bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA Biogenesis Is Required for Myc-Induced B-Cell Lymphoma Development and Survival
Authors: Arrate Maria Pia , Vincent Tiffaney , Odvody Jessica , Kar Rekha , Jones Stephen N. , Eischen Christine M. 
Published: June 2010

Abstract
Many tumor cells express globally reduced levels of microRNAs (miRNA), suggesting that decreased miRNA expression in premalignant cells contributes to their tumorigenic phenotype. In support of this, Dicer, an RNase III–like enzyme that controls the maturation of miRNA, was recently shown to function as a haploinsufficient tumor suppressor in nonhematopoietic cells. Because the Myc oncoprotein, a critical inducer of B-cell lymphomas, was reported to suppress the expression of multiple miRNAs in lymphoma cells, it was presumed that a deficiency of Dicer and subsequent loss of miRNA maturation would accelerate Myc-induced lymphoma development. We report here that, surprisingly, a haploinsufficiency of Dicer in B cells failed to promote B-cell malignancy or accelerate Myc-induced B-cell lymphomagenesis in mice. Moreover, deletion of Dicer in B cells of CD19-cre+/Eμ-myc mice significantly inhibited lymphomagenesis, and all lymphomas that did arise in these mice lacked functional Cre expression and retained at least one functional Dicer allele. Uncharacteristically, the lymphomas that frequently developed in the CD19-cre+/Dicerfl/fl/Eμ-myc mice were of very early precursor B-cell origin, a stage of B-cell development prior to Cre expression. Therefore, loss of Dicer function was not advantageous for lymphomagenesis, but rather, Dicer ablation was strongly selected against during Myc-induced B-cell lymphoma development. Moreover, deletion of Dicer in established B-cell lymphomas resulted in apoptosis, revealing that Dicer is required for B-cell lymphoma survival. Thus, Dicer does not function as a haploinsufficient tumor suppressor in B cells and is required for B-cell lymphoma development and survival. Cancer Res; 70(14); 6083–92. ©2010 AACR.
Membrane Type 1-Matrix Metalloproteinase Cleaves Off the NH2-Terminal Portion of Heparin-Binding Epidermal Growth Factor and Converts It into a Heparin-Independent Growth Factor
Authors: Koshikawa Naohiko , Mizushima Hiroto , Minegishi Tomoko , Iwamoto Ryo , Mekada Eisuke , Seiki Motoharu 
Published: June 2010

Abstract
Epidermal growth factor (EGF) receptors (ErbB) and EGF family members represent promising targets for cancer therapy. Heparin-binding EGF (HB-EGF) is a member of the EGF family and is an important target for therapy in some types of human cancers. Processing of HB-EGF by proprotein convertases, and successively, by ADAM family proteases, generates a soluble growth factor that requires heparin as a cofactor. Although heparin potentiates HB-EGF activity in vitro, it is not clear how the heparin-binding activity of HB-EGF is regulated. Here, we show that membrane type 1-matrix metalloproteinase (MT1-MMP; MMP14), a potent invasion-promoting protease, markedly enhances HB-EGF–dependent tumor formation in mice. MT1-MMP additionally cleaves HB-EGF and removes the NH2-terminal 20 amino acids that are important for binding heparin. Consequently, the processing of HB-EGF by MT1-MMP converts HB-EGF into a heparin-independent growth factor with enhanced mitogenic activity, and thereby, expression of both proteins costimulates tumor cell growth in vitro and in vivo. The ErbB family of receptors expressed in human gastric carcinoma cells play a role in mediating enhanced HB-EGF activity by MT1-MMP during invasive cell growth in collagen. Thus, we shed light on a new mechanism whereby HB-EGF activity is regulated that should be considered when designing HB-EGF–targeted cancer therapy. Cancer Res; 70(14); 6093–103. ©2010 AACR.
Identification of Internalizing Human Single-Chain Antibodies Targeting Brain Tumor Sphere Cells
Authors: Zhu Xiaodong , Bidlingmaier Scott , Hashizume Rintaro , James C. David , Berger Mitchel S. , Liu Bin 
Published: June 2010

