bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modeling cadmium accumulation in indigenous yellow perch (Perca flavescens)
Authors: Kraemer Lisa D. , Campbell Peter G.C. , Hare Landis 
Published: August 2008

We used field data from transplantation and caging studies with juvenile yellow perch ( Perca flavescens ) to test a kinetic bioaccumulation model for cadmium (Cd). The model, which considers both dietary and aqueous sources of Cd, was first used to predict the dynamics of Cd accumulation in perch exposed to high ambient Cd for 70 days. Model simulations for hepatic Cd agreed well with the observed time course of Cd accumulation in the liver, but for the gills and gut, the predicted accumulations after 70 days were about three times higher than the observed values, suggesting that these latter organs can alter their ability to take up and (or) eliminate Cd. The model was also used to predict steady-state Cd concentrations in the gills, gut, and liver of perch living in lakes along a Cd gradient. Agreement between predicted and observed steady-state Cd concentrations was reasonable in lakes with low to moderate Cd concentrations, but in lakes with high dissolved Cd (>1.5 nmol·L–1), the model overestimated Cd accumulation, particularly in the gills and gut. These results suggest that kinetic bioaccumulation models may better apply to some organs than to others. Because metal-induced toxicity is normally organ-specific, their application in a risk assessment context should be undertaken with caution.
A modified approach for determination of nonlinear properties in seismic response analyses for 200 m high core rock-fill dams
Authors: Li Hongjun , Chi Shichun , Lin Gao , Zhong Hong 
Published: August 2008

Equivalent linear analyses are widely used for estimation of site response and safety status of rock-fill dams subjected to strong earthquakes. However, the average normalized curves incorporated in the equivalent-linear iterative process cannot precisely depict the variations of dynamic parameters with shearing strain for one type of soil material under a wide range of confining pressures. Thus, a modified approach for the determination of nonlinear properties for soil elements confined under a broad range of effective pressures in site response analyses for high rock-fill dams (>200 m) is proposed. In this approach, the normalized confining-pressure-interpolating curves (CPI curves) of each soil element under different effective stress are obtained by linearly interpolating or extrapolating by its in situ stress. By comparing the results obtained by equivalent linear analyses incorporating the average curves and the CPI curves, respectively, the impact of utilizing the recommended curves when determining nonlinear soil properties on site response analyses of high rock-fill dams (>200 m) is discussed. It is shown that the refinement in the determination of nonlinear properties during site response can be utilized in the near future by incorporating the results of this study in practice.
Clogging of unsaturated gravel permeated with landfill leachate
Authors: McIsaac Reagan , Rowe R. Kerry 
Published: August 2008

The results of an experimental investigation into the clogging of unsaturated, uniformly graded 50 mm gravel permeated with municipal solid waste landfill leachate are reported. The flow of leachate within the unsaturated gravel was heterogeneous and occurred in free-draining flow pathways. The leachate experienced reductions in the concentrations of both the organic and inorganic constituents after passing through the unsaturated gravel although there was very little clogging within the unsaturated gravel. The average drainable porosity was reduced by 8% after 8 years permeation. The biofilm was limited to areas on the gravel where leachate could be retained; predominantly on top of lateral gravel surfaces and near particle-to-particle contacts. As a result, only a small fraction of the total surface area of the unsaturated gravel was covered with biofilm. The short leachate retention time and the sporadic distribution of biofilm limited the degree of contact between the bacteria and the leachate and hence limited biologically induced clogging within the unsaturated gravel. The data suggest that leachate collection systems should be designed and operated such that the drainage material of the leachate collection system remains unsaturated for as long as possible.
A Pivotal Role for Heat Shock Protein 90 in Ewing Sarcoma Resistance to Anti-Insulin-like Growth Factor 1 Receptor Treatment:In vitroandIn vivoStudy
Authors: Martins Ana Sofia , Ordoñez José Luis , García-Sánchez Alfredo , Herrero David , Sevillano Victoria , Osuna Daniel , Mackintosh Carlos , Caballero Gemma , Otero Ana Pastora , Poremba Christopher , Madoz-Gúrpide Juan , de Alava Enrique 
Published: August 2008

