bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Glutamate Cysteine Ligase Activity Sensitizes Human Breast Cancer Cells to the Toxicity of 2-Deoxy-d-Glucose
Authors: Andringa Kelly K. , Coleman Mitchell C. , Aykin-Burns Nukhet , Hitchler Michael J. , Walsh Susan A. , Domann Frederick E. , Spitz Douglas R. 
Published: February 2006

Abstract
It has been hypothesized that cancer cells increase glucose metabolism to protect against metabolic fluxes of hydroperoxides via glutathione-dependent peroxidases. 2-Deoxy-d-glucose, inhibits glucose metabolism and has been shown to cause cytotoxicity in cancer cells that is partially mediated by disruptions in thiol metabolism. In the current study, human breast cancer cells were continuously treated (24 hours) with 2-deoxy-d-glucose, and total glutathione content as well as the expression of the first enzyme in the glutathione synthetic pathway [glutamate cysteine ligase (GCL)] were found to be induced 2.0-fold. Inhibiting GCL activity during 2-deoxy-d-glucose exposure using l-buthionine-[S,R]-sulfoximine (BSO) significantly enhanced the cytotoxic effects of 2-deoxy-d-glucose and caused increases in endpoints indicative of oxidative stress, including % oxidized glutathione and steady-state levels of pro-oxidants as assayed using an oxidation-sensitive fluorescent probe. These results show that treatment of human breast cancer cells with 2-deoxy-d-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of GCL mRNA, GCL activity, and glutathione content. Furthermore, inhibition of 2-deoxy-d-glucose–mediated induction of GCL activity with BSO increases endpoints indicative of oxidative stress and sensitizes cancer cells to 2-deoxy-d-glucose–induced cytotoxicity. These results support the hypothesis that drug combinations capable of inhibiting both glucose and hydroperoxide metabolism may provide an effective biochemical strategy for sensitizing human cancer cells to metabolic oxidative stress. (Cancer Res 2006; 66(3): 1605-10)
Discovering Clinical Biomarkers of Ionizing Radiation Exposure with Serum Proteomic Analysis
Authors: Ménard Cynthia , Johann Donald , Lowenthal Mark , Muanza Thierry , Sproull Mary , Ross Sally , Gulley James , Petricoin Emanuel , Coleman C. Norman , Whiteley Gordon , Liotta Lance , Camphausen Kevin 
Published: February 2006

AbstractIn this study, we sought to explore the merit of proteomic profiling strategies in patients with cancer before and during radiotherapy in an effort to discover clinical biomarkers of radiation exposure. Patients with a diagnosis of cancer provided informed consent for enrollment on a study permitting the collection of serum immediately before and during a course of radiation therapy. High-resolution surface-enhanced laser desorption and ionization-time of flight (SELDI-TOF) mass spectrometry (MS) was used to generate high-throughput proteomic profiles of unfractionated serum samples using an immobilized metal ion-affinity chromatography nickel-affinity chip surface. Resultant proteomic profiles were analyzed for unique biomarker signatures using supervised classification techniques. MS-based protein identification was then done on pooled sera in an effort to begin to identify specific protein fragments that are altered with radiation exposure. Sixty-eight patients with a wide range of diagnoses and radiation treatment plans provided serum samples both before and during ionizing radiation exposure. Computer-based analyses of the SELDI protein spectra could distinguish unexposed from radiation-exposed patient samples with 91% to 100% sensitivity and 97% to 100% specificity using various classifier models. The method also showed an ability to distinguish high from low dose-volume levels of exposure with a sensitivity of 83% to 100% and specificity of 91% to 100%. Using direct identity techniques of albumin-bound peptides, known to underpin the SELDI-TOF fingerprints, 23 protein fragments/peptides were uniquely detected in the radiation exposure group, including an interleukin-6 precursor protein. The composition of proteins in serum seems to change with ionizing radiation exposure. Proteomic analysis for the discovery of clinical biomarkers of radiation exposure warrants further study. (Cancer Res 2006; 66(3): 1844-50)
The Immunomodulatory Benzodiazepine Bz-423 Inhibits B-Cell Proliferation by Targeting c-Myc Protein for Rapid and Specific Degradation
Authors: Sundberg Thomas B. , Ney Gina M. , Subramanian Chitra , Opipari Anthony W. , Glick Gary D. 
Published: February 2006

