bluuebunny/crossref_metadata_2025_split huggingface dataset:
Src Stimulates Fibroblast Growth Factor Receptor-2 Shedding by an ADAM15 Splice Variant Linked to Breast Cancer
Authors: Maretzky Thorsten , Le Gall Sylvain M. , Worpenberg-Pietruk Susanne , Eder Jörg , Overall Christopher M. , Huang Xin-Yun , Poghosyan Zaruhi , Edwards Dylan R. , Blobel Carl P. 
Published: June 2009

Abstract
ADAMs (a disintegrin and metalloproteinase) have important roles in development and diseases such as cancer. Previously, an ADAM15 splice variant (ADAM15B), which contains an inserted cytoplasmic Src-binding site, was linked to clinical aggressiveness in breast cancer, yet little was known about how this splice variant affects the function of ADAM15. Here, we show that ADAM15B has enhanced catalytic activity in cell-based assays compared with ADAM15A, which lacks a Src-binding site, using shedding of fibroblast growth factor receptor 2iiib variant as an assay for catalytic activity. Moreover, the enhanced activity of ADAM15B compared with ADAM15A depends on Src because it is abolished by Src-kinase inhibitors and in Src−/− cells, but not in Src−/− cells rescued with Src. These findings provide insights into the mechanism of how a splice variant linked to clinical agressiveness in breast cancer causes increased activity of ADAM15B, and suggest that inhibitors of the ADAM15 protease activity or of the interaction of ADAM15B with Src could be useful to treat breast cancer in patients with dysregulated ADAM15B. [Cancer Res 2009;69(11):4573–6]
Targeting LMO2 with a Peptide Aptamer Establishes a Necessary Function in Overt T-Cell Neoplasia
Authors: Appert Alex , Nam Chang-Hoon , Lobato Natividad , Priego Eva , Miguel Ricardo Nunez , Blundell Tom , Drynan Lesley , Sewell Helen , Tanaka Tomoyuki , Rabbitts Terence 
Published: June 2009

Abstract
LMO2 is a transcription regulator involved in human T-cell leukemia, including some occurring in X-SCID gene therapy trials, and in B-cell lymphomas and prostate cancer. LMO2 functions in transcription complexes via protein-protein interactions involving two LIM domains and causes a preleukemic T-cell development blockade followed by clonal tumors. Therefore, LMO2 is necessary but not sufficient for overt neoplasias, which must undergo additional mutations before frank malignancy. An open question is the importance of LMO2 in tumor development as opposed to sustaining cancer. We have addressed this using a peptide aptamer that binds to the second LIM domain of the LMO2 protein and disrupts its function. This specificity is mediated by a conserved Cys-Cys motif, which is similar to the zinc-binding LIM domains. The peptide inhibits Lmo2 function in a mouse T-cell tumor transplantation assay by preventing Lmo2-dependent T-cell neoplasia. Lmo2 is, therefore, required for sustained T-cell tumor growth, in addition to its preleukemic effect. Interference with LMO2 complexes is a strategy for controlling LMO2-mediated cancers, and the finger structure of LMO2 is an explicit focus for drug development. [Cancer Res 2009;69(11):4784–90]
ERG Is a Megakaryocytic Oncogene
Authors: Salek-Ardakani Samira , Smooha Gil , de Boer Jasper , Sebire Neil J. , Morrow Michelle , Rainis Liat , Lee Sandy , Williams Owen , Izraeli Shai , Brady Hugh J.M. 
Published: June 2009

