bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53
Authors: Supiot Stéphane , Hill Richard P. , Bristow Robert G. 
Published: April 2008

Abstract
Nutlin-3 is a small-molecule inhibitor that acts to inhibit MDM2 binding to p53 and subsequent p53-dependent DNA damage signaling. Whether Nutlin-3 alters cell toxicity following DNA damage under oxic versus hypoxic conditions has not been studied. The potential radiosensitization (0-10 Gy) properties of Nutlin-3 (dose range, 2-10 μmol/L for up to 24 h) were investigated in vitro using three prostate cancer cell lines, 22RV1 [wild-type p53 (WTp53)], DU145 (mutated p53), and PC-3 (p53-null) under oxic (21% O2), hypoxic (0.2% O2), and anoxic (0% O2) conditions. As a single agent, Nutlin-3 (2-10 μmol/L) stabilized p53 and p21WAF levels and was toxic to WTp53-22RV1 cells (IC50, 4.3 μmol/L) but had minimal toxicity toward p53-deficient cells (IC50, &gt;10 μmol/L). When combined with radiation under oxic conditions, Nutlin-3 decreased clonogenic survival in all three cell lines: 22RV1 [sensitizing enhancement ratio (SER), 1.24], DU145 (SER, 1.27), and PC-3 (SER, 1.12). Anoxia induced p53 protein expression in 22RV1 cells and this was augmented by Nutlin-3 treatment. Furthermore, Nutlin-3 was more effective as a radiosensitizer under hypoxic conditions particularly in WTp53-expressing cells: 22RV1 (SER, 1.78), DU145 (SER, 1.31), and PC-3 (SER, 1.28). The decrease in clonogenic survival with Nutlin-3 was not correlated to altered levels of radiation-induced apoptosis within the three cell lines. Our results indicate that Nutlin-3 can act as a radiosensitizer via p53-independent mechanisms under low O2 levels. Nutlin-3 may be a useful adjunct to improve the therapeutic ratio using precision radiotherapy targeted to hypoxic cells and warrants further study in vivo. [Mol Cancer Ther 2008;7(4):993–9]
Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism
Authors: Shim Minsub , Eling Thomas E. 
Published: April 2008

AbstractNAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of the transforming growth factor-β superfamily, is involved in many cellular processes, such as inflammation, apoptosis/survival, and tumorigenesis. Vitamin E succinate (VES) is the succinate derivative of α-tocopherol and has antitumorigenic activity in a variety of cell culture and animal models. In the current study, the regulation and role of NAG-1 expression in PC-3 human prostate carcinoma cells by VES was examined. VES treatment induced growth arrest and apoptosis as well as an increase in NAG-1 protein and mRNA levels in a time- and concentration-dependent manner. VES treatment induced nuclear translocation and activation of p38 kinase. Pretreatment with p38 kinase inhibitor blocked the VES-induced increase in NAG-1 protein and mRNA levels, whereas an inhibition of protein kinase C, Akt, c-Jun NH2-terminal kinase, or MEK activity had no effect on VES-induced NAG-1 levels. Forced expression of constitutively active MKK6, an upstream kinase for p38, induced an increase in NAG-1 promoter activity, whereas p38 kinase inhibitor blocked MKK6-induced increase in NAG-1 promoter activity. VES treatment resulted in &gt;3-fold increase in the half-life of NAG-1 mRNA in a p38 kinase-dependent manner and transient transfection experiment showed that VES stabilizes NAG-1 mRNA through AU-rich elements in 3′-untranslated region of NAG-1 mRNA. The inhibition of NAG-1 expression by small interfering RNA significantly blocked VES-induced poly(ADP-ribose) polymerase cleavage, suggesting that NAG-1 may play an important role in VES-induced apoptosis. These results indicate that VES-induced expression of NAG-1 mRNA/protein is regulated by transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner and NAG-1 can be chemopreventive/therapeutic target in prostate cancer. [Mol Cancer Ther 2008;7(4):961–71]
WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells
Authors: Cuddihy Andrew R. , Jalali Farid , Coackley Carla , Bristow Robert G. 
Published: April 2008