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor for which there is no curative treatment to date. Resistance to conventional therapies and tumor recurrence pose major challenges to treatment and management of this disease, and therefore new therapeutic strategies need to be developed. Previous studies by other investigators have shown that a subpopulation of GBM cells can grow as neurosphere-like cells when cultured in restrictive medium and exhibits enhanced tumor-initiating ability and resistance to therapy. We report here the identification of internalizing human single-chain antibodies (scFv) targeting GBM tumor sphere cells. We selected a large naive phage antibody display library on the glycosylation-dependent CD133 epitope–positive subpopulation of GBM cells grown as tumor spheres and identified internalizing scFvs that target tumor sphere cells broadly, as well as scFvs that target the CD133-positive subpopulation. These scFvs were found to be efficiently internalized by GBM tumor sphere cells. One scFv GC4 inhibited self-renewal of GBM tumor sphere cells in vitro. We have further developed a full-length human IgG1 based on this scFv, and found that it potently inhibits proliferation of GBM tumor sphere cells and GBM cells grown in regular nonselective medium. Taken together, these results show that internalizing human scFvs targeting brain tumor sphere cells can be readily identified from a phage antibody display library, which could be useful for further development of novel therapies that target subpopulations of GBM cells to combat recurrence and resistance to treatment. Mol Cancer Ther; 9(7); 2131–41. ©2010 AACR.
p53-Independent Induction of G1 Arrest and p21WAF1/CIP1 Expression by Ascofuranone, an Isoprenoid Antibiotic, through Downregulation of c-Myc
Authors: Jeong Ji-Hak , Kang Shin-Sung , Park Kwan-Kyu , Chang Hyeun-Wook , Magae Junji , Chang Young-Chae 
Published: June 2010

Abstract
Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G1 arrest without cytoxicity with upregulation of p53 and p21WAF1/CIP1 while downregulating c-Myc and G1 cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21WAF1/CIP1 expression and subsequent G1 arrest through the release of p21WAF1/CIP1 promoter from c-Myc–mediated transcriptional repression, independent of p53. Ascofuranone-induced p21WAF1/CIP1 associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21WAF1/CIP1 through p53-independent suppression of c-Myc expression, leading to cytostatic G1 arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53. Mol Cancer Ther; 9(7); 2102–13. ©2010 AACR.
Potent and Selective Inhibition of Polycythemia by the Quinoxaline JAK2 Inhibitor NVP-BSK805
Authors: Baffert Fabienne , Régnier Catherine H. , De Pover Alain , Pissot-Soldermann Carole , Tavares Gisele A. , Blasco Francesca , Brueggen Josef , Chène Patrick , Drueckes Peter , Erdmann Dirk , Furet Pascal , Gerspacher Marc , Lang Marc , Ledieu David , Nolan Lynda , Ruetz Stephan , Trappe Joerg , Vangrevelinghe Eric , Wartmann Markus , Wyder Lorenza , Hofmann Francesco , Radimerski Thomas 
Published: June 2010

Abstract
The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2V617F mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2V617F and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2V617F-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2V617F cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats. Mol Cancer Ther; 9(7); 1945–55. ©2010 AACR.
The Pan-Bcl-2 Inhibitor (−)-Gossypol Triggers Autophagic Cell Death in Malignant Glioma
Authors: Voss Valerie , Senft Christian , Lang Verena , Ronellenfitsch Michael W. , Steinbach Joachim P. , Seifert Volker , Kögel Donat 
Published: June 2010

