bluuebunny/crossref_metadata_2025_split huggingface dataset:
Avalonia, Armorica, Perunica: terranes, microcontinents, microplates or palaeobiogeographical provinces?
Authors: Servais Thomas , Sintubin Manuel 
Published: December 2009

Abstract
In recent decades various research studies have focused on the reconstruction of Palaeozoic Europe, reflecting the complex geodynamic history related to the formation of the supercontinent Pangaea. It has been demonstrated that Palaeozoic Europe comprises a series of tectonostratigraphical units, or ‘terranes’, located between the remnants of three major palaeocontinents, Gondwana, Laurentia and Baltica. Some of these ‘terranes’ have been referred to as ‘microcontinents’, a typical (palaeo-)geographical term, and as ‘microplates’, a typical plate-tectonic term, giving rise to misunderstandings and a continuing scientific debate. This confusion is based primarily on an inconsistent use of different palaeogeographical terms by specialists from different scientific disciplines. Whereas large palaeocontinents such as Baltica and Siberia have been named as terranes by some workers, several peri-Gondwanan ‘terranes’ have been attributed to microcontinents or microplates, without conclusive reasoning. This paper is a critical review of the terminology used for three European peri-Gondwanan palaeogeographical entities: ‘Avalonia’, ‘Armorica’ and ‘Perunica’. The review indicates that only Avalonia should be considered as a separate (micro-)continent on a separate (micro-)plate. Armorica has many different definitions and is commonly considered to be composed of several terranes. It is, however, not at all evident if Armorica was a separate (micro-)continent and/or an independent (micro-)plate. For Perunica, defined originally as a separate microplate, current evidence demonstrates that it can probably be considered only as a palaeobiogeographical province.
Late Ordovician carbonate productivity and glaciomarine record under quiescent and active extensional tectonics in NE Spain
Authors: Álvaro J. Javier , Van Vliet-Lanoë Brigitte 
Published: December 2009

Abstract
Carbonate productivity and glaciomarine deposits of the Ordovician–Silurian transition display different sedimentary architectures in the Iberian and Hesperian Chains of NE Spain, as a result of quiescent and active extensional tectonics on platforms fringing North Gondwana. The late Katian carbonate productivity of the Iberian platform reflects the onset of bryozoan–pelmatozoan meadows and mud-mound complexes throughout an intra-shelf ramp, whereas carbonate nucleation of prominent carbonate factories took place on the top of isolated palaeo-highs in the Hesperian platform. In both cases, the end of carbonate productivity is associated with glacioeustatic regression, subaerial exposure and karstification, pre‐dating widespread precipitation of iron ore deposits in the vicinity of palaeo‐highs. The Hirnantian glacioeustatic transgression is represented lithostratigraphically by the Orea Formation. In the Iberian platform, the formation consists of two distinct depositional sequences bounded by the progradation of conglomeratic channels, and is dominated by the record of massive and crudely stratified diamictites, with tabular geometries and deposited subaqueously as ‘rain-out’ facies. In contrast, the Hesperian platform is rich in disrupted diamictites, which form strongly deformed units interpreted as submarine slumps associated with active synsedimentary faults. In both cases, the anomalous occurrence of massive diamictites, rich in boulder- to sand-sized carbonate dropstones, and displaying rapid variations in density and size, suggests that distinct iceberg ‘drift lanes’ existed, indicating current activity in the open sea.
Encoding information flow in AURA
Authors: Jia Limin , Zdancewic Steve 
Published: December 2009

Two of the main ways to protect security-sensitive resources in computer systems are to enforce access-control policies and information-flow policies. In this paper, we show how to enforce information-flow policies in AURA, which is a programming language for access control. When augmented with this mechanism for enforcing information-flow polices, AURA can further improve the security of reference monitors that implement access control.
We show how to encode security types and lattices of security labels using AURA's existing constructs for authorization logic. We prove a noninterference theorem for this encoding. We also investigate how to use expressive access control specified in authorization logic as the policies for information declassification.
Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors
Authors: Gramza Ann W. , Corless Christopher L. , Heinrich Michael C. 
Published: December 2009

Abstract
Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. These concepts are directly relevant to the development of targeted molecular therapy for other solid tumors. (Clin Cancer Res 2009;15(24):7510–8)
Resistance to Trastuzumab in Breast Cancer
Authors: Pohlmann Paula R. , Mayer Ingrid A. , Mernaugh Ray 
Published: December 2009