AbstractEwing Sarcoma (ES) shows several deregulated autocrine loops mediating cell survival and proliferation. Therefore, their blockade is a promising therapeutic approach. We previously reported the in vitro effect of insulin-like growth factor 1 receptor (IGF1R)/KIT pathway blockade on ES cell lines, and we now extend our observations to changes induced by this treatment in interacting proteins/networks. A proteomic analysis revealed that Heat Shock Protein (HSP)90 was differentially expressed between ES cell lines sensitive and resistant to specific IGF1R/KIT inhibitors. We therefore inhibited HSP90 with 17-allylamino-17-demethoxygeldanamycin (17-AAG) and siRNA, and observed that ES cell line growth and survival were reduced, especially in the resistant cell lines. Conversely, HSP90 induced–expression conferred resistance to anti-IGF1R/KIT treatment in the sensitive cell lines. 17-AAG treatment induced HSP90 client protein degradation, including AKT, KIT, or IGF1R, by inhibiting their physical interaction with HSP90. Xenograft models developed with A673 ES cell line confirmed that HSP90 inhibition, alone or combined with IGF1R inhibition, significantly reduced tumor growth and expression of client proteins. Remarkably, using two independent clinical sample sets, we have found that nearly half of IGF1R-positive tumors also show HSP90 overexpression. This delineates a subset of patients that could benefit from combination of anti-HSP90 agents when considering IGF1R-targeting therapies. Importantly, sensitivity to drugs such as ADW/IMA depends not only on the levels of expression and basal activation of IGF1R/KIT, but also, and for the first time reported in ES, on the development of the stress response mechanism. Accordingly, HSP90 expression could be a predictive factor of response to IGF1R-targeting therapies. [Cancer Res 2008;68(15):6260–70]
Cyclic AMP Response Element-Binding Protein Overexpression: A Feature Associated with Negative Prognosis in Never Smokers with Non–Small Cell Lung Cancer
Authors: Seo Hye-Sook , Liu Diane D. , Bekele B. Nebiyou , Kim Mi-Kyoung , Pisters Katherine , Lippman Scott M. , Wistuba Ignacio I. , Koo Ja Seok 
Published: August 2008

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Recent advances in targeted therapies hold promise for the development of new treatments for certain subsets of cancer patients by targeting specific signaling molecule. Based on the identification of the transcription factor cyclic AMP response element-binding protein (CREB) as an important regulator of growth of several types of cancers and our recent findings of its importance in normal differentiation of bronchial epithelial cells, we hypothesized that CREB plays an important pathobiologic role in lung carcinogenesis. We conducted this initial study to determine whether the expression and activation status of CREB are altered in non–small cell lung cancer (NSCLC) and of any prognostic importance in NSCLC patients. We found that the expression levels of mRNA and protein of CREB and phosphorylated CREB (p-CREB) were significantly higher in most of the NSCLC cell lines and tumor specimens than in the normal human tracheobronchial epithelial cells and adjacent normal lung tissue, respectively. Analysis of CREB mRNA expression and the CREB gene copy number showed that CREB overexpression occurred mainly at the transcriptional level. Immunohistochemical analysis of tissue microarray slides containing sections of NSCLC specimens obtained from 310 patients showed that a decreased survival duration was significantly associated with overexpression of CREB or p-CREB in never smokers but not in current or former smokers with NSCLC. These are the first reported results illustrating the potential of CREB as a molecular target for the prevention and treatment of NSCLC, especially in never smokers. [Cancer Res 2008;68(15):6065–73]
Androgen Levels Increase by Intratumoral De novo Steroidogenesis during Progression of Castration-Resistant Prostate Cancer
Authors: Locke Jennifer A. , Guns Emma S. , Lubik Amy A. , Adomat Hans H. , Hendy Stephen C. , Wood Catherine A. , Ettinger Susan L. , Gleave Martin E. , Nelson Colleen C. 
Published: August 2008

