bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating Methylated-DCR2Gene in Serum as an Indicator of Prognosis and Therapeutic Efficacy in Patients withMYCNNonamplified Neuroblastoma
Authors: Yagyu Shigeki , Gotoh Takahiro , Iehara Tomoko , Miyachi Mitsuru , Katsumi Yoshiki , Tsubai-Shimizu Satoko , Kikuchi Ken , Tamura Shinichi , Tsuchiya Kunihiko , Imamura Toshihiko , Misawa-Furihata Akiko , Sugimoto Tohru , Sawada Tadashi , Hosoi Hajime 
Published: November 2008

AbstractBackground: MYCN amplification (MNA) in neuroblastoma is a strong indicator of poor prognosis. However, some MYCN nonamplified (non-MNA) cases show poor outcomes, and examining the status of the gene requires an operation, which may have surgical complications. Therefore, a new marker is needed to identify cases of non-MNA neuroblastomas with poor prognoses using less risky procedures. Aberrant hypermethylation of the DCR2 promoter has recently been associated with rapidly progressing neuroblastoma. We aimed to develop a noninvasive DCR2 methylation assay for patients with neuroblastoma using serum DNA, which predominantly originates from tumor-released DNA.Methods: Using DNA-based real-time PCR, we simultaneously quantified a methylated-DCR2 specific sequence (M) and a reference sequence (R) located in the promoter region in serum DNA, and evaluated DCR2 methylation status as M/R ratios in 86 patients with neuroblastoma.Results: Serum DCR2 M/R ratios were strongly correlated with those in the tumor (r = 0.67; P = 0.002). DCR2 methylation was associated with stage both in the whole neuroblastoma group and in the non-MNA group (P &lt; 0.001), and DCR2-methylated patients showed significantly poorer 5-year event-free survival in the whole neuroblastoma group (43% versus 84%; P &lt; 0.001), especially in the non-MNA group (12% versus 96%;P &lt; 0.001). Among five DCR2-methylated patients whose clinical courses were followed, serum M/R ratios were close to 0 in the patients in remission, whereas the ratios increased in patients who relapsed.Conclusions: Detection of methylated-DCR2 in serum DNA has promise as a noninvasive assay for predicting prognosis and therapeutic efficacy in neuroblastoma, especially in non-MNA cases. Furthermore, it might be a sensitive marker of tumor recurrence in DCR2-methylated cases.
DNA Vaccines Targeting Tumor Antigens to B7 Molecules on Antigen-Presenting Cells Induce Protective Antitumor Immunity and Delay Onset of HER-2/Neu-Driven Mammary Carcinoma
Authors: Sloots Arjen , Mastini Cristina , Rohrbach Florian , Weth Robert , Curcio Claudia , Burkhardt Ute , Jäger Elke , Forni Guido , Cavallo Federica , Wels Winfried S. 
Published: November 2008

AbstractPurpose: Presentation of tumor antigens by professional antigen-presenting cells (APC) is critical for the induction of tumor-specific T-cell responses. To facilitate targeted delivery of tumor antigens to APC, we generated DNA vaccines that encode secreted fusion proteins consisting of the extracellular domain of CTLA-4 for binding to costimulatory B7 molecules on APC, fused to residues 1 to 222 of human ErbB2 (HER-2) or a corresponding 224 residues fragment of its rat homologue Neu.Experimental Design: Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in murine tumor models with transfected renal carcinoma cells expressing the respective antigens and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas.Results: Vaccination of BALB/c mice with CTLA-4-ErbB2222 plasmid DNA markedly improved tumor-free survival on challenge with ErbB2-expressing Renca cells in comparison with untargeted ErbB2222, accompanied by induction of stronger ErbB2-specific antibody and CTL responses. Likewise, a CTLA-4 vaccine carrying the unrelated NY-ESO-1 cancer-germline antigen was more effective than untargeted NY-ESO-1 in the protection of mice from challenge with NY-ESO-1-expressing tumor cells. Importantly, antitumoral activity of such a CTLA-4 fusion vaccine could be reproduced in immunotolerant BALB-neuT mice, where a corresponding CTLA-4-Neu224 DNA vaccine markedly delayed the onset of spontaneous Neu-driven mammary carcinomas.Conclusions: Our results show that plasmid DNA vaccines for in vivo expression of tumor antigens targeted to APC induce potent immune responses and antitumoral activities, providing a rationale for further development of this approach for specific cancer immunotherapy.
Average Predictability Time. Part II: Seamless Diagnoses of Predictability on Multiple Time Scales
Authors: DelSole Timothy , Tippett Michael K. 
Published: November 2008