Abstract
Myc proteins regulate cell growth and are oncogenic in many cancers. Although these proteins are validated molecular anticancer targets, new therapies aimed at modulating myc have yet to emerge. A benzodiazepine (Bz-423) that was discovered in efforts to find new drugs for lupus was found recently to have antiproliferative effects on Burkitt's lymphoma cells. We now show that the basis for the antiproliferative effects of Bz-423 is the rapid and specific depletion of c-myc protein, which is coupled to growth-suppressing effects on key regulators of proliferation and cell cycle progression. c-Myc is depleted as a result of signals coupled to Bz-423 binding its molecular target, the oligomycin sensitivity-conferring protein subunit of the mitochondrial F1Fo-ATPase. Bz-423 inhibits F1Fo-ATPase activity, blocking respiratory chain function and generating superoxide, which at growth-inhibiting concentrations triggers proteasomal degradation of c-myc. Bz-423-induced c-myc degradation is independent of glycogen synthase kinase but is substantially blocked by mutation of the phosphosensitive residue threonine 58, which when phosphorylated targets c-myc for ubiquitination and subsequent proteasomal degradation. Collectively, this work describes a new lead compound, with drug-like properties, which regulates c-myc by a novel molecular mechanism that may be therapeutically useful. (Cancer Res 2006; 66(3): 1775-82)
Syrian Hamster as a Permissive Immunocompetent Animal Model for the Study of Oncolytic Adenovirus Vectors
Authors: Thomas Maria A. , Spencer Jacqueline F. , La Regina Marie C. , Dhar Debanjan , Tollefson Ann E. , Toth Karoly , Wold William S.M. 
Published: February 2006

Abstract
Oncolytic adenoviruses represent an innovative approach to cancer therapy. These vectors are typically evaluated in immunodeficient mice with human xenograft tumors. However, in addition to being immunodeficient, this model is limited because normal and cancerous mouse tissues are poorly permissive for human adenovirus replication. This prompted us to search for a model that more accurately reflects the use of oncolytic adenoviruses in cancer patients. To this end, we developed a novel Syrian hamster model that is both immunocompetent and replication-permissive. We found that human adenovirus replicates well in Syrian hamster cell lines and confirmed replication in the lungs. Oncolytic adenovirus injection showed efficacy in three different hamster tumor models. Furthermore, i.t. oncolytic adenovirus injection resulted in suppression of primary and metastatic lesions, i.t. replication and necrosis, vector entrance into the bloodstream, replication in the liver and lungs, and anti-adenovirus antibody induction. Our findings show that the Syrian hamster is a promising immunocompetent model that is permissive to human adenovirus replication in tumors as well as normal tissues. Therefore, the Syrian hamster model may become a valuable tool for the field of oncolytic adenovirus vectors in which vector safety and efficacy can be evaluated. (Cancer Res 2006; 66(3): 1270-6)
Urogenital Carcinogenesis in Female CD1 Mice Induced by In utero Arsenic Exposure Is Exacerbated by Postnatal Diethylstilbestrol Treatment
Authors: Waalkes Michael P. , Liu Jie , Ward Jerrold M. , Powell Douglas A. , Diwan Bhalchandra A. 
Published: February 2006

Abstract
Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 μg/pup/d) or tamoxifen (10 μg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor-α (ER-α) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-α expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers. (Cancer Res 2006; 66(3): 1337-45)
Cofactor of BRCA1: A Novel Transcription Factor Regulator in Upper Gastrointestinal Adenocarcinomas
Authors: McChesney Patricia A. , Aiyar Sarah E. , Lee Ok-Jae , Zaika Alexander , Moskaluk Christopher , Li Rong , El-Rifai Wa'el 
Published: February 2006

Abstract
Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs. Immunohistochemical analysis of UGC tissue arrays that contained 70 tumor samples showed moderate-strong staining for COBRA1 in 60 (84%) tumors. Interestingly, the tumor samples showed absent-weak staining for TFF1 in 45 (65%) of the tumors. Simultaneous loss of TFF1 expression and overexpression of COBRA1 was observed in 42 of 70 (60%) tumors. Using small interfering RNA technology with gastric cancer cells, we have shown that COBRA1 inhibition leads to increased TFF1 promoter activity and gene expression. Promoter analysis of TFF1 indicated that regulation of TFF1 by COBRA1 is estrogen independent in contrast to breast cancer. Moreover, COBRA1 regulation of TFF1 in gastric cancer cells was independent of NELF-E. Using several truncated mutants and site mutants of the TFF1 promoter, we have shown that COBRA1 can negatively regulate the activator protein-1 (AP-1) complex at the TFF1 promoter and thus down-regulate TFF1 expression in gastric cancer cell lines. Electrophoretic mobility shift assay showed that COBRA1 attenuates AP-1 binding to DNA. Our results suggest COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia. (Cancer Res 2006; 66(3): 1346-53)
Rapid Alteration of MicroRNA Levels by Histone Deacetylase Inhibition
Authors: Scott Gary K. , Mattie Michael D. , Berger Crystal E. , Benz Stephen C. , Benz Christopher C. 
Published: February 2006