Abstract
Although systemic androgen deprivation prolongs life in advanced prostate cancer, remissions are temporary because patients almost uniformly progress to a state of a castration-resistant prostate cancer (CRPC) as indicated by recurring PSA. This complex process of progression does not seem to be stochastic as the timing and phenotype are highly predictable, including the observation that most androgen-regulated genes are reactivated despite castrate levels of serum androgens. Recent evidence indicates that intraprostatic levels of androgens remain moderately high following systemic androgen deprivation therapy, whereas the androgen receptor (AR) remains functional, and silencing the AR expression following castration suppresses tumor growth and blocks the expression of genes known to be regulated by androgens. From these observations, we hypothesized that CRPC progression is not independent of androgen-driven activity and that androgens may be synthesized de novo in CRPC tumors leading to AR activation. Using the LNCaP xenograft model, we showed that tumor androgens increase during CRPC progression in correlation to PSA up-regulation. We show here that all enzymes necessary for androgen synthesis are expressed in prostate cancer tumors and some seem to be up-regulated during CRPC progression. Using an ex vivo radiotracing assays coupled to high-performance liquid chromatography-radiometric/mass spectrometry detection, we show that tumor explants isolated from CRPC progression are capable of de novo conversion of [14C]acetic acid to dihydrotestosterone and uptake of [3H]progesterone allows detection of the production of six other steroids upstream of dihydrotestosterone. This evidence suggests that de novo androgen synthesis may be a driving mechanism leading to CRPC progression following castration. [Cancer Res 2008;68(15):6407–15]
Loss of MLL PHD Finger 3 Is Necessary for MLL-ENL–Induced Hematopoietic Stem Cell Immortalization
Authors: Chen Jing , Santillan Donna A. , Koonce Mark , Wei Wei , Luo Roger , Thirman Michael J. , Zeleznik-Le Nancy J. , Diaz Manuel O. 
Published: August 2008

Abstract
Reciprocal chromosomal translocations at the MLL gene locus result in expression of novel fusion proteins, such as MLL-ENL, associated with leukemia. The three PHD finger cassette, one of the highly conserved domains in MLL, is absent in all fusion proteins. This domain has been shown to interact with Cyp33, a cyclophilin which enhances the recruitment of histone deacetylases (HDAC) to the MLL repression domain and mediates HOX gene repression. Insertion of the third PHD finger of MLL into MLL-ENL allows the recruitment of Cyp33 and, subsequently, HDAC1 to the fusion protein. Furthermore, expression of the fusion protein with the PHD finger insertion mediates the down-regulation of the HOXC8 gene expression in a Cyp33-dependent manner. Finally, the addition of the PHD finger domain or the third PHD finger alone into MLL-ENL blocks the hematopoietic stem cell immortalization potential of the fusion protein in serial plating colony assays. Insertion of only the first and second PHD fingers has no such effect. These data support the hypothesis that the binding of Cyp33 to the MLL third PHD finger switches the MLL function from transactivation to repression. In the immortalizing MLL fusion protein, the loss of the PHD fingers, in combination with the gain of the activation domain of ENL or of other partner proteins, makes the fusion protein a constitutive transactivator. This leads to constitutive overexpression of MLL target genes that block stem cell commitment and promote stem cell renewal, probably the first step in MLL-related leukemogenesis. [Cancer Res 2008;68(15):6199–207]
Oxidative Stress Plays a Critical Role in Inactivating Mutant BRAF by Geldanamycin Derivatives
Authors: Fukuyo Yayoi , Inoue Masahiro , Nakajima Takuma , Higashikubo Ryuji , Horikoshi Nobuko T. , Hunt Clayton , Usheva Anny , Freeman Michael L. , Horikoshi Nobuo 
Published: August 2008

Abstract
The geldanamycin derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are promising chemotherapeutic drugs that inhibit heat shock protein 90 (HSP90) function. Previous studies have shown that 17-AAG/DMAG treatment induces the degradation of mutant BRAF (V600E) and inhibits the activation of mitogen-activated protein/extracellular signal-regulated kinase 1/2 (MEK1/2). We have found, however, that HSP90 inhibition alone is not sufficient for efficient BRAF(V600E) degradation in some cells. HSP90 inhibitors structurally unrelated to geldanamycin, radicicol and novobiocin, while inducing the degradation of the HSP90 client protein RAF-1 fail to induce BRAF(V600E) degradation or inhibit MEK1/2 activation in HT29 human colon cancer cells. Moreover, after treatment with 17-DMAG, the kinase activity of residual, undegraded BRAF(V600E) was also lost. Incubation of cells with a reactive oxygen species (ROS) scavenger, N-acetyl cysteine, partially restored kinase activity and also partially prevented BRAF(V600E) degradation due to 17-DMAG treatment. Conversely, treatment with the ROS producing drug menadione clearly inhibited MEK1/2 and reduced BRAF(V600E). These results suggest that in addition to direct inhibition of HSP90, the antitumor effect of geldanamycin and its derivatives is also mediated though the production of ROS, which may directly inactivate tumorigenic mutant BRAF(V600E). [Cancer Res 2008;68(15):6324–30]
Defective Transcription/Repair Factor IIH Recruitment to Specific UV Lesions in Trichothiodystrophy Syndrome
Authors: Chiganças Vanessa , Lima-Bessa Keronninn M. , Stary Anne , Menck Carlos F.M. , Sarasin Alain 
Published: August 2008