Abstract
This paper proposes a new method for diagnosing predictability on multiple time scales without time averaging. The method finds components that maximize the average predictability time (APT) of a system, where APT is defined as the integral of the average predictability over all lead times. Basing the predictability measure on the Mahalanobis metric leads to a complete, uncorrelated set of components that can be ordered by their contribution to APT, analogous to the way principal components decompose variance. The components and associated APTs are invariant to nonsingular linear transformations, allowing variables with different units and natural variability to be considered in a single state vector without normalization. For prediction models derived from linear regression, maximizing APT is equivalent to maximizing the sum of squared multiple correlations between the component and the time-lagged state vector. The new method is used to diagnose predictability of 1000-hPa zonal velocity on time scales from 6 h to decades. The leading predictable component is dominated by a linear trend and presumably identifies a climate change signal. The next component is strongly correlated with ENSO indices and hence is identified with seasonal-to-interannual predictability. The third component is related to annular modes and presents decadal variability as well as a trend. The next few components have APTs exceeding 10 days. A reconstruction of the tropical zonal wind field based on the leading seven components reveals eastward propagation of anomalies with time scales consistent with the Madden–Julian oscillation. The remaining components have time scales less than a week and hence are identified with weather predictability. The detection of predictability on these time scales without time averaging is possible by virtue of the fact that predictability on different time scales is characterized by different spatial structures, which can be optimally extracted by suitable projections.
A Climatology of the Gravest Waves in the Equatorial Lower and Middle Stratosphere: Method and Results for the ERA-40 Re-Analysis and the LMDz GCM
Authors: Lott François , Kuttippurath Jayanarayanan , Vial François 
Published: November 2008

Abstract
A climatology of the three-dimensional life cycle of the gravest waves in the tropical lower and middle stratosphere is presented. It shows that at periods around 10 days the gravest waves correspond to Kelvin and Rossby–gravity wave packets that substantially affect specific regions in the lower stratosphere. It also shows that the planetary-scale Kelvin waves with zonal wavenumber s = 1 and periods between 10 and 20 days produce a substantial signal. Still at the planetary scales, the climatology also shows that the global planetary Rossby waves with s = 1 and periods around 5 and 16 days have a substantial equatorial signature. This climatology is for all the dynamical fields (horizontal wind, temperature, and geopotential height) and relates the equatorial waves to the equatorial zonal mean flow evolution associated with the quasi-biennial oscillation.
The method used to extract the climatology is a composite analysis of the dynamical fields keyed on simple indexes measuring when the waves enter in the stratosphere. For the Kelvin waves, the Rossby–gravity waves, and the 5- and 16-day Rossby planetary waves, these indexes are related to the latitudinal means over the equatorial band of the temperature, the meridional wind, the geopotential height, and the zonal wind respectively. The method is applied first to ERA-40 and then to a simulation done with the LMDz GCM. When compared to the results from ERA-40, this reveals that the LMDz GCM underestimates the Rossby–gravity wave packets and a fraction of the Kelvin wave packets. This deficit is attributed to the fact that the model has a too coarse vertical resolution and an insufficient tropospheric forcing for the horizontal wavenumbers s &gt; 3.
Decadal Climatic Variability, Trends, and Future Scenarios for the North China Plain
Authors: Fu Guobin , Charles Stephen P. , Yu Jingjie , Liu Changming 
Published: November 2008

