 
Published: April 2011

Over 50 years after the end of the second world war, the German foundation ‘Remembrance, Responsibility and the Future’ was established in order to guarantee a collective compensation of victims of slave and forced labour and ‘aryanization’ in the nazi era. The Foundation was frequently praised as a final sign of the historical and moral responsibility of the German state and economy for ‘nazi wrongs’. Some survivors’ organizations and other participants of the international negotiations on the compensation settlement, in contrast, judged the Foundation as a late and hard-won compromise, which had little relation to the unpaid wages and the misery and repression suffered. In order to evaluate the Foundation as an element of the German compensation politics towards victims of National Socialism, it is necessary to take a close look at its genesis and conception. This article therefore explores which factors determined the international negotiations on a collective compensation settlement for former slave and forced labourers at the end of the twentieth century, and to what extent the survivors’ claims for recognition of the crimes committed, and a comprehensive and adequate compensation were realized. It will be shown that the Foundation was not the result of a voluntary and ‘humanitarian’ initiative of the German economy and government and that numerous victims’ groups were excluded from the modest payments made to especially harshly damaged survivors.
Cytolethal Distending Toxin Damages the Oral Epithelium of Gingival Explants
Authors: Damek-Poprawa M. , Haris M. , Volgina A. , Korostoff J. , DiRienzo J.M. 
Published: April 2011

The cytolethal distending toxin (Cdt), expressed by the periodontal pathogen Aggregatibacter actinomycetemcomitans, inhibits the proliferation of cultured epithelial cells by arresting the cell cycle. The gingival epithelium is an early line of defense against microbial assault. When damaged, bacteria collectively gain entry into underlying connective tissue where microbial products can affect infiltrating inflammatory cells, leading to the destruction of the attachment apparatus. Histological evaluation of rat and healthy human gingival tissue exposed ex vivo to the Cdt for 36 and 18 hours, respectively, revealed extensive detachment of the keratinized outer layer and distention of spinous and basal cells in the oral epithelium. Treated human tissue also exhibited disruption of rete pegs and dissolution of cell junctions. Cells in the connective tissue appeared unaffected. Primary gingival epithelial cells, but not gingival fibroblasts, isolated from the same healthy human tissue were cell-cycle-arrested when treated with the toxin. These findings provide new evidence that the Cdt severely damages the oral epithelium, ex vivo, by specifically targeting epithelial cells, in situ. The Cdt shows preferential targeting of the epithelium as opposed to connective tissue in animal and human gingival explant models. Abbreviations: cytolethal distending toxin (Cdt), connective tissue (CT), 4′,6-diamidino-2-phenylindole (DAPI), human gingival epithelial cells (HGEC), human gingival explants (HGX), human gingival fibroblasts (HGF), junctional epithelium (JE), oral epithelium (OE), rete pegs (RP), sulcular epithelium (SE)
Primer on Pramlintide, an Amylin Analog
Authors: Traina Andrea N. , Kane Michael P. 
Published: April 2011

Purpose Pramlintide is an injectable synthetic analog of human amylin. It is indicated for patients with type 1 or type 2 diabetes who are taking mealtime insulin but have been unable to achieve desired glucose targets. Pramlintide decreases postprandial glucose by lowering inappropriate postmeal glucagon secretion, slowing gastric emptying, and increasing satiety. As such, pramlintide targets several of the defects commonly seen in patients with diabetes. Given the unique characteristics of this agent in the treatment of diabetes, a practical guide to its use is presented. Conclusion Pramlintide treats diabetes with a novel mechanism of action, offering the potential for improved postprandial control and weight loss for patients with type 1 or type 2 diabetes. Providers and diabetes educators should be familiar with the utility of the medication as well as its potential limitations in order to fully educate patients and maximize treatment options for patients with diabetes.
Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom
Authors: Hay Charles R.M. , Palmer Ben , Chalmers Elizabeth , Liesner Ri , Maclean Rhona , Rangarajan Savita , Williams Michael , Collins Peter W. ,   on behalf of United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO)
Published: April 2011