Abstract
Antiapoptotic Bcl-2 family members suppress both apoptosis and autophagy and are of major importance for therapy resistance of malignant gliomas. To target these molecules, we used BH3 mimetics and analyzed the molecular mechanisms of cell death induced thereby. Glioma cells displayed only limited sensitivity to single-agent treatment with the BH3 mimetics HA14-1, BH3I-2′, and ABT-737, whereas the pan-Bcl-2 inhibitor (−)-gossypol efficiently induced cell death. Furthermore, (−)-gossypol potentiated cell death induced by temozolomide (TMZ) in MGMT (O6-methylguanine-DNA methyltransferase)-negative U343 cells and, to a lesser extent, in MGMT-expressing U87 cells. (−)-Gossypol triggered translocation of light chain 3 to autophagosomes and lysosomes and cytochrome c release, but cell death occurred in the absence of lysosomal damage and effector caspase activation. Lentiviral knockdown of Beclin1 and Atg5 in U87, U343, and MZ-54 cells strongly diminished the extent of cell death induced by (−)-gossypol and combined treatment with TMZ, indicating that autophagy contributed to this type of cell death. In contrast, stable knockdown of the endogenous autophagy inhibitor mammalian target of rapamycin increased autophagic cell death. Our data suggest that pan-Bcl-2 inhibitors are promising drugs that induce caspase-independent, autophagic cell death in apoptosis-resistant malignant glioma cells and augment the action of TMZ. Furthermore, they indicate that efficient killing of glioma cells requires neutralization of Mcl-1. Mol Cancer Res; 8(7); 1002–16. ©2010 AACR.
Serum Cytokine Analysis in a Positive Chemoprevention Trial: Selenium, Interleukin-2, and an Association with Squamous Preneoplastic Disease
Authors: Roth Mark J. , Katki Hormuzd A. , Wei Wen-Qiang , Qiao You-Lin , Bagni Rachel , Wang Guo-Qing , Whitby Denise , Dong Zhi-Wei , Gail Mitchell H. , Limburg Paul J. , Giffen Carol A. , Taylor Philip R. , Dawsey Sanford M. 
Published: June 2010

Abstract
This study represents a multiplex cytokine analysis of serum from a 10-month randomized, controlled trial of 238 subjects that investigated the effects of selenomethionine and/or celecoxib in subjects with mild or moderate esophageal squamous dysplasia. The original chemoprevention study found that, among those with mild dysplasia, selenomethionine treatment favorably altered dysplasia grade. The current analysis found that selenomethionine downregulated interleukin (IL)-2 by 9% (P = 0.04), whereas celecoxib downregulated IL-7 by 11% (P = 0.006) and upregulated IL-13 by 17% (P = 0.008). In addition, an increase in IL-7 tertile from baseline to t10 was significantly associated with an increase in dysplasia grade, both overall [odds ratio (OR), 1.47; P = 0.03] and among those with mild dysplasia at t0 (OR, 2.53; P = 0.001). An increase in IL-2 tertile from baseline to t10 was also nonsignificantly associated with worsening dysplasia for all participants (OR, 1.32; P = 0.098) and significantly associated with worsening dysplasia among those with mild dysplasia at baseline (OR, 2.0; P = 0.01). The association of increased IL-2 with worsening dysplasia remained significant in those on selenomethionine treatment who began the trial with mild dysplasia (OR, 2.52; P = 0.03). The current study shows that selenomethionine supplementation decreased serum IL-2 levels, whereas celecoxib treatment decreased IL-7 levels and increased IL-13 levels during a 10-month randomized chemoprevention trial. An increase in IL-2 or IL-7 was associated with increased severity of dysplasia over the course of the trial, especially in those who began the trial with mild dysplasia. The favorable effect of selenomethionine on esophageal dysplasia in the original trial may have been mediated in part by its effect in reducing the levels of IL-2. Cancer Prev Res; 3(7); 810–7. ©2010 AACR.
A Novel Sulindac Derivative Lacking Cyclooxygenase-Inhibitory Activities Suppresses Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate Model
Authors: Zhang Yong , Zhang Jinhui , Wang Lei , Quealy Emily , Gary Bernard D. , Reynolds Robert C. , Piazza Gary A. , Lü Junxuan 
Published: June 2010