Abstract
Observed decadal climatic variability and trends for the north China plain (NCP) are assessed for significance with Kendall’s test and discussed in light of future climate scenarios from multi-GCM outputs from the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4). The results indicate that the NCP has become warmer and drier over the last four decades. The annual precipitation has declined by about 43.9 mm (6.7%, although not statistically significant), and the annual means of daily mean, maximum, and minimum temperatures have increased by 0.83°, 0.18°, and 1.46°C, respectively, during the past 40 yr. Both trends for annual means of daily mean and minimum temperatures are statistically significant. The future climate of the NCP is projected to be warmer and, with less confidence, wetter. However, streamflow could decline under these projections, based on the results of the two-parameter climate elasticity of streamflow index. This will produce serious challenges for water resources management and likely lead to exacerbated problems for agriculture, industry, urban communities, and the environment.
Alongshelf Variability of Inner-Shelf Circulation along the Central Oregon Coast during Summer
Authors: Kirincich Anthony R. , Barth John A. 
Published: November 2008

Abstract
The spatial and temporal variability of inner-shelf circulation along the central Oregon coast during the 2004 upwelling season is described using a 70-km-long array of moorings along the 15-m isobath. Circulation at three stations located onshore of a submarine bank differed from that of a station north of the bank, despite the relatively uniform wind forcing and inner-shelf bathymetry present. During upwelling-favorable winds, strong southward alongshelf flow occurred north of the bank, no alongshelf flow occurred onshore of the northern part of the bank, and increasing southward flow occurred onshore of the southern part of the bank. During downwelling-favorable winds, strong northward flow occurred in the inner shelf onshore of the bank while weak flow occurred north of the bank. These alongshelf differences in inner-shelf circulation were due to the effects of the bank, which isolated the inner shelf onshore of the bank from the regional upwelling circulation that was evident at the northernmost station. As a result, circulation onshore of the bank was driven primarily by local wind forcing, while flow north of the bank was only partially driven by local winds. A secondary mode of variability, attributed to the movement of the regional upwelling jet due to remote forcings, contributed the bulk of the variability observed north of the bank. With the time-dependent wind forcing present, acceleration was an important term in the depth-averaged alongshelf momentum equation at all stations. During upwelling, bottom stress and acceleration opposed the wind stress north of the bank, while bottom stress was weaker onshore of the bank where the across-shelf momentum flux and the alongshelf pressure gradient balanced the residual of the acceleration and stresses. During downwelling, waters onshore of the bank surged northward at magnitudes much larger than that found north of the bank. These spatial variations developed as the season progressed and the regional upwelling circulation intensified, explaining known variations in growth and recruitment of nearshore invertebrate species.
A New Scheme for Improving the Seasonal Prediction of Summer Precipitation Anomalies
Authors: Wang Huijun , Fan Ke 
Published: November 2008

Abstract
A new scheme is developed to improve the seasonal prediction of summer precipitation in the East Asian and western Pacific region. The scheme is applied to the Development of a European Multimodel Ensemble System for Seasonal to Interannual Prediction (DEMETER) results. The new scheme is designed to consider both model predictions and observed spatial patterns of historical “analog years.” In this paper, the anomaly pattern correlation coefficient (ACC) between the prediction and the observation, as well as the root-mean-square error, is used to measure the prediction skill. For the prediction of summer precipitation in East Asia and the western Pacific (0°–40°N, 80°–130°E), the prediction skill for the six model ensemble hindcasts for the years of 1979–2001 was increased to 0.22 by using the new scheme from 0.12 for the original scheme. All models were initiated in May and were composed of nine member predictions, and all showed improvement when applying the new scheme. The skill levels of the predictions for the six models increased from 0.08, 0.08, 0.01, 0.14, −0.07, and 0.07 for the original scheme to 0.11, 0.14, 0.10, 0.22, 0.04, and 0.13, respectively, for the new scheme.
NOTCH is a key regulator of human T-cell acute leukemia initiating cell activity
Authors: Armstrong Florence , de la Grange Philippe Brunet , Gerby Bastien , Rouyez Marie-Christine , Calvo Julien , Fontenay Michaéla , Boissel Nicolas , Dombret Hervé , Baruchel André , Landman-Parker Judith , Roméo Paul-Henri , Ballerini Paola , Pflumio Françoise 
Published: November 2008

