bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequence Analysis and Characterization of a Transferable Hybrid Plasmid Encoding Multidrug Resistance and Enabling Zoonotic Potential for Extraintestinal
Escherichia coli
Authors: Johnson Timothy J. , Jordan Dianna , Kariyawasam Subhashinie , Stell Adam L. , Bell Nathan P. , Wannemuehler Yvonne M. , Alarcón Claudia Fernández , Li Ganwu , Tivendale Kelly A. , Logue Catherine M. , Nolan Lisa K. 
Published: February 2010

ABSTRACT

ColV plasmids of extraintestinal pathogenic
Escherichia coli
(ExPEC) encode a variety of fitness and virulence factors and have long been associated with septicemia and avian colibacillosis. These plasmids are found significantly more often in ExPEC, including ExPEC associated with human neonatal meningitis and avian colibacillosis, than in commensal
E. coli
. Here we describe pAPEC-O103-ColBM, a hybrid RepFIIA/FIB plasmid harboring components of the ColV pathogenicity island and a multidrug resistance (MDR)-encoding island. This plasmid is mobilizable and confers the ability to cause septicemia in chickens, the ability to cause bacteremia resulting in meningitis in the rat model of human disease, and the ability to resist the killing effects of multiple antimicrobial agents and human serum. The results of a sequence analysis of this and other ColV plasmids supported previous findings which indicated that these plasmid types arose from a RepFIIA/FIB plasmid backbone on multiple occasions. Comparisons of pAPEC-O103-ColBM with other sequenced ColV and ColBM plasmids indicated that there is a core repertoire of virulence genes that might contribute to the ability of some ExPEC strains to cause high-level bacteremia and meningitis in a rat model. Examination of a neonatal meningitis
E. coli
(NMEC) population revealed that approximately 58% of the isolates examined harbored ColV-type plasmids and that 26% of these plasmids had genetic contents similar to that of pAPEC-O103-ColBM. The linkage of the ability to confer MDR and the ability contribute to multiple forms of human and animal disease on a single plasmid presents further challenges for preventing and treating ExPEC infections.
An RNA Interference Screen Identifies Metabolic Regulators NR1D1 and PBP as Novel Survival Factors for Breast Cancer Cells with the ERBB2 Signature
Authors: Kourtidis Antonis , Jain Ritu , Carkner Richard D. , Eifert Cheryl , Brosnan M. Julia , Conklin Douglas S. 
Published: February 2010

Abstract
Overexpression of the adverse prognostic marker ERBB2 occurs in 30% of breast cancers; however, therapies targeting this gene have not proved to be as effective as was initially hoped. Transcriptional profiling meta-analyses have shown that there are ∼150 genes co-overexpressed with ERBB2, suggesting that these genes may represent alternative factors influencing ERBB2-positive tumors. Here we describe an RNA interference–based analysis of these genes that identifies transcriptional regulators of fat synthesis and storage as being critical for the survival of these cells. These transcription factors, nuclear receptor subfamily 1, group D, member 1 (NR1D1) and peroxisome proliferator activated receptor γ binding protein (PBP), both reside on ERBB2-containing 17q12-21 amplicons and are part of the ERBB2 expression signature. We show that NR1D1 and PBP act through a common pathway in upregulating several genes in the de novo fatty acid synthesis network, which is highly active in ERBB2-positive breast cancer cells. Malate dehydrogenase 1 and malic enzyme 1, enzymes that link glycolysis and fatty acid synthesis, are also regulated by NR1D1. The resulting high-level fat production from increased expression of these genes likely contributes to an abnormal cellular energy metabolism based on aerobic glycolysis. Together, these results show that the cells of this aggressive form of breast cancer are genetically preprogrammed to depend on NR1D1 and PBP for the energy production necessary for survival. Cancer Res; 70(5); 1783–92
Inactivation of Junctional Adhesion Molecule-A Enhances Antitumoral Immune Response by Promoting Dendritic Cell and T Lymphocyte Infiltration
Authors: Murakami Masato , Francavilla Chiara , Torselli Ilaria , Corada Monica , Maddaluno Luigi , Sica Antonio , Matteoli Gianluca , Iliev Iliyan Dimitrov , Mantovani Alberto , Rescigno Maria , Cavallaro Ugo , Dejana Elisabetta 
Published: February 2010