Abstract
Most trichothiodystrophy (TTD) patients present mutations in the xeroderma pigmentosum D (XPD) gene, coding for a subunit of the transcription/repair factor IIH (TFIIH) complex involved in nucleotide excision repair (NER) and transcription. After UV irradiation, most TTD/XPD patients are more severely affected in the NER of cyclobutane pyrimidine dimers (CPD) than of 6-4-photoproducts (6-4PP). The reasons for this differential DNA repair defect are unknown. Here we report the first study of NER in response to CPDs or 6-4PPs separately analyzed in primary fibroblasts. This was done by using heterologous photorepair; recombinant adenovirus vectors carrying photolyases enzymes that repair CPD or 6-4PP specifically by using the energy of light were introduced in different cell lines. The data presented here reveal that some TTD/XPD mutations affect the recruitment of TFIIH specifically to CPDs, but not to 6-4PPs. This deficiency is further confirmed by the inability of TTD/XPD cells to recruit, specifically for CPDs, NER factors that arrive in a TFIIH-dependent manner later in the NER pathway. For 6-4PPs, we show that TFIIH complexes carrying an NH2-terminal XPD mutated protein are also deficient in recruitment of NER proteins downstream of TFIIH. Treatment with the histone deacetylase inhibitor trichostatin A allows the recovery of TFIIH recruitment to CPDs in the studied TTD cells and, for COOH-terminal XPD mutations, increases the repair synthesis and survival after UV, suggesting that this defect can be partially related with accessibility of DNA damage in closed chromatin regions. [Cancer Res 2008;68(15):6074–83]
Tumor-Associated MICA Is Shed by ADAM Proteases
Authors: Waldhauer Inja , Goehlsdorf Dennis , Gieseke Friederike , Weinschenk Toni , Wittenbrink Mareike , Ludwig Andreas , Stevanovic Stefan , Rammensee Hans-Georg , Steinle Alexander 
Published: August 2008

Abstract
The immunoreceptor NKG2D promotes immunosurveillance of malignant cells and protects the host from tumor initiation by activating natural killer cells and costimulating CD8 T cells. NKG2D-mediated recognition of malignant cells by cytotoxic lymphocytes is enabled through the tumor-associated expression of NKG2D ligands (NKG2DL) resulting from cellular or genotoxic stress. Shedding of NKG2DL is thought to constitute a major countermechanism of tumor cells to subvert NKG2D-mediated immunosurveillance. Here, we report that the prototypical NKG2DL MICA is released by proteolytic cleavage in the stalk of the MICA ectodomain, where deletions, but not alanine substitutions, impede MICA shedding. Small compound-mediated stimulation and inhibition of MICA shedding adduced characteristics that indicated an involvement of members of the “a disintegrin and metalloproteinase” (ADAM) family. Accordingly, MICA shedding by tumor cells was inhibited by silencing of the related ADAM10 and ADAM17 proteases, which are known to promote tumor growth by releasing epidermal growth factor receptor ligands. Collectively, our data show that ADAM10 and ADAM17 are critically involved in the tumor-associated proteolytic release of soluble MICA facilitating tumor immune escape. Hence, therapeutic blockade of ADAM10 and ADAM17 seems promising for cancer treatment by targeting both growth and immune escape of tumors. [Cancer Res 2008;68(15):6368–76]
A Small-Molecule E2F Inhibitor Blocks Growth in a Melanoma Culture Model
Authors: Ma Yihong , Kurtyka Courtney A. , Boyapalle Sandhya , Sung Shen-Shu , Lawrence Harshani , Guida Wayne , Cress W. Douglas 
Published: August 2008