Abstract
Understanding the pathways that regulate the human T-cell acute lymphoblastic leukemia (T-ALL) initiating cells (T-LiC) activity has been hampered by the lack of biologic assays in which this human disease can be studied. Here we show that coculture of primary human T-ALL with a mouse stromal cell line expressing the NOTCH ligand delta-like-1 (DL1) reproducibly allowed maintenance of T-LiC and long-term growth of blast cells. Human T-ALL mutated or not on the NOTCH receptor required sustained activation of the NOTCH pathway via receptor/ligand interaction for growth and T-LiC activity. On the reverse, inhibition of the NOTCH pathway during primary cultures abolished in vitro cell growth and in vivo T-LiC activity. Altogether, these results demonstrate the major role of the NOTCH pathway activation in human T-ALL development and in the maintenance of leukemia-initiating cells.
Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes
Authors: Salzer Ulrich , Bacchelli Chiara , Buckridge Sylvie , Pan-Hammarström Qiang , Jennings Stephanie , Lougaris Vassilis , Bergbreiter Astrid , Hagena Tina , Birmelin Jennifer , Plebani Alessandro , Webster A. David B. , Peter Hans-Hartmut , Suez Daniel , Chapel Helen , McLean-Tooke Andrew , Spickett Gavin P. , Anover-Sombke Stephanie , Ochs Hans D. , Urschel Simon , Belohradsky Bernd H. , Ugrinovic Sanja , Kumararatne Dinakantha S. , Lawrence Tatiana C. , Holm Are M. , Franco Jose L. , Schulze Ilka , Schneider Pascal , Gertz E. Michael , Schäffer Alejandro A. , Hammarström Lennart , Thrasher Adrian J. , Gaspar H. Bobby , Grimbacher Bodo 
Published: November 2008

Abstract
TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell– specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n = 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferation-inducing ligand (APRIL). However, the majority (n = 41; 82%) of the pa-tients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001, relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD−CD27+ B cells (P = .019), benign lymphoproliferation (P < .001), and autoimmune complications (P = .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation.
Phosphoantigen-activated Vγ2Vδ2 T cells antagonize IL-2–induced CD4+CD25+Foxp3+ T regulatory cells in mycobacterial infection
Authors: Gong Guangming , Shao Lingyun , Wang Yunqi , Chen Crystal Y. , Huang Dan , Yao Shuyu , Zhan Ximei , Sicard Helene , Wang Richard , Chen Zheng W. 
Published: November 2008