Abstract
Junctional adhesion molecule-A (JAM-A)–null dendritic cells (DCs) are more motile and effective than their wild-type counterpart in promoting contact hypersensitivity reaction. Here, we show that the growth and aggressiveness of pancreatic islet cell carcinoma induced by SV40 T antigen expression in β cells (Rip1Tag2 mice) are significantly reduced in JAM-A–null mice. Because these tumor cells do not express JAM-A, we focused on changes in stroma reactivity. In the absence of JAM-A, tumors showed a small but significant reduction in angiogenesis and a marked increase in the immune reaction with enhanced infiltration of DCs (CD11c+ and MHC-II+) and CD4+ and CD8+ lymphocytes. In contrast, phagocyte number was not affected. DC capacity to produce cytokines was not significantly altered, but transmigration through JAM-A–null endothelial cells was increased as compared with JAM-A–positive endothelium. On adoptive transfer, JAM-A−/− DCs were recruited to tumors at slightly but significantly higher rate than JAM-A+/+ DCs. Ablation of CD4+ and CD8+ cells with specific antibodies abrogated the inhibitory effect of JAM-A deletion on tumor growth and angiogenesis. These findings support the idea that, in the Rip1Tag2 tumor model, abrogation of JAM-A reduces cancer development by increasing antitumor immune response. Cancer Res; 70(5); 1759–65
Loss of FOXA1/2 Is Essential for the Epithelial-to-Mesenchymal Transition in Pancreatic Cancer
Authors: Song Yan , Washington M. Kay , Crawford Howard C. 
Published: February 2010

Abstract
FOXA1 and FOXA2, members of the forkhead transcription factor family, are critical for epithelial differentiation in many endoderm-derived organs, including the pancreas. However, their role in tumor progression is largely unknown. Here, we identified FOXA1 and FOXA2 as important antagonists of the epithelial-to-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDA) through their positive regulation of E-cadherin and maintenance of the epithelial phenotype. In human PDA samples, FOXA1/2 are expressed in all epithelia from normal to well-differentiated cancer cells, but are lost in undifferentiated cancer cells. In PDA cell lines, FOXA1/2 expression is consistently suppressed in experimental EMT models and RNAi silencing of FOXA1/2 alone is sufficient to induce EMT. Conversely, ectopic FOXA1/2 expression can potently neutralize several EMT-related E-cadherin repressive mechanisms. Finally, ectopic FOXA2 expression could reactivate E-cadherin expression in a PDA cell line with extensive promoter hypermethylation. In fact, demethylation-mediated reactivation of E-cadherin expression in these cells required concurrent reactivation of endogenous FOXA2 expression. We conclude that suppression of FOXA1/2 expression is both necessary and sufficient for EMT during PDA malignant progression. Cancer Res; 70(5); 2115–25
Vitamin D Deficiency Promotes Human Breast Cancer Growth in a Murine Model of Bone Metastasis
Authors: Ooi Li Laine , Zhou Hong , Kalak Robert , Zheng Yu , Conigrave Arthur D. , Seibel Markus J. , Dunstan Colin R. 
Published: February 2010

Abstract
Vitamin D exerts antiproliferative, prodifferentiation, and proapoptotic effects on nonclassic target tissues such as breast. Blood levels of 25-hydroxyvitamin D [25(OH)D], the most sensitive indicator of vitamin D status, are inversely correlated with breast cancer risk; however, a causal relationship between vitamin D deficiency and breast cancer growth in bone has not been assessed. We examined the effect of vitamin D deficiency on the intraskeletal growth of the human breast cancer cell line MDA-MB-231-TxSA in a murine model of malignant bone lesions. Subsets of mice were treated concurrently with osteoprotegerin (OPG) to abrogate bone resorption. Outcomes were assessed by repeated radiographic and end-point micro–computed tomography and histologic analyses. Mice weaned onto a vitamin D–free diet developed vitamin D deficiency within 4 weeks [mean ± SE serum 25(OH)D: 11.5 ± 0.5 nmol/L], which was sustained throughout the study and was associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D–deficient than in vitamin D–sufficient mice after 2 weeks (radiographic osteolysis: +121.5%; histologic tumor area: +314%; P &lt; 0.05). Although OPG treatment reduced the size of radiographic osteolyses and tumor area in both groups, tumors remained larger in OPG-treated vitamin D–deficient compared with OPG-treated vitamin D–sufficient mice (0.53 ± 0.05 mm2 versus 0.19 ± 0.05 mm2; P &lt; 0.05). We conclude that vitamin D deficiency promotes the growth of human breast cancer cells in the bones of nude mice. These effects are partly mediated through secondary changes in the bone microenvironment, along with direct effects of vitamin D on tumor growth. Cancer Res; 70(5); 1835–44
Celastrol Suppresses Angiogenesis-Mediated Tumor Growth through Inhibition of AKT/Mammalian Target of Rapamycin Pathway
Authors: Pang Xiufeng , Yi Zhengfang , Zhang Jing , Lu Binbin , Sung Bokyung , Qu Weijing , Aggarwal Bharat B. , Liu Mingyao 
Published: February 2010