Abstract
New molecular cancer treatment strategies aim to reconstitute wild-type p53 (WTp53) function in mutant p53 (MTp53)–expressing tumors as a means of resensitizing cells to chemotherapy or radiotherapy. The success of this approach may depend on whether MTp53 proteins are acting in a dominant-negative or independent gain-of-function mode. Herein, we describe an isogenic, temperature-sensitive p53 model (p53A138V) in p53-null human H1299 lung cancer cells in which WTp53 can be selectively coexpressed with a temperature-sensitive MTp53 allele (A138V) during initial DNA damage and subsequent DNA repair. Cells expressing MTp53 alone or coexpressing induced WTp53 and MTp53 were tested for p53 transcription, G1 and G2 cell cycle checkpoints, apoptosis, and long-term clonogenic survival following DNA damage. Transient transfection of WTp53 into H1299 cells, or shift-down of H1299-p53A138V stable transfectants to 32°C to induce WTp53, led to increased p21WAF1 expression and G1 and G2 arrests following DNA damage but did not increase BAX expression or apoptosis. In contrast, both transient and stable expression of the p53A138V mutant in p53-null H1299 cells (e.g. testing gain-of-function) at 37°C blocked p21WAF1 induction following DNA damage. Cell death was secondary to mitotic catastrophe and/or tumor cell senescence. Overexpression of WTp53 did not resensitize resistant MTp53-expressing cells to ionizing radiation, cisplatinum, or mitomycin C. Our results suggest that human MTp53 proteins can lead to resistant phenotypes independent of WTp53-mediated transcription and checkpoint control. This should be considered when using p53 as a prognostic factor and therapeutic target. [Mol Cancer Ther 2008;7(4):980–92]
UBE1L represses PML/RARα by targeting the PML domain for ISG15ylation
Authors: Shah Sumit J. , Blumen Steven , Pitha-Rowe Ian , Kitareewan Sutisak , Freemantle Sarah J. , Feng Qing , Dmitrovsky Ethan 
Published: April 2008

Abstract
Acute promyelocytic leukemia (APL) is characterized by expression of promyelocytic leukemia (PML)/retinoic acid (RA) receptor α (RARα) protein and all-trans-RA-mediated clinical remissions. RA treatment can confer PML/RARα degradation, overcoming dominant-negative effects of this oncogenic protein. The present study uncovered independent retinoid degradation mechanisms, targeting different domains of PML/RARα. RA treatment is known to repress PML/RARα and augment ubiquitin-activating enzyme-E1-like (UBE1L) protein expression in NB4-S1 APL cells. We previously reported RA-induced UBE1L and the IFN-stimulated gene, 15-kDa protein ISG15ylation in APL cells. Whether the ubiquitin-like protein ISG15 directly conjugates with PML/RARα was not explored previously and is examined in this study. Transient transfection experiments with different PML/RARα domains revealed that RA treatment preferentially down-regulated the RARα domain, whereas UBE1L targeted the PML domain for repression. As expected, ubiquitin-specific protease 18 (UBP43/USP18), the ISG15 deconjugase, opposed UBE1L but not RA-dependent PML/RARα degradation. In contrast, the proteasomal inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal, inhibited both UBE1L- and RA-mediated PML/RARα degradation. Notably, UBE1L induced ISG15ylation of the PML domain of PML/RARα, causing its repression. These findings confirmed that RA triggers PML/RARα degradation through different domains and distinct mechanisms. Taken together, these findings advance prior work by establishing two pathways converge on the same oncogenic protein to cause its degradation and thereby promote antineoplastic effects. The molecular pharmacologic implications of these findings are discussed. [Mol Cancer Ther 2008;7(4):905–14]
Enhancement of antitumor properties of TRAIL by targeted delivery to the tumor neovasculature
Authors: Cao Lin , Du Pan , Jiang Shu-Han , Jin Guang-Hui , Huang Qi-Lai , Hua Zi-Chun 
Published: April 2008

AbstractTumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent with tumor-selective apoptotic activity. TRAIL plays a role in the innate and adaptive immune response and autoimmune disease and may also be involved in hepatic cell death and inflammation. For these reasons, chronic exposure to TRAIL may have deleterious side effects in patients as a cancer therapeutic. In this study, we have improved the antitumor activity of TRAIL by targeted delivery to the tumor vasculature, leading to dramatic enhancement of its therapeutic properties. TRAIL was fused to the ACDCRGDCFC peptide (named RGD-L-TRAIL), a ligand of αVβ3 and αVβ5 integrins. Biological activity was evaluated in vitro and antitumor efficacy was investigated in vivo as a single agent and in combination with irinotecan hydrochloride (CPT-11). The fusion protein RGD-L-TRAIL, but not TRAIL or RGE-L-TRAIL, specifically bound to microvascular endothelial cells in a dose-dependent manner and showed enhanced apoptosis-inducing activity (caspase-3 and caspase-8 activation) in αVβ3 and αVβ5 integrin-positive cancer cells. In addition, RGD-L-TRAIL was more effective in suppressing tumor growth of COLO-205 tumor-bearing mice than an equivalent dose of TRAIL. The antitumor effect of RGD-L-TRAIL was further enhanced by combination with CPT-11 in both TRAIL-sensitive COLO-205 and TRAIL-resistive HT-29 tumor xenograft models. Our findings suggest that the novel fusion protein RGD-L-TRAIL can directly target tumor endothelial cells as well as αVβ3 and αVβ5 integrin-positive tumor cells. The tumor-targeted delivery of TRAIL derivatives, such as RGD-L-TRAIL, may prove to be a promising lead candidate for cancer therapy. [Mol Cancer Ther 2008;7(4):851–61]
2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition
Authors: Zhong Diansheng , Liu Xiuju , Schafer-Hales Katherine , Marcus Adam I. , Khuri Fadlo R. , Sun Shi-Yong , Zhou Wei 
Published: April 2008

AbstractThe compound 2-deoxyglucose (2-DG) enhances chemotherapy/radiotherapy in cell lines and animal models, prompting two phase I clinical trials with this cancer therapeutic. Although its mechanism of action has not been fully elucidated, it is hypothesized that the molecular basis of 2-DG activity is related to glycolysis inhibition. Here, we report that 2-DG induced Akt phosphorylation at Thr308 and Ser473 as early as 15 min post-treatment. These phosphorylation events required phosphatidylinositol-3-kinase activity but were not related to LKB1/AMP-activated protein kinase signaling, the inhibition of glycolysis or epidermal growth factor receptor signaling. The 2-DG-mediated Akt phosphorylation also led to the phosphorylation of Akt downstream targets, such as Foxo3a, GSK3β, and Chk1. Because the functional consequence of Akt activation includes chemotherapy/radiotherapy resistance, our data suggested that the combination of phosphatidylinositol-3-kinase/Akt inhibitory agents in 2-DG-based chemotherapy/radiotherapy may result in enhanced therapeutic efficacy. [Mol Cancer Ther 2008;7(4):809–17]
The Impact of Snow Model Complexity at Three CLPX Sites
Authors: Feng Xia , Sahoo Alok , Arsenault Kristi , Houser Paul , Luo Yan , Troy Tara J. 
Published: April 2008

Abstract
Many studies have developed snow process understanding by exploring the impact of snow model complexity on simulation performance. This paper revisits this topic using several recently developed land surface models, including the Simplified Simple Biosphere Model (SSiB); Noah; Variable Infiltration Capacity (VIC); Community Land Model, version 3 (CLM3); Snow Thermal Model (SNTHERM); and new field measurements from the Cold Land Processes Field Experiment (CLPX). Offline snow cover simulations using these five snow models with different physical complexity are performed for the Rabbit Ears Buffalo Pass (RB), Fraser Experimental Forest headquarters (FHQ), and Fraser Alpine (FA) sites between 20 September 2002 and 1 October 2003. These models simulate the snow accumulation and snowpack ablation with varying skill when forced with the same meteorological observations, initial conditions, and similar soil and vegetation parameters.
All five models capture the basic features of snow cover dynamics but show remarkable discrepancy in depicting snow accumulation and ablation, which could result from uncertain model physics and/or biased forcing. The simulated snow depth in SSiB during the snow accumulation period is consistent with the more complicated CLM3 and SNTHERM; however, early runoff is noted, owing to neglected water retention within the snowpack. Noah is consistent with SSiB in simulating snow accumulation and ablation at RB and FA, but at FHQ, Noah underestimates snow depth and snow water equivalent (SWE) as a result of a higher net shortwave radiation at the surface, resulting from the use of a small predefined maximum snow albedo. VIC and SNTHERM are in good agreement with each other, and they realistically reproduce snow density and net radiation. CLM3 is consistent with VIC and SNTHERM during snow accumulation, but it shows early snow disappearance at FHQ and FA. It is also noted that VIC, CLM3, and SNTHERM are unable to capture the observed runoff timing, even though the water storage and refreezing effects are included in their physics.
A set of sensitivity experiments suggest that Noah’s snow simulation is improved with a higher maximum albedo and that VIC exhibits little improvement with a larger fresh snow albedo. There are remarkable differences in the vegetation impact on snow simulation for each snow model. In the presence of forest cover, SSiB shows a substantial increase in snow depth and SWE, Noah and VIC show a slight change though VIC experiences a later onset of snowmelt, and CLM3 has a reduction in its snow depth. Finally, we observe that a refined precipitation dataset significantly improves snow simulation, emphasizing the importance of accurate meteorological forcing for land surface modeling.
Developing alternative masculinities as a strategy to address gender-based violence
Authors: Sathiparsad Reshma 
Published: April 2008