Abstract
Improved understanding of the molecular mechanisms by which small-molecule inhibitors of histone deacetylases (HDAC) induce programs, such as cellular differentiation and apoptosis, would undoubtedly assist their clinical development as anticancer agents. As modulators of gene transcript levels, HDAC inhibitors (HDACi) typically affect only 5% to 10% of actively transcribed genes with approximately as many mRNA transcripts being up-regulated as down-regulated. Using microRNA (miRNA) array analysis, we report rapid alteration of miRNA levels in response to the potent hydroxamic acid HDACi LAQ824 in the breast cancer cell line SKBr3. Within 5 hours of exposure to a proapoptotic dose of LAQ824, significant changes were measured in 40% of the &gt;60 different miRNA species expressed in SKBr3 cells with 22 miRNA species down-regulated and 5 miRNAs up-regulated. To explore a potential functional link between HDACi induced mRNA up-regulation and miRNA down-regulation, antisense experiments were done against miR-27a and miR-27b, both abundantly expressed and down-regulated in SKBr3 cells by LAQ824. Correlating a set of genes previously determined by cDNA array analysis to be rapidly up-regulated by LAQ824 in SKBr3 with a database of potential 3′ untranslated region miRNA binding elements, two genes containing putative miR-27 anchor elements were identified as transcriptionally up-regulated following miR-27 antisense transfection, ZBTB10/RINZF, a Sp1 repressor, and RYBP/DEDAF, an apoptotic facilitator. These findings emphasize the importance of post-transcriptional mRNA regulation by HDACi in addition to their established effects on promoter-driven gene expression. (Cancer Res 2006; 66(3): 1277-81)
Targeting Heat Shock Response to Sensitize Cancer Cells to Proteasome and Hsp90 Inhibitors
Authors: Zaarur Nava , Gabai Vladimir L. , Porco John A. , Calderwood Stuart , Sherman Michael Y. 
Published: February 2006

Abstract
Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression of such induction may sensitize cancer cells to these drugs. Here, we knocked out the major heat shock transcription factor HSF-1 in several cancer cell lines using small interfering RNA and showed that such cells, which can no longer induce Hsps in response to proteasome and Hsp90 inhibitors, become more sensitive to these drugs. Furthermore, we developed a high-throughput screen for small molecules that inhibit induction of Hsps. The first step was a cell-based screen for inhibitors of Hsps-mediated luciferase refolding followed by a counterscreen for toxicity. The second step was a direct testing for inhibition of Hsp induction by immunoblotting with anti-Hsp72 antibody. After screening of 20,000 compounds from several diversity libraries, we focused on a compound we called NZ28, which potently inhibited induction of Hsps by heat shock, proteasome, and Hsp90 inhibitors in a variety of cell lines, and showed no significant toxicity. After testing of a set of analogues of NZ28, we identified a structural element that was critical for the activity. We also identified another inhibitor of the Hsp induction that was practically nontoxic. This compound, which we called emunin, strongly sensitized myeloma cells to proteasome and Hsp90 inhibitors and prostate carcinoma cells to proteasome inhibitors. This work indicates that targeting the heat shock response may facilitate use of proteasome and Hsp90 inhibitors for cancer treatment. (Cancer Res 2006; 66(3): 1783-91)
Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas
Authors: Hendrix Neali D. , Wu Rong , Kuick Rork , Schwartz Donald R. , Fearon Eric R. , Cho Kathleen R. 
Published: February 2006

Abstract
Wnt signaling plays a key role in development and adult tissues via effects on cell proliferation, motility, and differentiation. The cellular response to Wnt ligands largely depends on their ability to stabilize β-catenin and the ability of β-catenin to bind and activate T-cell factor (TCF) transcription factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have constitutive activation of Wnt signaling as a result of oncogenic mutations in the β-catenin protein or inactivating mutations in key negative regulators of β-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor proteins. We used oligonucleotide microarrays to identify genes of which expression was activated in OEAs with β-catenin dysregulation compared with OEAs lacking Wnt/β-catenin pathway defects. Using microarray and quantitative PCR-based approaches, we found that fibroblast growth factor (FGF9) expression was increased &gt;6-fold in primary OEAs with Wnt/β-catenin pathway defects compared with OEAs lacking such defects. Evidence that β-catenin and TCFs regulate FGF9 expression in several epithelial cell lines was obtained. We found FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate invasion of epithelial and endothelial cells through Matrigel in transwell assays. Furthermore, FGF9 could promote neoplastic transformation of the E1A-immortalized RK3E epithelial cell line, and short hairpin RNA–mediated inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which carries a β-catenin mutation, inhibited neoplastic growth properties of the cells. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/β-catenin pathway defects. (Cancer Res 2006; 66(3): 1354-62)
Observations of the 11 June Dryline during IHOP_2002—A Null Case for Convection Initiation
Authors: Cai Huaqing , Lee Wen-Chau , Weckwerth Tammy M. , Flamant Cyrille , Murphey Hanne V. 
Published: February 2006

