bluuebunny/crossref_metadata_2025_split huggingface dataset:
Forward modelling as a method for predicting the distribution of deep-marine sands: an example from the Peïra Cava Sub-basin
Authors: Aas Tor Even , Basani Riccardo , Howell John , Hansen Ernst 
Published: February 2014

Abstract
The aerial extent, thickness and internal distribution of grain-size are key, bed-scale controls on turbidite reservoir performance. Process-based modelling provides a method for predicting both the sandbody thickness and the grain-size distribution within the bed. The goal of the current study is to test such an approach on the Annot Sandstone in the Peïra Cava Sub-basin in SE France, and determine whether the process-based model can reliably recreate the bed characteristics observed in the outcrop. Turbidity currents were modelled using a commercially available software solution called MassFlow3D that is based on computational fluid dynamics. The goal of the current study was to accurately replicate a single bed (termed MU5). To achieve this goal, the base of the basin was structurally restored and then a simplified simulation of the beds below MU5 was generated using four flow events in order to recreate the bathymetry on to which MU5 was simulated. Several versions of MU5 were simulated with different input parameters for the flow, and the results were compared with the observed thickness and grain-size distribution from the outcrop. The study suggests that process-based modelling has the potential to be a useful tool in reservoir modelling.

Supplementary material:

Multi-phase flow modelling of transport, deposition and erosion of sediments is available at
http://www.geolsoc.org.uk/SUP18719
.
Classification of annotation semirings over containment of conjunctive queries
Authors: Kostylev Egor V. , Reutter Juan L. , Salamon András Z. 
Published: February 2014

We study the problem of query containment of conjunctive queries over annotated databases. Annotations are typically attached to tuples and represent metadata, such as probability, multiplicity, comments, or provenance. It is usually assumed that annotations are drawn from a commutative semiring. Such databases pose new challenges in query optimization, since many related fundamental tasks, such as query containment, have to be reconsidered in the presence of propagation of annotations.
We axiomatize several classes of semirings for each of which containment of conjunctive queries is equivalent to existence of a particular type of homomorphism. For each of these types, we also specify all semirings for which existence of a corresponding homomorphism is a sufficient (or necessary) condition for the containment. We develop new decision procedures for containment for some semirings which are not in any of these classes. This generalizes and systematizes previous approaches.
Aspect-driven, data-reflective and context-aware user interfaces design
Authors: Cerny Tomas , Cemus Karel , Donahoo Michael J. , Song Eunjee 
Published: February 2014

The increasing use of Web-based applications continues to broaden the user groups of enterprise applications at large. Since ordinary users often equate the quality of user interface (UI) with the quality of the entire application, the importance of providing easy-to-use UIs has been significantly increasing. Unfortunately, designing a single UI satisfying all end users remains challenging. To address this issue, researchers and developers are looking to Context-aware/Adaptive UIs (CUIs) that aim to provide end users with more personalized user interaction experiences. Although multiple proposals have been made, very few production systems provide such malleable interfaces due to the excessive cost of development and maintenance.
In this paper, we propose a technique that aims to reduce development and maintenance efforts of CUI to a level comparable with a single UI. Unlike most of the existing CUI approaches, our technique does not involve an external UI model. Instead, it aims to reflect runtime-information and structures already captured in the application, while extending them to provide an appropriate CUI. With this technique, developers do not design forms or tables directly for each page or panel. Instead they design generic and reusable transformation rules capable of presenting application data instances in the UI while considering the runtime context. To demonstrate our technique and its impact on CUI development and maintenance, we provide a case study. Moreover, we present our experience from its application to an existing production-level enterprise application, with high demands on performance.
Activation of the Glutamate Receptor GRM1 Enhances Angiogenic Signaling to Drive Melanoma Progression
Authors: Wen Yu , Li Jiadong , Koo Jasmine , Shin Seung-Shick , Lin Yong , Jeong Byeong-Seon , Mehnert Janice M. , Chen Suzie , Cohen-Sola Karine A. , Goydos James S. 
Published: February 2014

AbstractGlutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1-mediated activation of the AKT–mTOR–HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients. Cancer Res; 74(9); 2499–509. ©2014 AACR.
CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy
Authors: Ding Liya , Chen Shuai , Liu Ping , Pan Yunqian , Zhong Jian , Regan Kevin M. , Wang Liguo , Yu Chunrong , Rizzardi Anthony , Cheng Liang , Zhang Jun , Schmechel Stephen C. , Cheville John C. , Van Deursen Jan , Tindall Donald J. , Huang Haojie 
Published: February 2014