Abstract
Ets-related gene (ERG) is a member of the ETS transcription factor gene family located on Hsa21. ERG is known to have a crucial role in establishing definitive hematopoiesis and is required for normal megakaryopoiesis. Truncated forms of ERG are associated with multiple cancers such as Ewing's sarcoma, prostate cancer, and leukemia as part of oncogenic fusion translocations. Increased expression of ERG is highly indicative of poor prognosis in acute myeloid leukemia and ERG is expressed in acute megakaryoblastic leukemia (AMKL); however, it is unclear if expression of ERG per se has a leukemogenic activity. We show that ectopic expression of ERG in fetal hematopoietic progenitors promotes megakaryopoiesis and that ERG alone acts as a potent oncogene in vivo leading to rapid onset of leukemia in mice. We observe that the endogenous ERG is required for the proliferation and maintenance of AMKL cell lines. ERG also strongly cooperates with the GATA1s mutated protein, found in Down syndrome AMKL, to immortalize megakaryocyte progenitors, suggesting that the additional copy of ERG in trisomy 21 may have a role in Down syndrome AMKL. These data suggest that ERG is a hematopoietic oncogene that may play a direct role in myeloid leukemia pathogenesis. [Cancer Res 2009;69(11):4665–73]
Up-regulation of C-Terminal Tensin-like Molecule Promotes the Tumorigenicity of Colon Cancer through β-Catenin
Authors: Liao Yi-Chun , Chen Nien-Tsu , Shih Yi-Ping , Dong Ying , Lo Su Hao 
Published: June 2009

Abstract
C-terminal tensin-like (cten) is a focal adhesion molecule belonging to the tensin family. Previous studies have suggested that cten may function as a prostate-specific tumor suppressor. Here, we show that although cten is expressed at a very low level in normal colon, its expression is significantly up-regulated in colon cancer. Furthermore, a high population of cten is found in the nucleus, where it interacts with β-catenin, a critical player in the canonical Wnt pathway. This interaction may contribute to the role of cten in enhancing the colony formation, anchorage-independent growth, and invasiveness of colon cancer cells. Our studies have identified cten as a novel nuclear partner of β-catenin, showed an oncogenic activity of cten in colon cancers, and revealed cten as a potential biomarker and target for colon cancers. [Cancer Res 2009;69(11):4563–6]
Aurora-A and hBora Join the Game of Polo
Authors: Macurek Libor , Lindqvist Arne , Medema René H. 
Published: June 2009

Abstract
Overactivation of both Polo-like kinase-1 (Plk1) and Aurora-A is linked to cancer development, and small-molecule inhibitors that target these kinases are currently tested as anticancer drugs. Here, we discuss recent advances in the understanding of the functional crosstalk between Plk1 and Aurora-A before and during mitosis. Several recent findings have led to a better appreciation of how the activities of these distinct mitotic kinases are intertwined. Such insight is important for the expected utility of small-molecule inhibitors targeting Plk1 or Aurora-A, and it might help us to improve their application. [Cancer Res 2009;69(11):4555–8]
Multipotent CD15+ Cancer Stem Cells in Patched-1–Deficient Mouse Medulloblastoma
Authors: Ward Ryan J. , Lee Lilian , Graham Kevin , Satkunendran Thevagi , Yoshikawa Koichi , Ling Erick , Harper Lauren , Austin Ryan , Nieuwenhuis Erica , Clarke Ian D. , Hui Chi-chung , Dirks Peter B. 
Published: June 2009

Abstract
Subpopulations of tumorigenic cells have been identified in many human tumors, although these cells may not be very rare in some types of cancer. Here, we report that medulloblastomas arising from Patched-1–deficient mice contain a subpopulation of cells that show a neural precursor phenotype, clonogenic and multilineage differentiation capacity, activated Hedgehog signaling, wild-type Patched-1 expression, and the ability to initiate tumors following allogeneic orthotopic transplantation. The normal neural stem cell surface antigen CD15 enriches for the in vitro proliferative and in vivo tumorigenic potential from uncultured medulloblastomas, supporting the existence of a cancer stem cell hierarchy in this clinically relevant mouse model of cancer. [Cancer Res 2009;69(11):4682–90]
The Role of HuR in Gemcitabine Efficacy in Pancreatic Cancer: HuR Up-regulates the Expression of the Gemcitabine Metabolizing Enzyme Deoxycytidine Kinase
Authors: Costantino Christina L. , Witkiewicz Agnieszka K. , Kuwano Yuki , Cozzitorto Joseph A. , Kennedy Eugene P. , Dasgupta Abhijit , Keen Judith C. , Yeo Charles J. , Gorospe Myriam , Brody Jonathan R. 
Published: June 2009