Abstract
The detailed analysis of the three-dimensional structure of a dryline observed over the Oklahoma panhandle during the International H2O Project (IHOP_2002) on 11 June 2002 is presented. High-resolution observations obtained from the National Center for Atmospheric Research Electra Doppler Radar (ELDORA), S-band dual-polarization Doppler radar (S-Pol), water vapor differential absorption lidar (DIAL) Lidar pour l'Etude des Interactions Aérosols Nuages Dynamique Rayonnement et du Cycle de l'Eau (LEANDRE II; translated as Lidar for the Study of Aerosol–Cloud–Dynamics–Radiation Interactions and of the Water Cycle) as well as Learjet dropsondes are used to reveal the evolution of the dryline structure during late afternoon hours when the dryline was retreating to the northwest. The dryline reflectivity shows significant variability in the along-line direction. Dry air was observed to overrun the moist air in vertical cross sections similar to a density current. The updrafts associated with the dryline were 2–3 m s−1 and were able to initiate boundary-layer-based clouds along the dryline. The formation of this dryline was caused by high equivalent potential temperature air pushing northwestward toward a stationary front in the warm sector.
Middle-level clouds with radar reflectivity greater than 18 dBZe near the dryline were detected by ELDORA. A roll boundary, which was associated with larger convergence and moisture content, was evident in the S-Pol data. It is found that the instability parameters most favorable for convection initiation were actually associated with the roll boundary, not the dryline. A storm was initiated near the roll boundary probably as a result of the combination of the favorable instability parameters and stronger upward forcing. It is noted that both the 11 June 2002 dryline and the roll boundary presented in this paper would not be identified if the special datasets from IHOP_2002 were not available.
Although all model runs [fifth-generation Pennsylvania State University–NCAR Mesoscale Model (MM5), Meso Eta, and Rapid Update Cycle (RUC)] suggested deep convection over the Oklahoma panhandle and several cloud lines were observed near the dryline, the dryline itself did not initiate any storms. The reasons why the dryline failed to produce any storm inside the IHOP_2002 intensive observation region are discussed. Both synoptic-scale and mesoscale conditions that were detrimental to convection initiation in this case are investigated in great detail.
The Dryline on 22 May 2002 during IHOP_2002: Convective-Scale Measurements at the Profiling Site
Authors: Demoz Belay , Flamant Cyrille , Weckwerth Tammy , Whiteman David , Evans Keith , Fabry Frédéric , Di Girolamo Paolo , Miller David , Geerts Bart , Brown William , Schwemmer Geary , Gentry Bruce , Feltz Wayne , Wang Zhien 
Published: February 2006

Abstract
A detailed analysis of the structure of a double dryline observed over the Oklahoma panhandle during the first International H2O Project (IHOP_2002) convective initiation (CI) mission on 22 May 2002 is presented. A unique and unprecedented set of high temporal and spatial resolution measurements of water vapor mixing ratio, wind, and boundary layer structure parameters were acquired using the National Aeronautics and Space Administration (NASA) scanning Raman lidar (SRL), the Goddard Lidar Observatory for Winds (GLOW), and the Holographic Airborne Rotating Lidar Instrument Experiment (HARLIE), respectively. These measurements are combined with the vertical velocity measurements derived from the National Center for Atmospheric Research (NCAR) Multiple Antenna Profiler Radar (MAPR) and radar structure function from the high-resolution University of Massachusetts frequency-modulated continuous-wave (FMCW) radar to reveal the evolution and structure of the late afternoon double-dryline boundary layer. The eastern dryline advanced and then retreated over the Homestead profiling site in the Oklahoma panhandle, providing conditions ripe for a detailed observation of the small-scale variability within the boundary layer and the dryline. In situ aircraft data, dropsonde and radiosonde data, along with NCAR S-band dual-polarization Doppler radar (S-Pol) measurements, are also used to provide the larger-scale picture of the double-dryline environment.
Moisture and temperature jumps of about 3 g kg−1 and 1–2 K, respectively, were observed across the eastern radar fine line (dryline), more than the moisture jumps (1–2 g kg−1) observed across the western radar fine line (secondary dryline). Most updraft plumes observed were located on the moist side of the eastern dryline with vertical velocities exceeding 3 m s−1 and variable horizontal widths of 2–5 km, although some were as wide as 7–8 km. These updrafts were up to 1.5 g kg−1 moister than the surrounding environment.
Although models suggested deep convection over the Oklahoma panhandle and several cloud lines were observed near the dryline, the dryline itself did not initiate any storms over the intensive observation region (IOR). Possible reasons for this lack of convection are discussed. Strong capping inversion and moisture detrainment between the lifting condensation level and the level of free convection related to an overriding drier air, together with the relatively small near-surface moisture values (less than 10 g kg−1), were detrimental to CI in this case.