AbstractHER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20 to 25% of invasive breast cancers. It can be therapeutically targeted by trastuzumab, a humanized IgG1 kappa light chain monoclonal antibody. Although trastuzumab is currently considered one of the most effective treatments in oncology, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. Understanding the mechanisms of action and resistance to trastuzumab is therefore crucial for the development of new therapeutic strategies. This review discusses proposed trastuzumab mode of action as well as proposed mechanisms for resistance. Mechanisms for resistance are grouped into four main categories: (1) obstacles preventing trastuzumab binding to HER2; (2) upregulation of HER2 downstream signaling pathways; (3) signaling through alternate pathways; and (4) failure to trigger an immune-mediated mechanism to destroy tumor cells. These potential mechanisms through which trastuzumab resistance may arise have been used as a guide to develop drugs, presently in clinical trials, to overcome resistance. The mechanisms conferring trastuzumab resistance, when completely understood, will provide insight on how best to treat HER2-overexpressing breast cancer. The understanding of each mechanism of resistance is therefore critical for the educated development of strategies to overcome it, as well as for the development of tools that would allow definitive and efficient patient selection for each therapy. (Clin Cancer Res 2009;15(24):7479–91)
Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity
Authors: Puig Teresa , Turrado Carlos , Benhamú Bellinda , Aguilar Helena , Relat Joana , Ortega-Gutiérrez Silvia , Casals Gemma , Marrero Pedro F. , Urruticoechea Ander , Haro Diego , López-Rodríguez María Luz , Colomer Ramon 
Published: December 2009

Abstract
Purpose: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma. The natural polyphenol (−)-epigallocatechin-3-gallate blocks in vitro FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and in vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models.
Experimental Design: We evaluated the in vitro effects of the compounds on breast cancer cell growth (SK-Br3, MCF-7, and MDA-MB-231), apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase], cell signaling (HER2, ERK1/2, and AKT), and fatty acid metabolism enzymes (FASN and CPT-1). In vivo, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells.
Results: Two compounds potently inhibited FASN activity and showed high cytotoxicity. Moreover, the compounds induced apoptosis and caused a marked decrease in the active forms of HER2, AKT, and ERK1/2 proteins. Interestingly, the compounds did not stimulate CPT-1 activity in vitro. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss in vivo.
Conclusions: The synthesized polyphenolic compounds represent a novel class of FASN inhibitors, with in vitro and in vivo anticancer activity, that do not exhibit cross-activation of β-oxidation and do not induce weight loss in animals. One of the compounds blocked the growth of breast cancer xenografts. These FASN inhibitors may represent new agents for breast cancer treatment. (Clin Cancer Res 2009;15(24):7608–15)
Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia
Authors: Milojkovic Dragana , Apperley Jane 
Published: December 2009

Abstract
Targeted therapy in the form of selective tyrosine kinase inhibitors (TKI) has transformed the approach to management of chronic myeloid leukemia (CML) and dramatically improved patient outcome to the extent that imatinib is currently accepted as the first-line agent for nearly all patients presenting with CML, regardless of the phase of the disease. Impressive clinical responses are obtained in the majority of patients in chronic phase; however, not all patients experience an optimal response to imatinib, and furthermore, the clinical response in a number of patients will not be sustained. The process by which the leukemic cells prove resistant to TKIs and the restoration of BCR-ABL1 signal transduction from previous inhibition has initiated the pursuit for the causal mechanisms of resistance and strategies by which to surmount resistance to therapeutic intervention. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance, however, it is increasingly evident that the presence of mutations does not explain all cases of resistance and does not account for the failure of TKIs to eliminate minimal residual disease in patients who respond optimally. The focus of exploring TKI resistance has expanded to include the mechanism by which the drug is delivered to its target and the impact of drug influx and efflux proteins on TKI bioavailability. The limitations of imatinib have inspired the development of second generation TKIs in order to overcome the effect of resistance to this primary therapy. (Clin Cancer Res 2009;15(24):7519–27)
Resistance to Targeted Therapies: Refining Anticancer Therapy in the Era of Molecular Oncology
Authors: Ellis Lee M. , Hicklin Daniel J. 
Published: December 2009

Abstract
The advent of targeted therapy for treatment of human cancers has added significantly to our armamentarium as we strive to prolong patient survival while minimizing toxicity. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy. The articles in this CCR Focus provide insights into molecular mechanisms of resistance to targeted therapy. Recent discoveries of the molecular pathways that mediate intrinsic resistance to targeted therapy have led to the identification of predictive biomarkers that allow for better patient selection for front line treatment. Equally important, the identification of mechanisms of acquired resistance following front line therapy has led to the discovery of novel agents that overcome these resistance mechanisms. Improving the efficacy of targeted therapies in the future will require expanding our understanding of resistance mechanisms, the development of new generations of rationally designed targeted agents, and translating this information to the clinic to select patients for appropriate therapy. (Clin Cancer Res 2009;15(24):7471–8)
Validation and Intercomparison of Satellite Rainfall Estimates over Colombia
Authors: Dinku Tufa , Ruiz Franklyn , Connor Stephen J. , Ceccato Pietro 
Published: December 2009