Abstract
The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.
Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease
Authors: Toubai Tomomi , Sun Yaping , Tawara Isao , Friedman Ann , Liu Chen , Evers Rebecca , Nieves Evelyn , Malter Chelsea , Chockley Peter , Maillard Ivan , Winandy Susan , Reddy Pavan 
Published: April 2011

Abstract
Host hematopoietically derived APCs play a vital role in the initiation of GVH responses. However, the APC autonomous molecular mechanisms that are critical for the induction of GVHD are not known. We report here that the Ikaros-Notch axis in host hematopoietically derived APCs regulates the severity of acute GVHD across multiple clinically relevant murine models of experimental bone marrow transplantation. In the present study, Ikaros deficiency (Ik−/−) limited to host hematopoietically derived APCs enhanced donor T-cell expansion and intensified acute GVHD, as determined by survival and other GVHD-specific parameters. The Ik−/− conventional CD8+ and CD8−CD11c+ dendritic cells (DCs), the most potent APCs, showed no increase in the expression of activation markers or in response to TLR stimulation compared with wild-type controls. However, Ik−/− DCs demonstrated an enhanced stimulation of allogeneic T cells. Deficiency of Ikaros in the conventional CD8+ and CD8−CD11c+ DCs was associated with an increase in Notch signaling, the blockade of which mitigated the enhanced in vitro and in vivo allostimulatory capacity. Therefore, the Ikaros-Notch axis is a novel pathway that modulates DC biology in general, and targeting this pathway in host hematopoietically derived APCs may reduce GVHD.
Differential expression and function of breast regression protein 39 (BRP-39) in murine models of subacute cigarette smoke exposure and allergic airway inflammation
Authors: Nikota Jake K , Botelho Fernando M , Bauer Carla MT , Jordana Manel , Coyle Anthony J , Humbles Alison A , Stampfli Martin R 
Published: April 2011

Abstract

Background
While the presence of the chitinase-like molecule YKL40 has been reported in COPD and asthma, its relevance to inflammatory processes elicited by cigarette smoke and common environmental allergens, such as house dust mite (HDM), is not well understood. The objective of the current study was to assess expression and function of BRP-39, the murine equivalent of YKL40 in a murine model of cigarette smoke-induced inflammation and contrast expression and function to a model of HDM-induced allergic airway inflammation.

Methods
CD1, C57BL/6, and BALB/c mice were room air- or cigarette smoke-exposed for 4 days in a whole-body exposure system. In separate experiments, BALB/c mice were challenged with HDM extract once a day for 10 days. BRP-39 was assessed by ELISA and immunohistochemistry. IL-13, IL-1R1, IL-18, and BRP-39 knock out (KO) mice were utilized to assess the mechanism and relevance of BRP-39 in cigarette smoke- and HDM-induced airway inflammation.

Results
Cigarette smoke exposure elicited a robust induction of BRP-39 but not the catalytically active chitinase, AMCase, in lung epithelial cells and alveolar macrophages of all mouse strains tested. Both BRP-39 and AMCase were increased in lung tissue after HDM exposure. Examining smoke-exposed IL-1R1, IL-18, and IL-13 deficient mice, BRP-39 induction was found to be IL-1 and not IL-18 or IL-13 dependent, while induction of BRP-39 by HDM was independent of IL-1 and IL-13. Despite the importance of BRP-39 in cellular inflammation in HDM-induced airway inflammation, BRP-39 was found to be redundant for cigarette smoke-induced airway inflammation and the adjuvant properties of cigarette smoke.

Conclusions
These data highlight the contrast between the importance of BRP-39 in HDM- and cigarette smoke-induced inflammation. While functionally important in HDM-induced inflammation, BRP-39 is a biomarker of cigarette smoke induced inflammation which is the byproduct of an IL-1 inflammatory pathway.
dbOGAP - An Integrated Bioinformatics Resource for Protein O-GlcNAcylation
Authors: Wang Jinlian , Torii Manabu , Liu Hongfang , Hart Gerald W , Hu Zhang-Zhi 
Published: April 2011

Abstract

Background
Protein O-GlcNAcylation (or O-GlcNAc-ylation) is an O-linked glycosylation involving the transfer of β-N-acetylglucosamine to the hydroxyl group of serine or threonine residues of proteins. Growing evidences suggest that protein O-GlcNAcylation is common and is analogous to phosphorylation in modulating broad ranges of biological processes. However, compared to phosphorylation, the amount of protein O-GlcNAcylation data is relatively limited and its annotation in databases is scarce. Furthermore, a bioinformatics resource for O-GlcNAcylation is lacking, and an O-GlcNAcylation site prediction tool is much needed.