AbstractRNA-binding protein HuR binds U- or AU-rich sequences in the 3′-untranslated regions of target mRNAs, stabilizing them and/or modulating their translation. Given the links of HuR with cancer, we studied the consequences of modulating HuR levels in pancreatic cancer cells. HuR-overexpressing cancer cells, in some instances, are roughly up to 30-fold more sensitive to treatment with gemcitabine, the main chemotherapeutic component of treatment regimens for pancreatic ductal adenocarcinoma (PDA), compared with control cells. In pancreatic cancer cells, HuR associates with deoxycytidine kinase (dCK) mRNA, which encodes the enzyme that metabolizes and thereby activates gemcitabine. Gemcitabine exposure to pancreatic cancer cells enriches the association between HuR and dCK mRNA and increases cytoplasmic HuR levels. Accordingly, HuR overexpression elevates, whereas HuR silencing reduces, dCK protein expression in pancreatic cancer cells. In a clinical correlate study of gemcitabine treatment, we found a 7-fold increase in risk of mortality in PDA patients with low cytoplasmic HuR levels compared with patients with high HuR levels, after adjusting for other treatments and demographic variables. These data support the notion that HuR is a key mediator of gemcitabine efficacy in cancer cells, at least in part through its ability to regulate dCK levels posttranscriptionally. We propose that HuR levels in PDA modulate the therapeutic efficacy of gemcitabine, thus serving as a marker of the clinical utility of this common chemotherapeutic agent and a potential target for intervention in pancreatic cancer. [Cancer Res 2009;69(11):4567–72]
CAR Mechanics: Driving T Cells into the MUC of Cancer
Authors: Maher John , Wilkie Scott 
Published: June 2009

AbstractSeveral monoclonal antibodies bind in a highly selective manner to tumor-associated glycoforms of MUC1. We set out to exploit this by developing a MUC1-specific chimeric antigen receptor. Difficulties were encountered in this endeavor, owing to MUC1-imposed steric hindrance and antigenic heterogeneity. These issues were addressed by the iterative engineering of all components of the fusion receptor. Our experience underlines the need for careful individual optimization of immunotherapeutic reagents as dictated by the molecular vagaries of the target under study. [Cancer Res 2009;69(11):4559–62]
Bacterial Cytosine Deaminase Mutants Created by Molecular Engineering Show Improved 5-Fluorocytosine–Mediated Cell KillingIn vitroandIn vivo
Authors: Fuchita Michi , Ardiani Andressa , Zhao Lei , Serve Kinta , Stoddard Barry L. , Black Margaret E. 
Published: June 2009

AbstractCytosine deaminase is used in combination with 5-fluorocytosine as an enzyme-prodrug combination for targeted genetic cancer treatment. This approach is limited by inefficient gene delivery and poor prodrug conversion activities. Previously, we reported individual point mutations within the substrate binding pocket of bacterial cytosine deaminase (bCD) that result in marginal improvements in the ability to sensitize cells to 5-fluorocytosine (5FC). Here, we describe an expanded random mutagenesis and selection experiment that yielded enzyme variants, which provide significant improvement in prodrug sensitization. Three of these mutants were evaluated using enzyme kinetic analyses and then assayed in three cancer cell lines for 5FC sensitization, bystander effects, and formation of 5-fluorouracil metabolites. All variants displayed 18- to 19-fold shifts in substrate preference toward 5FC, a significant reduction in IC50 values and improved bystander effect compared with wild-type bCD. In a xenograft tumor model, the best enzyme mutant was shown to prevent tumor growth at much lower doses of 5FC than is observed when tumor cells express wild-type bCD. Crystallographic analyses of this construct show the basis for improved activity toward 5FC, and also how two different mutagenesis strategies yield closely related but mutually exclusive mutations that each result in a significant alteration of enzyme specificity. [Cancer Res 2009;69(11):4791–9]
Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles forBRAF, PIK3CA, andAKT1
Authors: Ricarte-Filho Julio C. , Ryder Mabel , Chitale Dhananjay A. , Rivera Michael , Heguy Adriana , Ladanyi Marc , Janakiraman Manickam , Solit David , Knauf Jeffrey A. , Tuttle R. Michael , Ghossein Ronald A. , Fagin James A. 
Published: June 2009