Abstract
Seven different satellite rainfall estimates are evaluated at daily and 10-daily time scales and a spatial resolution of 0.25° latitude/longitude. The reference data come from a relatively dense station network of about 600 rain gauges over Colombia. This region of South America has a very complex terrain with mountain ranges that form the northern tip of the Andes Mountains, valleys between the mountain ranges, and a vast plain that is part of the Amazon. The climate is very diverse with an extremely wet Pacific coast, a dry region in the north, and different rainfall regimes between the two extremes. The evaluated satellite rainfall products are the Tropical Rainfall Measuring Mission 3B42 and 3B42RT products, the NOAA/Climate Prediction Center morphing technique (CMORPH), Precipitation Estimation from Remotely Sensed Information using Artificial Neural Network (PERSIANN), the Naval Research Laboratory’s blended product (NRLB), and two versions of the Global Satellite Mapping of Precipitation moving vector with Kalman filter (GSMaP_MVK and GSMaP_MVK+). The validation and intercomparison of these products is done for the whole as well as different parts of the country. Validation results are reasonably good for daily rainfall over such complex terrain. The best results were obtained for the eastern plain, and the performance of the products was relatively poor over the Pacific coast. In comparing the different satellite products, it was seen that PERSIANN and GSMaP-MVK exhibited poor performance, with significant overestimation by PERSSIAN and serious underestimation by GSMaP-MVK. CMORPH and GSMaP-MVK+ exhibited the best performance among the products evaluated here.
A New Look at Snowpack Trends in the Cascade Mountains
Authors: Stoelinga Mark T. , Albright Mark D. , Mass Clifford F. 
Published: December 2009

Abstract
This study examines the changes in Cascade Mountain spring snowpack since 1930. Three new time series facilitate this analysis: a water-balance estimate of Cascade snowpack from 1930 to 2007 that extends the observational record 20 years earlier than standard snowpack measurements; a radiosonde-based time series of lower-tropospheric temperature during onshore flow, to which Cascade snowpack is well correlated; and a new index of the North Pacific sea level pressure pattern that encapsulates modes of variability to which Cascade spring snowpack is particularly sensitive.
Cascade spring snowpack declined 23% during 1930–2007. This loss is nearly statistically significant at the 5% level. The snowpack increased 19% during the recent period of most rapid global warming (1976–2007), though this change is not statistically significant because of large annual variability. From 1950 to 1997, a large and statistically significant decline of 48% occurred. However, 80% of this decline is connected to changes in the circulation patterns over the North Pacific Ocean that vary naturally on annual to interdecadal time scales. The residual time series of Cascade snowpack after Pacific variability is removed displays a relatively steady loss rate of 2.0% decade−1, yielding a loss of 16% from 1930 to 2007. This loss is very nearly statistically significant and includes the possible impacts of anthropogenic global warming.
The dates of maximum snowpack and 90% melt out have shifted 5 days earlier since 1930. Both shifts are statistically insignificant. A new estimate of the sensitivity of Cascade spring snowpack to temperature of −11% per °C, when combined with climate model projections of 850-hPa temperatures offshore of the Pacific Northwest, yields a projected 9% loss of Cascade spring snowpack due to anthropogenic global warming between 1985 and 2025.
Malignant transformation of Slp65-deficient pre-B cells involves disruption of the Arf-Mdm2-p53 tumor suppressor pathway
Authors: Ta Van B. T. , de Bruijn Marjolein J. W. , ter Brugge Petra J. , van Hamburg Jan Piet , Diepstraten Hans J. A. , van Loo Pieter Fokko , Kersseboom Rogier , Hendriks Rudi W. 
Published: December 2009

AbstractThe adapter protein Slp65 is a key component of the precursor-B (pre-B) cell receptor. Slp65-deficient mice spontaneously develop pre-B cell leukemia, but the mechanism by which Slp65−/− pre-B cells become malignant is unknown. Loss of Btk, a Tec-family kinase that cooperates with Slp65 as a tumor suppressor, synergizes with deregulation of the c-Myc oncogene during lymphoma formation. Here, we report that the presence of the immunoglobulin heavy chain transgene VH81X prevented tumor development in Btk−/−Slp65−/− mice. This finding paralleled the reported effect of a human immunoglobulin heavy chain transgene on lymphoma development in Eμ-myc mice, expressing transgenic c-Myc. Because activation of c-Myc strongly selects for spontaneous inactivation of the p19Arf-Mdm2-p53 tumor suppressor pathway, we investigated whether disruption of this pathway is a common alteration in Slp65−/− pre-B cell tumors. We found that combined loss of Slp65 and p53 in mice transformed pre-B cells very efficiently. Aberrations in p19Arf, Mdm2, or p53 expression were found in all Slp65−/− (n = 17) and Btk−/−Slp65−/− (n = 32) pre-B cell leukemias analyzed. In addition, 9 of 10 p53−/−Slp65−/− pre-B cell leukemias manifested significant Mdm2 protein expression. These data indicate that malignant transformation of Slp65−/− pre-B cells involves disruption of the p19Arf-Mdm2-p53 tumor suppressor pathway.
STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease
Authors: Li Geqiang , Miskimen Kristy L. , Wang Zhengqi , Xie Xiu Yan , Brenzovich Jennifer , Ryan John J. , Tse William , Moriggl Richard , Bunting Kevin D. 
Published: December 2009