Description
We developed a database of O-GlcNAcylated proteins and sites, dbOGAP, primarily based on literature published since O-GlcNAcylation was first described in 1984. The database currently contains ~800 proteins with experimental O-GlcNAcylation information, of which ~61% are of humans, and 172 proteins have a total of ~400 O-GlcNAcylation sites identified. The O-GlcNAcylated proteins are primarily nucleocytoplasmic, including membrane- and non-membrane bounded organelle-associated proteins. The known O-GlcNAcylated proteins exert a broad range of functions including transcriptional regulation, macromolecular complex assembly, intracellular transport, translation, and regulation of cell growth or death. The database also contains ~365 potential O-GlcNAcylated proteins inferred from known O-GlcNAcylated orthologs. Additional annotations, including other protein posttranslational modifications, biological pathways and disease information are integrated into the database. We developed an O-GlcNAcylation site prediction system, OGlcNAcScan, based on Support Vector Machine and trained using protein sequences with known O-GlcNAcylation sites from dbOGAP. The site prediction system achieved an area under ROC curve of 74.3% in five-fold cross-validation. The dbOGAP website was developed to allow for performing search and query on O-GlcNAcylated proteins and associated literature, as well as for browsing by gene names, organisms or pathways, and downloading of the database. Also available from the website, the OGlcNAcScan tool presents a list of predicted O-GlcNAcylation sites for given protein sequences.

Conclusions
dbOGAP is the first public bioinformatics resource to allow systematic access to the O-GlcNAcylated proteins, and related functional information and bibliography, as well as to an O-GlcNAcylation site prediction tool. The resource will facilitate research on O-GlcNAcylation and its proteomic identification.
Word sense disambiguation for event trigger word detection in biomedicine
Authors: Martinez David , Baldwin Timothy 
Published: April 2011

Abstract
This paper describes a method for detecting event trigger words in biomedical text based on a word sense disambiguation (WSD) approach. We first investigate the applicability of existing WSD techniques to trigger word disambiguation in the BioNLP 2009 shared task data, and find that we are able to outperform a traditional CRF-based approach for certain word types. On the basis of this finding, we combine the WSD approach with the CRF, and obtain significant improvements over the standalone CRF, gaining particularly in recall.
Pancreatic adenocarcinoma-associated polymyositis treated with corticosteroids along with cancer specific treatment: case report
Authors: Syrios John , Kechagias Georgios , Xynos Ioannis D , Gamaletsou Maria N , Papageorgiou Aristea , Agrogiannis George , Tsavaris Nicolas 
Published: April 2011

Abstract

Background
Adenocarcinoma of the pancreas only rarely is associated with inflammatory myopathy. In this setting, polymyositis may be treated with glucocorticoids in combination with cancer specific treatment.

Case presentation
We present the case of a 52-year-old man with stage IIA pancreatic tail adenocarcinoma who underwent surgical treatment and six months into therapy with gemcitabine he developed symmetrical, painful, proximal muscle weakness with peripheral oedema. Re-evaluation with imaging modalities, muscle histology and biochemistry conferred the diagnosis of polymyositis associated with pancreatic cancer progression. The patient was treated with glucocorticoids along with gemcitabine and erlotinib which resulted in complete remission within six months. He remained in good health for a further six months on erlotinib maintenance therapy when a new computer tomography scan showed pancreatic cancer relapse and hence prompted 2nd line chemotherapy with gemcitabine.

Conclusions
Polymyositis associated with pancreatic cancer may respond to glucocorticoids along with cancer specific treatment.