Abstract
Nonsteroidal anti-inflammatory drugs including sulindac are well documented to be highly effective for cancer chemoprevention. However, their cyclooxygenase (COX)-inhibitory activities cause severe gastrointestinal, renal, and cardiovascular toxicities, limiting their chronic use. Recent studies suggest that COX-independent mechanisms may be responsible for the chemopreventive benefits of nonsteroidal anti-inflammatory drugs and support the potential for the development of a novel generation of sulindac derivatives lacking COX inhibition for cancer chemoprevention. A prototypic sulindac derivative with a N,N-dimethylammonium substitution called sulindac sulfide amide (SSA) was recently identified to be devoid of COX-inhibitory activity yet displays much more potent tumor cell growth-inhibitory activity in vitro compared with sulindac sulfide. In this study, we investigated the androgen receptor (AR) signaling pathway as a potential target for its COX-independent antineoplastic mechanism and evaluated its chemopreventive efficacy against prostate carcinogenesis using the transgenic adenocarcinoma of mouse prostate model. The results showed that SSA significantly suppressed the growth of human and mouse prostate cancer cells expressing AR in strong association with G1 arrest, and decreased AR level and AR-dependent transactivation. Dietary SSA consumption dramatically attenuated prostatic growth and suppressed AR-dependent glandular epithelial lesion progression through repressing cell proliferation in the transgenic adenocarcinoma of mouse prostate mice, whereas it did not significantly affect neuroendocrine carcinoma growth. Overall, the results suggest that SSA may be a chemopreventive candidate against prostate glandular epithelial carcinogenesis. Cancer Prev Res; 3(7); 885–95. ©2010 AACR.
Multimodel Estimates of Atmospheric Response to Modes of SST Variability and Implications for Droughts
Authors: Pegion Philip J. , Kumar Arun 
Published: June 2010

Abstract
A set of idealized global model experiments was performed by several modeling centers as part of the Drought Working Group of the U.S. Climate Variability and Predictability component of the World Climate Research Programme (CLIVAR). The purpose of the experiments was to assess the role of the leading modes of sea surface temperature (SST) variability on the climate over the continents, with particular emphasis on the influence of SSTs on surface climate variability and droughts over the United States. An analysis based on several models gives more creditability to the results since it relies on the assessment of impacts that are robust across different models.
Coordinated atmospheric general circulation model (AGCM) simulations forced with three modes of SST variability were analyzed. The results show that the SST-forced precipitation variability over the central United States is dominated by the SST mode with maximum loading in the central Pacific Ocean. The SST mode with loading in the Atlantic Ocean, and a mode that is dominated by trends in SSTs, lead to a smaller response.
Based on the response to the idealized SSTs, the precipitation response for the twentieth century was also reconstructed. A comparison with the Atmospheric Model Intercomparison Project (AMIP) simulations forced with the observed SSTs illustrates that the reconstructed precipitation variability was similar to the one in the AMIP simulations, further supporting the conclusion that the SST modes identified in the present analysis play a dominant role in the precipitation variability over the United States. One notable exception is the Dust Bowl of the 1930s, and further analysis regarding this major climate extreme is discussed.
Climate Sensitivity Distributions Dependence on the Possibility that Models Share Biases
Authors: Lemoine Derek M. 
Published: June 2010

Abstract
Uncertainty about biases common across models and about unknown and unmodeled feedbacks is important for the tails of temperature change distributions and thus for climate risk assessments. This paper develops a hierarchical Bayes framework that explicitly represents these and other sources of uncertainty. It then uses models’ estimates of albedo, carbon cycle, cloud, and water vapor–lapse rate feedbacks to generate posterior probability distributions for feedback strength and equilibrium temperature change. The posterior distributions are especially sensitive to prior beliefs about models’ shared structural biases: nonzero probability of shared bias moves some probability mass toward lower values for climate sensitivity even as it thickens the distribution’s positive tail. Obtaining additional models of these feedbacks would not constrain the posterior distributions as much as narrowing prior beliefs about shared biases or, potentially, obtaining feedback estimates having biases uncorrelated with those impacting climate models. Carbon dioxide concentrations may need to fall below current levels to maintain only a 10% chance of exceeding official 2°C limits on global average temperature change.
The Munich Myocardial Infarction Registry: impact of C-reactive protein and kidney function on hospital mortality in diabetic patients
Authors: Schnell Oliver , Braun Karl Friedrich , Müller Martin , Standl Eberhard , Otter Wolfgang 
Published: June 2010