Abstract
Phosphorylated signal transducer and activator of transcription 5 (STAT5) is a biomarker and potential molecular target for hematologic malignancies. We have shown previously that lethal myeloproliferative disease (MPD) in mice mediated by persistently activated STAT5 (STAT5aS711F) requires the N-domain, but the mechanism was not defined. We now demonstrate by retrovirally complementing STAT5abnull/null primary mast cells that relative to wild-type STAT5a, STAT5a lacking the N-domain (STAT5aΔN) ineffectively protected against cytokine withdrawal-induced cell death. Both STAT5a and STAT5aΔN bound to a site in the bcl-2 gene and both bound near the microRNA 15b/16 cluster. However, only STAT5a could effectively induce bcl-2 mRNA and reciprocally suppress miR15b/16 leading to maintained bcl-2 protein levels. After retroviral complementation of STAT5abnull/null fetal liver cells and transplantation, persistently active STAT5aS711F lacking the N-domain (STAT5aΔNS711F) was insufficient to protect c-Kit+Lin−Sca-1+ (KLS) cells from apoptosis and unable to induce bcl-2 expression, whereas STAT5aS711F caused robust KLS cell expansion, induction of bcl-2, and lethal MPD. Severe attenuation of MPD by STAT5aΔNS711F was reversed by H2k/bcl-2 transgenic expression. Overall, these studies define N-domain–dependent survival signaling as an Achilles heel of persistent STAT5 activation and highlight the potential therapeutic importance of targeting STAT5 N-domain–mediated regulation of bcl-2 family members.
DescFold: A web server for protein fold recognition
Authors: Yan Ren-Xiang , Si Jing-Na , Wang Chuan , Zhang Ziding 
Published: December 2009

Abstract

Background
Machine learning-based methods have been proven to be powerful in developing new fold recognition tools. In our previous work [Zhang, Kochhar and Grigorov (2005) Protein Science, 14: 431-444], a machine learning-based method called DescFold was established by using Support Vector Machines (SVMs) to combine the following four descriptors: a profile-sequence-alignment-based descriptor using Psi-blast e-values and bit scores, a sequence-profile-alignment-based descriptor using Rps-blast e-values and bit scores, a descriptor based on secondary structure element alignment (SSEA), and a descriptor based on the occurrence of PROSITE functional motifs. In this work, we focus on the improvement of DescFold by incorporating more powerful descriptors and setting up a user-friendly web server.

Results
In seeking more powerful descriptors, the profile-profile alignment score generated from the COMPASS algorithm was first considered as a new descriptor (i.e., PPA). When considering a profile-profile alignment between two proteins in the context of fold recognition, one protein is regarded as a template (i.e., its 3D structure is known). Instead of a sequence profile derived from a Psi-blast search, a structure-seeded profile for the template protein was generated by searching its structural neighbors with the assistance of the TM-align structural alignment algorithm. Moreover, the COMPASS algorithm was used again to derive a profile-structural-profile-alignment-based descriptor (i.e., PSPA). We trained and tested the new DescFold in a total of 1,835 highly diverse proteins extracted from the SCOP 1.73 version. When the PPA and PSPA descriptors were introduced, the new DescFold boosts the performance of fold recognition substantially. Using the SCOP_1.73_40% dataset as the fold library, the DescFold web server based on the trained SVM models was further constructed. To provide a large-scale test for the new DescFold, a stringent test set of 1,866 proteins were selected from the SCOP 1.75 version. At a less than 5% false positive rate control, the new DescFold is able to correctly recognize structural homologs at the fold level for nearly 46% test proteins. Additionally, we also benchmarked the DescFold method against several well-established fold recognition algorithms through the LiveBench targets and Lindahl dataset.

Conclusions
The new DescFold method was intensively benchmarked to have very competitive performance compared with some well-established fold recognition methods, suggesting that it can serve as a useful tool to assist in template-based protein structure prediction. The DescFold server is freely accessible at http://202.112.170.199/DescFold/index.html.