Abstract
Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.
miR-28-5p Promotes Chromosomal Instability in VHL-Associated Cancers by Inhibiting Mad2 Translation
Authors: Hell Michael P. , Thoma Claudio R. , Fankhauser Niklaus , Christinat Yann , Weber Thomas C. , Krek Wilhelm 
Published: February 2014

Abstract
Chromosomal instability enables tumor development, enabled in part by aberrant expression of the mitotic checkpoint protein Mad2. Here we identify a novel regulatory mechanism for Mad2 expression involving miR-28-5p-mediated inhibition of Mad2 translation, and we demonstrate that this mechanism is triggered by inactivation of the tumor suppressor VHL, the most common event in clear cell renal cell carcinoma (ccRCC). In VHL-positive cancer cells, enhanced expression of miR-28-5p diminished Mad2 levels and promoted checkpoint weakness and chromosomal instability. Conversely, in checkpoint-deficient VHL-negative renal carcinoma cells, inhibition of miR-28-5p function restored Mad2 levels, mitotic checkpoint proficiency, and chromosomal stability. Notably, chromosome missegregation errors and aneuploidy that were produced in a mouse model of acute renal injury (as a result of kidney-specific ablation of pVHL function) were reverted in vivo also by genetic inhibition of miR-28-5p. Finally, bioinformatic analyses in human ccRCC associated loss of VHL with increased miR-28-5p expression and chromosomal instability. Together, our results defined miR-28-5p as a critical regulator of Mad2 translation and mitotic checkpoint function. By identifying a potential mediator of chromosomal instability in VHL-associated cancers, our work also suggests a novel microRNA-based therapeutic strategy to target aneuploid cells in VHL-associated cancers. Cancer Res; 74(9); 2432–43. ©2014 AACR.
Noninvasive Quantification of Solid Tumor Microstructure Using VERDICT MRI
Authors: Panagiotaki Eletheria , Walker-Samuel Simon , Siow Bernard , Johnson S. Peter , Rajkumar Vineeth , Pedley R. Barbara , Lythgoe Mark F. , Alexander Daniel C. 
Published: February 2014

Abstract
There is a need for biomarkers that are useful for noninvasive imaging of tumor pathophysiology and drug efficacy. Through its use of endogenous water, diffusion-weighted MRI (DW-MRI) can be used to probe local tissue architecture and structure. However, most DW-MRI studies of cancer tissues have relied on simplistic mathematical models, such as apparent diffusion coefficient (ADC) or intravoxel incoherent motion (IVIM) models, which produce equivocal results on the relation of the model parameter estimate with the underlying tissue microstructure. Here, we present a novel technique called VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) to quantify and map histologic features of tumors in vivo. VERDICT couples DW-MRI to a mathematical model of tumor tissue to access features such as cell size, vascular volume fraction, intra- and extracellular volume fractions, and pseudo-diffusivity associated with blood flow. To illustrate VERDICT, we used two tumor xenograft models of colorectal cancer with different cellular and vascular phenotypes. Our experiments visualized known differences in the tissue microstructure of each model and the significant decrease in cell volume resulting from administration of the cytotoxic drug gemcitabine, reflecting the apoptotic volume decrease. In contrast, the standard ADC and IVIM models failed to detect either of these differences. Our results illustrate the superior features of VERDICT for cancer imaging, establishing it as a noninvasive method to monitor and stratify treatment responses. Cancer Res; 74(7); 1902–12. ©2014 AACR.
Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies
Authors: Salgia Ravi , Patel Premal , Bothos John , Yu Wei , Eppler Steve , Hegde Priti , Bai Shuang , Kaur Surinder , Nijem Ihsan , Catenacci Daniel V.T. , Peterson Amy , Ratain Mark J. , Polite Blase , Mehnert Janice M. , Moss Rebecca A. 
Published: February 2014

Abstract
Purpose: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET.
Experimental Design: This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies.
Results: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years.
Conclusions: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. Clin Cancer Res; 20(6); 1666–75. ©2014 AACR.
High-Resolution Array CGH and Gene Expression Profiling of Alveolar Soft Part Sarcoma
Authors: Selvarajah Shamini , Pyne Saumyadipta , Chen Eleanor , Sompallae Ramakrishna , Ligon Azra H. , Nielsen Gunnlaugur P. , Dranoff Glenn , Stack Edward , Loda Massimo , Flavin Richard 
Published: February 2014