English This article discusses research using focus groups and personal interviews with rural male youth on gender-based violence. The findings revealed that many of the youth considered relationship violence acceptable, but the article highlights the fluid, multiple and contextual nature of masculinity that surfaced. The significance of these alternative responses for interventions is emphasized. French Cet article commente une recherche menée au moyen de groupes de discussion et d'entrevues personnelles auprès de jeunes hommes de milieux ruraux sur le sujet de la violence sexospécifique. Les résultats révèlent que bon nombre de ces jeunes considèrent acceptable la violence relationnelle, mais l'article met en relief la nature variable, multiple et contextuelle de la masculinité qui s'en est dégagée. L'accent est donc mis sur le sens de ces nouvelles réponses en intervention. Spanish Este artículo discute la investigación utilizando grupos focales y entrevistas personales, con jóvenes varones rurales, sobre violencia de género. Los hallazgos revelan que muchos de los jóvenes consideraron aceptable la violencia en las relaciones, pero el artículo destaca la naturaleza fluida, múltiple y contextual de la masculinidad que sale a la superficie. Se enfatiza la significación de estas respuestas alternativas para las intervenciones.
The intersection of cultural practices and ethics in a rights-based society
Authors: Ross Eleanor 
Published: April 2008

English This article interrogates various African cultural beliefs and practices, and advocates for the development of an indigenous Afro-centric model of social work to promote the healing process, and as a way of teaching social work students about the dilemmas inherent in respecting cultural practices which impinge on the rights of others. French Cet article se penche sur différentes croyances et pratiques culturelles africaines et plaide en faveur du développement d'un modèle de travail social propre à l'Afrique. Ce modèle permettrait non seulement de promouvoir le processus de guérison, mais aussi de sensibiliser les étudiants en travail social sur les dilemmes que suscite le respect des pratiques culturelles qui affectent les droits des autres. Spanish Este artículo cuestiona varias creencias y prácticas culturales africanas y aboga por el desarrollo de un modelo de trabajo social indígena Afro-céntrico, para promover el proceso terapéutico y como una forma de enseñanza en trabajo social acerca de los dilemas inherentes respecto de las prácticas culturales que afectan los derechos de otros.
Correlation between ethnicity and filial responsibility among three ethnic groups in Israel
Authors: Sultany Tom , Lavie Yotam , Haimov Iris 
Published: April 2008

English This study examines the association between ethnicity and culture to attitude toward filial responsibility in Israel. The results revealed that Ethiopian immigrant students scored significantly higher on all the dimensions. The study's results support the role of culture as an important factor in shaping perceptions of filial responsibilities toward aging parents. French Cette étude examine les liens qui existent entre l'origine ethnique, la culture et l'attitude envers la responsabilité filiale en Israël. Les résultants révèlent que les étudiants immigrants éthiopiens enregistrent des scores plus élevés dans toutes les dimensions. Les résultats de cette étude confirment que la culture est un facteur important dans la définition des perceptions de la responsabilité filiale à l'égard de parents âgés Spanish Este estudio examina la relación entre etnicidad y cultura en la actitud hacia la responsabilidad filial en Israel. Los resultados revelaron que los estudiantes etíopes inmigrantes obtuvieron una calificación significativamente más alta en todas las dimensiones. Los resultados del estudio respaldan el papel de la cultura como un factor importante en las formas de percepción de las responsabilidades filiales.
Placenta growth factor augments endothelin-1 and endothelin-B receptor expression via hypoxia-inducible factor-1α
Authors: Patel Nitin , Gonsalves Caryn S. , Malik Punam , Kalra Vijay K. 
Published: April 2008