Introduction: The aim of this study was to analyse hospital mortality with regards to the presence of diabetes, elevation of C-reactive protein (CRP) levels and impaired kidney function (IKF) on admission. Methods: All patients in the Munich Myocardial Infarction Registry (1999—2004, n = 2,015) were assessed. In both the diabetic ( n = 770, 38%) and non-diabetic ( n = 1,245, 61.2%) groups, CRP and kidney function on admission were analysed with regards to hospital outcome. Results: In diabetic patients, both a CRP level >7 mg/L and a glomerular filtration rate (GFR) < 60 ml/min were independent risk factors for mortality (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8—6.9 and OR 4.4, 95% CI 2.4—8.3, respectively). In non-diabetic patients with CRP levels equal or below the median and absence of IKF, hospital mortality was 0.7% whereas the presence of the triad of diabetes, CRP levels above the median and IKF increased hospital mortality to 23.5%. Conclusion: The registry demonstrates that the presence of the triad of diabetes, elevated CRP levels and reduced GFR on admission is associated with an excessive hospital mortality. Optimised early interventions are to be initiated to potentially overcome the unfavourable prognosis.
Interaction prediction and classification of PDZ domains
Authors: Kalyoncu Sibel , Keskin Ozlem , Gursoy Attila 
Published: June 2010

Abstract

Background
PDZ domain is a well-conserved, structural protein domain found in hundreds of signaling proteins that are otherwise unrelated. PDZ domains can bind to the C-terminal peptides of different proteins and act as glue, clustering different protein complexes together, targeting specific proteins and routing these proteins in signaling pathways. These domains are classified into classes I, II and III, depending on their binding partners and the nature of bonds formed. Binding specificities of PDZ domains are very crucial in order to understand the complexity of signaling pathways. It is still an open question how these domains recognize and bind their partners.

Results
The focus of the current study is two folds: 1) predicting to which peptides a PDZ domain will bind and 2) classification of PDZ domains, as Class I, II or I-II, given the primary sequences of the PDZ domains. Trigram and bigram amino acid frequencies are used as features in machine learning methods. Using 85 PDZ domains and 181 peptides, our model reaches high prediction accuracy (91.4%) for binary interaction prediction which outperforms previously investigated similar methods. Also, we can predict classes of PDZ domains with an accuracy of 90.7%. We propose three critical amino acid sequence motifs that could have important roles on specificity pattern of PDZ domains.

Conclusions
Our model on PDZ interaction dataset shows that our approach produces encouraging results. The method can be further used as a virtual screening technique to reduce the search space for putative candidate target proteins and drug-like molecules of PDZ domains.
Transdifferentiation-inducing HCCR-1 oncogene
Authors: Ha Seon-Ah , Kim Hyun K , Yoo JinAh , Kim SangHee , Shin Seung M , Lee Youn S , Hur Soo Y , Kim Yong W , Kim Tae E , Chung Yeun J , Jeun Shin S , Kim Dong W , Park Yong G , Kim Jin , Shin Soon Y , Lee Young H , Kim Jin W 
Published: June 2010

Abstract

Background
Cell transdifferentiation is characterized by loss of some phenotypes along with acquisition of new phenotypes in differentiated cells. The differentiated state of a given cell is not irreversible. It depends on the up- and downregulation exerted by specific molecules.

Results
We report here that HCCR-1, previously shown to play an oncogenic role in human cancers, induces epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) in human and mouse, respectively. The stem cell factor receptor CD117/c-Kit was induced in this transdifferentiated (EMT) sarcoma tissues. This MET occurring in HCCR-1 transfected cells is reminiscent of the transdifferentiation process during nephrogenesis. Indeed, expression of HCCR-1 was observed during the embryonic development of the kidney. This suggests that HCCR-1 might be involved in the transdifferentiation process of cancer stem cell.

Conclusions
Therefore, we propose that HCCR-1 may be a regulatory factor that stimulates morphogenesis of epithelia or mesenchyme during neoplastic transformation.