AbstractPatients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [18F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET–positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors. [Cancer Res 2009;69(11):4885–93]
Cortex and Memory: Emergence of a New Paradigm
Authors: Fuster Joaquín M. 
Published: June 2009

Abstract
Converging evidence from humans and nonhuman primates is obliging us to abandon conventional models in favor of a radically different, distributed-network paradigm of cortical memory. Central to the new paradigm is the concept of memory network or cognit—that is, a memory or an item of knowledge defined by a pattern of connections between neuron populations associated by experience. Cognits are hierarchically organized in terms of semantic abstraction and complexity. Complex cognits link neurons in noncontiguous cortical areas of prefrontal and posterior association cortex. Cognits overlap and interconnect profusely, even across hierarchical levels (heterarchically), whereby a neuron can be part of many memory networks and thus many memories or items of knowledge.
Impact of Airborne Doppler Radar Data Assimilation on the Numerical Simulation of Intensity Changes of Hurricane Dennis near a Landfall
Authors: Pu Zhaoxia , Li Xuanli , Sun Juanzhen 
Published: June 2009

Abstract
Accurate forecasting of a hurricane’s intensity changes near its landfall is of great importance in making an effective hurricane warning. This study uses airborne Doppler radar data collected during the NASA Tropical Cloud Systems and Processes (TCSP) field experiment in July 2005 to examine the impact of airborne radar observations on the short-range numerical simulation of hurricane track and intensity changes. A series of numerical experiments is conducted for Hurricane Dennis (2005) to study its intensity changes near a landfall. Both radar reflectivity and radial velocity–derived wind fields are assimilated into the Weather Research and Forecasting (WRF) model with its three-dimensional variational data assimilation (3DVAR) system. Numerical results indicate that the radar data assimilation has greatly improved the simulated structure and intensity changes of Hurricane Dennis. Specifically, the assimilation of radar reflectivity data shows a notable influence on the thermal and hydrometeor structures of the initial vortex and the precipitation structure in the subsequent forecasts, although its impact on the intensity and track forecasts is relatively small. In contrast, assimilation of radar wind data results in moderate improvement in the storm-track forecast and significant improvement in the intensity and precipitation forecasts of Hurricane Dennis. The hurricane landfall, intensification, and weakening during the simulation period are well captured by assimilating both radar reflectivity and wind data.
The Global Hydrological Cycle and Atmospheric Shortwave Absorption in Climate Models under CO2 Forcing
Authors: Takahashi Ken 
Published: June 2009

Abstract
The spread among the predictions by climate models for the strengthening of the global hydrological cycle [i.e., the global mean surface latent heat flux (LH), or, equivalently, precipitation] at a given level of CO2-induced global warming is of the same magnitude as the intermodel mean. By comparing several climate models from the World Climate Research Programme (WCRP) Coupled Model Intercomparison Project phase 3 (CMIP3) database under idealized CO2 forcings, it is shown that differences in the increase in global atmospheric shortwave heating (SWabs) induced by clear-sky absorption, presumably by water vapor, partly explains this spread. The increases in SWabs and LH present similar spreads across models but are anticorrelated, so the sum SWabs + LH increases more robustly than either alone. This is consistent with a recently proposed theory (Takahashi) that predicts that this sum (or, equivalently, the net longwave divergence minus the surface sensible heat flux) is constrained by energy conservation and robust longwave physics.
The intermodel scatter in SWabs changes is explained neither by differences in the radiative transfer models nor in intermodel differences in global water vapor content change, but perhaps by more subtle aspects of the changes in the water vapor distribution. Nevertheless, the fact that the radiative transfer models generally underestimate the increase in SWabs relative to the corresponding line-by-line calculation for a given change in water vapor content suggests that the climate models might be overestimating the rate of increase in the global hydrological cycle with global warming.
Drought in the Southeastern United States: Causes, Variability over the Last Millennium, and the Potential for Future Hydroclimate Change*
Authors: Seager Richard , Tzanova Alexandrina , Nakamura Jennifer 
Published: June 2009