AbstractPulmonary hypertension (PHT) develops in sickle cell disease (SCD) and is associated with high mortality. We previously showed that erythroid cells produce placenta growth factor (PlGF), which activates monocytes to induce proinflammatory cytochemokines, contributing to the baseline inflammation and severity in SCD. In this study, we observed that PlGF increased expression of endothelin-1 (ET-1) and endothelin-B receptor (ET-BR) from human pulmonary microvascular endothelial cells (HPMVECs) and monocytes, respectively. PlGF-mediated ET-1 and ET-BR expression occurred via activation of PI-3 kinase, reactive oxygen species and hypoxia inducible factor-1α (HIF-1α). PlGF increased binding of HIF-1α to the ET-1 and ET-BR promoters; this effect was abrogated with mutation of hypoxia response elements in the promoter regions and HIF-1α siRNA and confirmed by chromatin immunoprecipitation analysis. Furthermore, PlGF-mediated ET-1 release from HPMVECs and ET-BR expression in monocytes creates a PlGF–ET-1–ET-BR loop, leading to increased expression of MCP-1 and IL-8. Our studies show that PlGF-induced expression of the potent vasoconstrictor ET-1 and its cognate ET-BR receptor occur via activation of HIF-1α, independent of hypoxia. PlGF levels are intrinsically elevated from the increased red cell turnover in SCD and in other chronic anemia (eg, thalassemia) and may contribute to inflammation and PHT seen in these diseases.
K-OPLS package: Kernel-based orthogonal projections to latent structures for prediction and interpretation in feature space
Authors: Bylesjö Max , Rantalainen Mattias , Nicholson Jeremy K , Holmes Elaine , Trygg Johan 
Published: April 2008

AbstractBackgroundKernel-based classification and regression methods have been successfully applied to modelling a wide variety of biological data. The Kernel-based Orthogonal Projections to Latent Structures (K-OPLS) method offers unique properties facilitating separate modelling of predictive variation and structured noise in the feature space. While providing prediction results similar to other kernel-based methods, K-OPLS features enhanced interpretational capabilities; allowing detection of unanticipated systematic variation in the data such as instrumental drift, batch variability or unexpected biological variation.ResultsWe demonstrate an implementation of the K-OPLS algorithm for MATLAB and R, licensed under the GNU GPL and available athttp://www.sourceforge.net/projects/kopls/. The package includes essential functionality and documentation for model evaluation (using cross-validation), training and prediction of future samples. Incorporated is also a set of diagnostic tools and plot functions to simplify the visualisation of data, e.g. for detecting trends or for identification of outlying samples. The utility of the software package is demonstrated by means of a metabolic profiling data set from a biological study of hybrid aspen.ConclusionThe properties of the K-OPLS method are well suited for analysis of biological data, which in conjunction with the availability of the outlined open-source package provides a comprehensive solution for kernel-based analysis in bioinformatics applications.
A probe-treatment-reference (PTR) model for the analysis of oligonucleotide expression microarrays
Authors: Ge Huanying , Cheng Chao , Li Lei M 
Published: April 2008

AbstractBackgroundMicroarray pre-processing usually consists of normalization and summarization. Normalization aims to remove non-biological variations across different arrays. The normalization algorithms generally require the specification of reference and target arrays. The issue of reference selection has not been fully addressed. Summarization aims to estimate the transcript abundance from normalized intensities. In this paper, we consider normalization and summarization jointly by a new strategy of reference selection.ResultsWe propose a Probe-Treatment-Reference (PTR) model to streamline normalization and summarization by allowing multiple references. We estimate parameters in the model by the Least Absolute Deviations (LAD) approach and implement the computation by median polishing. We show that the LAD estimator is robust in the sense that it has bounded influence in the three-factor PTR model. This model fitting, implicitly, defines an "optimal reference" for each probe-set. We evaluate the effectiveness of the PTR method by two Affymetrix spike-in data sets. Our method reduces the variations of non-differentially expressed genes and thereby increases the detection power of differentially expressed genes.ConclusionOur results indicate that the reference effect is important and should be considered in microarray pre-processing. The proposed PTR method is a general framework to deal with the issue of reference selection and can readily be applied to existing normalization algorithms such as the invariant-set, sub-array and quantile method.