Abstract
Understanding the molecular basis and target of traditional medicine is critical for drug development. Celastrol, derived from Trypterygium wilfordii Hook F. (“Thunder of God Vine”), a traditional Chinese medicine plant, has been assigned anticancer activities, but its mechanism is not well understood. Here, we investigated whether Celastrol could inhibit angiogenesis-mediated tumor growth and, if so, through what mechanism. When given s.c. to mice bearing human prostate cancer (PC-3 cell) xenografts, Celastrol (2 mg/kg/d) significantly reduced the volume and the weight of solid tumors and decreased tumor angiogenesis. We found that this agent inhibited vascular endothelial growth factor (VEGF)–induced proliferation, migration, invasion, and capillary-like structure formation by primary cultured human umbilical vascular endothelial cells (HUVEC) in a dose-dependent manner. Furthermore, Celastrol abrogated VEGF-induced sprouting of the vessels from aortic rings and inhibited vascular formation in the Matrigel plug assay in vivo. To understand the molecular mechanism of these activities, we next examined the signaling pathways in treated HUVECs and PC-3 tumor cells. Celastrol suppressed the VEGF-induced activation of AKT, mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (P70S6K). Additionally, we found that Celastrol inhibited the proliferation of prostate cancer cells and induced apoptosis, and these effects correlated with the extent of inhibition of AKT/mTOR/P70S6K signaling. Taken together, our results suggest that Celastrol targets the AKT/mTOR/P70S6K pathway, which leads to suppression of tumor growth and angiogenesis. Cancer Res; 70(5); 1951–9
Role of Secreted Frizzled-Related Protein 3 in Human Renal Cell Carcinoma
Authors: Hirata Hiroshi , Hinoda Yuji , Ueno Koji , Majid Shahana , Saini Sharanjot , Dahiya Rajvir 
Published: February 2010

Abstract
The secreted frizzled-related protein (sFRP) family plays an important role in the inhibition of the Wnt signaling pathway in various cancers. The functional significance of Wnt antagonist sFRP3 has not been investigated in renal cancer. We performed tissue microarray and found that the level of sFRP3 protein was high in normal kidney, low in primary renal cancer tissues, and high in metastatic renal cancer tissues. Therefore, we hypothesized that sFRP3 may play an important role in metastatic renal cancer. To test this hypothesis, we performed a series of experiments to determine the role of sFRP3 using primary and metastatic renal cancer cell lines. Functional analysis showed increased numbers of viable and invaded cells and tube formation and decreased numbers of apoptotic cells in the sFRP3-transfected renal cancer cell line A498. Promotion of tumor growth was also observed in nude mice injected with sFRP3-transfected A498 cells. In contrast, the number of viable cells and invasive cells was decreased in sFRP3 mRNA knockdown metastatic cells (ACHN and Hs891.T). To investigate the mechanism of sFRP3 function, we performed microarray analysis to see which genes were upregulated or downregulated by sFRP3 expression. Among these genes, MMP-3 and ANGPT1 were significantly upregulated in sFRP3-transfected cells. In conclusion, this is the first report to show that sFRP3 expression promotes cell growth, invasion, and inhibition of apoptosis in renal cancer cells. Cancer Res; 70(5); 1896–905
Immunotherapeutic Suppression of Indoleamine 2,3-Dioxygenase and Tumor Growth with Ethyl Pyruvate
Authors: Muller Alexander J. , DuHadaway James B. , Jaller Daniel , Curtis Peter , Metz Richard , Prendergast George C. 
Published: February 2010