Abstract
An assessment of the nature and causes of drought in the southeastern United States is conducted as well as an assessment of model projections of anthropogenically forced hydroclimate change in this region. The study uses observations of precipitation, model simulations forced by historical SSTs from 1856 to 2007, tree-ring records of moisture availability over the last millennium, and climate change projections conducted for the Fourth Assessment Report of the Intergovernmental Panel on Climate Change. From the perspective of the historical record, the recent drought that began in winter 2005/06 was a typical event in terms of amplitude and duration. Observations and model simulations are used to show that dry winter half-years in the Southeast are weakly associated with La Niñas in the tropical Pacific but that this link varies over time and was possibly of opposite sign from about 1922 to 1950. Summer-season precipitation variability in the Southeast appears governed by purely internal atmospheric variability. As such, model simulations forced by historical SSTs have very limited skill in reproducing the instrumental record of Southeast precipitation variability and actual predictive skill is also presumably low. Tree-ring records show that the twentieth century has been moist from the perspective of the last millennium and free of long and severe droughts that were abundant in previous centuries. The tree-ring records show a 21-yr-long uninterrupted drought in the mid-sixteenth century, a long period of dry conditions in the early to mid-nineteenth century, and that the Southeast was also affected by some of the medieval megadroughts centered in western North America. Climate model projections predict that in the near term, future precipitation in the Southeast will increase but that evaporation will also increase. The median of the projections predicts a modest reduction in the atmospheric supply of water vapor to the region; however, the multimodel ensemble exhibits considerable variation, with a quarter to a third of the models projecting an increase in precipitation minus evaporation. The recent drought, forced by reduced precipitation and with reduced evaporation, has no signature of model-projected anthropogenic climate change.
Pentad Evolution of the 1988 Drought and 1993 Flood over the Great Plains: An NARR Perspective on the Atmospheric and Terrestrial Water Balance
Authors: Weaver Scott J. , Ruiz-Barradas Alfredo , Nigam Sumant 
Published: June 2009

Abstract
The evolution of the atmospheric and land surface states during extreme hydroclimate episodes over North America is investigated using the North American Regional Reanalysis (NARR), which additionally, and successfully, assimilates precipitation. The pentad-resolution portrayals of the atmospheric and terrestrial water balance over the U.S. Great Plains during the 1988 summer drought and the July 1993 floods are analyzed to provide insight into the operative mechanisms including regional circulation (e.g., the Great Plains low-level jet, or GPLLJ) and hydroclimate (e.g., precipitation, evaporation, soil moisture recharge, runoff).
The submonthly (but supersynoptic time scale) fluctuations of the GPLLJ are found to be very influential, through related moisture transport and kinematic convergence (e.g., ∂υ/∂y), with the jet anomalies in the southern plains leading the northern precipitation and related moisture flux convergence, accounting for two-thirds of the dry and wet episode precipitation amplitude. The soil moisture influence on hydroclimate evolution is assessed to be marginal as evaporation anomalies are found to lag precipitation ones, a lead–lag not discernible at monthly resolution. The pentad analysis thus corroborates the authors’ earlier findings on the importance of transported moisture over local evaporation in Great Plains’ summer hydroclimate variability.
The regional water budgets—atmospheric and terrestrial—are found to be substantially unbalanced, with the terrestrial imbalance being unacceptably large. Pentad analysis shows the atmospheric imbalance to arise from the sluggishness of the NARR evaporation, including its overestimation in wet periods. The larger terrestrial imbalance, on the other hand, has its origins in the striking unresponsiveness of the NARR’s runoff, which is underestimated in wet episodes.
Finally, the influence of ENSO and North Atlantic Oscillation (NAO) variability on the GPLLJ is quantified during the wet episode, in view of the importance of moisture transports. It is shown that a significant portion (∼25%) of the GPLLJ anomaly (and downstream precipitation) is attributable to NAO and ENSO’s influence, and that this combined influence prolongs the wet episode beyond the period of the instigating GPLLJ.