Abstract
Purpose: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis.
Experimental Design: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL–TFE3 fusion and, hence, confirm the aCGH observations.
Results: FISH analysis identified the ASPL–TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P &lt; 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation.
Conclusion: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS. Clin Cancer Res; 20(6); 1521–30. ©2014 AACR.
The Impact of EGFR T790M Mutations and BIM mRNA Expression on Outcome in Patients with EGFR-Mutant NSCLC Treated with Erlotinib or Chemotherapy in the Randomized Phase III EURTAC Trial
Authors: Costa Carlota , Molina Miguel Angel , Drozdowskyj Ana , Giménez-Capitán Ana , Bertran-Alamillo Jordi , Karachaliou Niki , Gervais Radj , Massuti Bartomeu , Wei Jia , Moran Teresa , Majem Margarita , Felip Enriqueta , Carcereny Enric , Garcia-Campelo Rosario , Viteri Santiago , Taron Miquel , Ono Mayumi , Giannikopoulos Petros , Bivona Trever , Rosell Rafael 
Published: February 2014

Abstract
Purpose: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations.
Experimental Design: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non–small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225).
Results: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P &lt; 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P = 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P = 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR = 0.35; P = 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR = 0.49; P = 0.0122) and overall survival (HR = 0.53; P = 0.0323).
Conclusions: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies. Clin Cancer Res; 20(7); 2001–10. ©2014 AACR.
Fatostatin Displays High Antitumor Activity in Prostate Cancer by Blocking SREBP-Regulated Metabolic Pathways and Androgen Receptor Signaling
Authors: Li Xiangyan , Chen Yi-Ting , Hu Peizhen , Huang Wen-Chin 
Published: February 2014

Abstract
Current research links aberrant lipogenesis and cholesterogenesis with prostate cancer development and progression. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis and cholesterogenesis via the regulation of genes related to fatty acid and cholesterol biosynthesis. Overexpression of SREBPs has been reported to be significantly associated with aggressive pathologic features in human prostate cancer. Our previous results showed that SREBP-1 promoted prostate cancer growth and castration resistance through induction of lipogenesis and androgen receptor (AR) activity. In the present study, we evaluated the anti–prostate tumor activity of a novel SREBP inhibitor, fatostatin. We found that fatostatin suppressed cell proliferation and anchorage-independent colony formation in both androgen-responsive LNCaP and androgen-insensitive C4-2B prostate cancer cells. Fatostatin also reduced in vitro invasion and migration in both the cell lines. Further, fatostatin caused G2–M cell-cycle arrest and induced apoptosis by increasing caspase-3/7 activity and the cleavages of caspase-3 and PARP. The in vivo animal results demonstrated that fatostatin significantly inhibited subcutaneous C4-2B tumor growth and markedly decreased serum prostate-specific antigen (PSA) level compared with the control group. The in vitro and in vivo effects of fatostatin treatment were due to blockade of SREBP-regulated metabolic pathways and the AR signaling network. Our findings identify SREBP inhibition as a potential new therapeutic approach for the treatment of prostate cancer. Mol Cancer Ther; 13(4); 855–66. ©2014 AACR.
Essential Role of the Linear Ubiquitin Chain Assembly Complex in Lymphoma Revealed by Rare Germline Polymorphisms
Authors: Yang Yibin , Schmitz Roland , Mitala Joseph , Whiting Amanda , Xiao Wenming , Ceribelli Michele , Wright George W. , Zhao Hong , Yang Yandan , Xu Weihong , Rosenwald Andreas , Ott German , Gascoyne Randy D. , Connors Joseph M. , Rimsza Lisa M. , Campo Elias , Jaffe Elaine S. , Delabie Jan , Smeland Erlend B. , Braziel Rita M. , Tubbs Raymond R. , Cook James R. , Weisenburger Dennis D. , Chan Wing C. , Wiestner Adrian , Kruhlak Michael J. , Iwai Kazuhiro , Bernal Federico , Staudt Louis M. 
Published: February 2014

AbstractConstitutive activation of NF-κB is a hallmark of the activated B cell–like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IκB kinase-γ, a necessary event in some pathways that engage NF-κB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (∼1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 α-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31–RBCK1 association, LUBAC enzymatic activity, and NF-κB engagement. In the BCR pathway, LUBAC associates with the CARD11–MALT1–BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 α-helical peptide based on the ABC DLBCL–associated Q622L polymorphism inhibited RNF31–RBCK1 binding, decreased NF-κB activation, and killed ABC DLBCL cells, credentialing this protein–protein interface as a therapeutic target.Significance: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis. Cancer Discov; 4(4); 480–93. ©2014 AACR.See related commentary by Grumati and Dikic, p. 394This article is highlighted in the In This Issue feature, p. 377