Abstract
Efforts to improve cancer care in the developing world will benefit from the identification of simple, inexpensive, and broadly applicable medical modalities based on emergent innovations in treatment, such as targeting mechanisms of tumoral immune tolerance. In this report, we offer preclinical evidence that the low-cost, anti-inflammatory agent ethyl pyruvate elicits a potent immune-based antitumor response through inhibition of indoleamine 2,3-dioxygenase (IDO), a key tolerogenic enzyme for many human tumors. Consistent with its reported ability to interfere with NF-κB function, ethyl pyruvate blocks IDO induction both in vitro and in vivo. Antitumor activity was achieved in mice with a noncytotoxic dosing regimen of ethyl pyruvate shown previously to protect against lethality from sepsis. Similar outcomes were obtained with the functional ethyl pyruvate analogue 2-acetamidoacrylate. Ethyl pyruvate was ineffective at suppressing tumor outgrowth in both athymic and Ido1-deficient mice, providing in vivo corroboration of the importance of T-cell–dependent immunity and IDO targeting for ethyl pyruvate to achieve antitumor efficacy. Although ethyl pyruvate has undergone early-phase clinical testing, this was done without consideration of its possible applicability to cancer. Our findings that IDO is effectively blocked by ethyl pyruvate treatment deepen emerging links between IDO and inflammatory processes. Further, these findings rationalize oncologic applications for this agent by providing a compelling basis to reposition ethyl pyruvate as a low-cost immunochemotherapy for clinical evaluation in cancer patients. Cancer Res; 70(5); 1845–53
Critical Role of Gα12 and Gα13 for Human Small Cell Lung Cancer Cell Proliferation In vitro and Tumor Growth In vivo
Authors: Grzelinski Marius , Pinkenburg Olaf , Büch Thomas , Gold Maike , Stohr Stefanie , Kalwa Hermann , Gudermann Thomas , Aigner Achim 
Published: February 2010

Abstract
Purpose: In small cell lung cancer cells (SCLC), various autocrine stimuli lead to the parallel activation of Gq/11 and G12/13 proteins. Although the contribution of the Gq/11-phospholipase C-β cascade to mitogenic effects in SCLC cells is well established, the relevance of G12/13 signaling is still elusive. In other tumor entities, G12/13 activation promotes invasiveness without affecting cellular proliferation. Here, we investigate the role of G12/13-dependent signaling in SCLC.
Experimental Design: We used small hairpin RNA–mediated targeting of Gα12, Gα13, or both in H69 and H209 cells and analyzed the effects of Gα12 and/or Gα13 knockdown on tumor cells in vitro, tumor growth in vivo, and mitogen-activated protein kinase (MAPK) activation.
Results: Lentiviral expression of small hairpin RNAs resulted in robust and specific Gα12 and Gα13 knockdown as well as markedly inhibited proliferation, colony formation, and bradykinin-promoted stimulation of cell growth. Analyzing the activation status of all three major MAPK families revealed nonredundant functions of Gα12 and Gα13 in SCLC and a marked p42/p44 activation upon Gα12/Gα13 knockdown. In a s.c. tumor xenograft mouse model, Gα12 or Gα13 downregulation led to decreased tumor growth due to reduced tumor cell proliferation. More importantly, Gα12/Gα13 double knockdown completely abolished H69 tumorigenicity in mice.
Conclusions: Gα12 and Gα13 exert a complex pattern of nonredundant effects in SCLC, and in contrast to other tumor types, SCLC cell proliferation in vitro and tumorigenicity in vivo critically depend on G12/13 signaling. Due to the complete abolishment of tumorgenicity in our study, RNAi-mediated double knockdown may provide a promising new avenue in SCLC treatment. Clin Cancer Res; 16(5); 1402–15
Equatorial Mountain Torques and Cold Surge Preconditioning
Authors: Mailler Sylvain , Lott François 
Published: February 2010