Abstract
HLM006474 was identified using a computer-based virtual screen and the known crystal structure of the DNA-bound E2F4/DP2 heterodimer. Treatment of multiple cell lines with HLM006474 resulted in the loss of intracellular E2F4 DNA-binding activity as measured by electrophoretic mobility shift assay within hours. Overnight exposure to HLM006474 resulted in down-regulation of total E2F4 protein as well as known E2F targets. The effects of HLM006474 treatment on different cell lines varied but included a reduction in cell proliferation and an increase in apoptosis. HLM006474 induced apoptosis in a manner distinct from cisplatin and doxorubicin. E2F4-null mouse embryonic fibroblasts were less sensitive than wild-type counterparts to the apoptosis-inducing activity of the compound, revealing its biological specificity. A375 cells were extremely sensitive to the apoptosis-inducing activity of the compound in two-dimensional culture, and HLM006474 was a potent inhibitor of melanocytes proliferation and subsequent invasion in a three-dimensional tissue culture model system. Together, these results suggest that interference with E2F activity using small molecules may have clinical application in cancer therapy. [Cancer Res 2008;68(15):6292–9]
A Six-Gene Signature Predicting Breast Cancer Lung Metastasis
Authors: Landemaine Thomas , Jackson Amanda , Bellahcène Akeila , Rucci Nadia , Sin Soraya , Abad Berta Martin , Sierra Angels , Boudinet Alain , Guinebretière Jean-Marc , Ricevuto Enrico , Noguès Catherine , Briffod Marianne , Bièche Ivan , Cherel Pascal , Garcia Teresa , Castronovo Vincent , Teti Anna , Lidereau Rosette , Driouch Keltouma 
Published: August 2008

Abstract
The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular mechanisms are unclear. All existing data were obtained either using statistical association between gene expression measurements found in primary tumors and clinical outcome, or using experimentally derived signatures from mouse tumor models. Here, we describe a distinct approach that consists of using tissue surgically resected from lung metastatic lesions and comparing their gene expression profiles with those from nonpulmonary sites, all coming from breast cancer patients. We show that the gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in breast cancer. We identified a set of 21 lung metastasis–associated genes. Using a cohort of 72 lymph node–negative breast cancer patients, we developed a 6-gene prognostic classifier that discriminated breast primary cancers with a significantly higher risk of lung metastasis. We then validated the predictive ability of the 6-gene signature in 3 independent cohorts of breast cancers consisting of a total of 721 patients. Finally, we show that the signature improves risk stratification independently of known standard clinical variables and a previously established lung metastasis signature based on an experimental breast cancer metastasis model. [Cancer Res 2008;68(15):6092–9]
Differential Cellular Internalization of Anti-CD19 and -CD22 Immunotoxins Results in Different Cytotoxic Activity
Authors: Du Xing , Beers Richard , FitzGerald David J. , Pastan Ira 
Published: August 2008

AbstractB-cell malignancies routinely express surface antigens CD19 and CD22. Immunotoxins against both antigens have been evaluated, and the immunotoxins targeting CD22 are more active. To understand this disparity in cytotoxicity and guide the screening of therapeutic targets, we compared two immunotoxins, FMC63(Fv)-PE38–targeting CD19 and RFB4(Fv)-PE38 (BL22)–targeting CD22. Six lymphoma cell lines have 4- to 9-fold more binding sites per cell for CD19 than for CD22, but BL22 is 4- to 140-fold more active than FMC63(Fv)-PE38, although they have a similar cell binding affinity (Kd, ∼7 nmol/L). In 1 hour, large amounts of BL22 are internalized (2- to 3-fold more than the number of CD22 molecules on the cell surface), whereas only 5.2% to 16.6% of surface-bound FMC63(Fv)-PE38 is internalized. The intracellular reservoir of CD22 decreases greatly after immunotoxin internalization, indicating that it contributes to the uptake of BL22. Treatment of cells with cycloheximide does not reduce the internalization of BL22. Both internalized immunotoxins are located in the same vesicles. Our results show that the rapid internalization of large amounts of BL22 bound to CD22 makes CD22 a better therapeutic target than CD19 for immunotoxins and probably for other immunoconjugates that act inside cells. [Cancer Res 2008;68(15):6300–5]