Abstract
Although Foxp3+ T regulatory cells (Tregs) are well documented for their ability to suppress various immune cells, T-cell subsets capable of counteracting Tregs have not been demonstrated. Here, we assessed phosphoantigen-activated Vγ2Vδ2 T cells for the ability to interplay with Tregs in the context of mycobacterial infection. A short-term IL-2 treatment regimen induced marked expansion of CD4+CD25+Foxp3+ T cells and subsequent suppression of mycobacterium-driven increases in numbers of Vγ2Vδ2 T cells. Surprisingly, activation of Vγ2Vδ2 T cells by adding phosphoantigen Picostim to the IL-2 treatment regimen down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Consistently, in vitro activation of Vγ2Vδ2 T cells by phosphoantigen plus IL-2 down-regulated IL-2–induced expansion of CD4+CD25+Foxp3+ T cells. Interestingly, anti–IFN-γ–neutralizing antibody, not anti–TGF-β or anti–IL-4, reduced the ability of activated Vγ2Vδ2 T cells to down-regulate Tregs, suggesting that autocrine IFN-γ and its network contributed to Vγ2Vδ2 T cells' antagonizing effects. Furthermore, activation of Vγ2Vδ2 T cells by Picostim plus IL-2 treatment appeared to reverse Treg-driven suppression of immune responses of phosphoantigen-specific IFNγ+ or perforin+ Vγ2Vδ2 T cells and PPD-specific IFNγ+αβ T cells. Thus, phos-phoantigen activation of Vγ2Vδ2 T cells antagonizes IL-2–induced expansion of Tregs and subsequent suppression of Ag-specific antimicrobial T-cell responses in mycobacterial infection.
Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid
Authors: Ro Dae-Kyun , Ouellet Mario , Paradise Eric M , Burd Helcio , Eng Diana , Paddon Chris J , Newman Jack D , Keasling Jay D 
Published: November 2008

Abstract

Background
Due to the global occurrence of multi-drug-resistant malarial parasites (Plasmodium falciparum), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (Artemisia annua). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from A. annua. In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required.

Results
Three plant genes coding for amorphadiene synthase, amorphadiene oxidase (AMO or CYP71AV1), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 μg mL-1 in shake-flask cultures and 1 g L-1 in bio-reactors with the use of Leu2d selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance (PDR) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by yeast microarray further demonstrated that the induction of drug-resistant genes such as ABC transporters and major facilitator superfamily (MSF) genes is the primary cellular stress-response; in addition, oxidative and osmotic stress responses were observed in the engineered yeast.

Conclusion
The data presented here suggest that the engineered yeast producing artemisinic acid suffers oxidative and drug-associated stresses. The use of plant-derived transporters and optimizing AMO activity may improve the yield of artemisinic acid production in the engineered yeast.
Anti-oxidant inhibition of hyaluronan fragment-induced inflammatory gene expression
Authors: Eberlein Michael , Scheibner Kara A , Black Katharine E , Collins Samuel L , Chan-Li Yee , Powell Jonathan D , Horton Maureen R 
Published: November 2008

AbstractBackgroundThe balance between reactive oxygen species (ROS) and endogenous anti-oxidants is important in maintaining healthy tissues. Excessive ROS states occur in diseases such as ARDS and Idiopathic Pulmonary Fibrosis. Redox imbalance breaks down the extracellular matrix component hyaluronan (HA) into fragments that activate innate immune responses and perpetuate tissue injury. HA fragments, via a TLR and NF-κB pathway, induce inflammatory gene expression in macrophages and epithelial cells. NAC and DMSO are potent anti-oxidants which may help balance excess ROS states.MethodsWe evaluated the effect of H2O2, NAC and DMSO on HA fragment induced inflammatory gene expression in alveolar macrophages and epithelial cells.ResultsNAC and DMSO inhibit HA fragment-induced expression of TNF-α and KC protein in alveolar and peritoneal macrophages. NAC and DMSO also show a dose dependent inhibition of IP-10 protein expression, but not IL-8 protein, in alveolar epithelial cells. In addition, H2O2synergizes with HA fragments to induce inflammatory genes, which are inhibited by NAC. Mechanistically, NAC and DMSO inhibit HA induced gene expression by inhibiting NF-κB activation, but NAC had no influence on HA-fragment-AP-1 mediated gene expression.ConclusionROS play a central role in a pathophysiologic "vicious cycle" of inflammation: tissue injury generates ROS, which fragment the extracellular matrix HA, which in turn synergize with ROS to activate the innate immune system and further promote ROS, HA fragment generation, inflammation, tissue injury and ultimately fibrosis. The anti-oxidants NAC and DMSO, by inhibiting the HA induced inflammatory gene expression, may help re-balance excessive ROS induced inflammation.