Abstract
The evolution of the two components of the equatorial mountain torque (EMT) applied by mountains on the atmosphere is analyzed in the NCEP reanalysis. A strong lagged relationship between the EMT component along the Greenwich axis TM1 and the EMT component along the 90°E axis TM2 is found, with a pronounced signal on TM1 followed by a signal of opposite sign on TM2. It is shown that this result holds for the major massifs (Antarctica, the Tibetan Plateau, the Rockies, and the Andes) if a suitable axis system is used for each of them. For the midlatitude mountains, this relationship is in part associated with the development of cold surges.
Following these results, two hypotheses are made: (i) the mountain forcing on the atmosphere is well measured by the regional EMTs and (ii) this forcing partly drives the cold surges. To support these, a purely dynamical linear model is proposed: it is written on the sphere, uses an f-plane quasigeostrophic approximation, and includes the mountain forcings. In this model, a positive (negative) peak in TM1 produced by a mountain massif in the Northern (Southern) Hemisphere is due to a large-scale high surface pressure anomaly poleward of the massif. At a later stage, high pressure and low temperature anomalies develop in the lower troposphere east of the mountain, explaining the signal on TM2 and providing the favorable conditions for the cold surge development.
It is concluded that the EMT is a good measure of the dynamical forcing of the atmospheric flow by the mountains and that the poleward forces exerted by mountains on the atmosphere are substantial drivers of the cold surges, at least in their early stage. Therefore, the EMT time series can be an important diagnostic to assess the representation of mountains in general circulation models.
A Gaussian Mixture Model Approach to Forecast Verification
Authors: Lakshmanan Valliappa , Kain John S. 
Published: February 2010

Abstract
Verification methods for high-resolution forecasts have been based either on filtering or on objects created by thresholding the images. The filtering methods do not easily permit the use of deformation while identifying objects based on thresholds can be problematic. In this paper, a new approach is introduced in which the observed and forecast fields are broken down into a mixture of Gaussians, and the parameters of the Gaussian mixture model fit are examined to identify translation, rotation, and scaling errors. The advantages of this method are discussed in terms of the traditional filtering or object-based methods and the resulting scores are interpreted on a standard verification dataset.
Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogénétique Hématologique study
Authors: Coyaud Etienne , Struski Stephanie , Prade Nais , Familiades Julien , Eichner Ruth , Quelen Cathy , Bousquet Marina , Mugneret Francine , Talmant Pascaline , Pages Marie-Pierre , Lefebvre Christine , Penther Dominique , Lippert Eric , Nadal Nathalie , Taviaux Sylvie , Poppe Bruce , Luquet Isabelle , Baranger Laurence , Eclache Virginie , Radford Isabelle , Barin Carole , Mozziconacci Marie-Joëlle , Lafage-Pochitaloff Marina , Antoine-Poirel Hélène , Charrin Christiane , Perot Christine , Terre Christine , Brousset Pierre , Dastugue Nicole , Broccardo Cyril 
Published: February 2010

Abstract
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.
BisoGenet: a new tool for gene network building, visualization and analysis
Authors: Martin Alexander , Ochagavia Maria E , Rabasa Laya C , Miranda Jamilet , Fernandez-de-Cossio Jorge , Bringas Ricardo 
Published: February 2010

Abstract

Background
The increasing availability and diversity of omics data in the post-genomic era offers new perspectives in most areas of biomedical research. Graph-based biological networks models capture the topology of the functional relationships between molecular entities such as gene, protein and small compounds and provide a suitable framework for integrating and analyzing omics-data. The development of software tools capable of integrating data from different sources and to provide flexible methods to reconstruct, represent and analyze topological networks is an active field of research in bioinformatics.

Results
BisoGenet is a multi-tier application for visualization and analysis of biomolecular relationships. The system consists of three tiers. In the data tier, an in-house database stores genomics information, protein-protein interactions, protein-DNA interactions, gene ontology and metabolic pathways. In the middle tier, a global network is created at server startup, representing the whole data on bioentities and their relationships retrieved from the database. The client tier is a Cytoscape plugin, which manages user input, communication with the Web Service, visualization and analysis of the resulting network.

Conclusion
BisoGenet is able to build and visualize biological networks in a fast and user-friendly manner. A feature of Bisogenet is the possibility to include coding relations to distinguish between genes and their products. This feature could be instrumental to achieve a finer grain representation of the bioentities and their relationships. The client application includes network analysis tools and interactive network expansion capabilities. In addition, an option is provided to allow other networks to be converted to BisoGenet. This feature facilitates the integration of our software with other tools available in the Cytoscape platform. BisoGenet is available at http://bio.cigb.edu.cu/bisogenet-cytoscape/.