bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interferon γ Enhances the Effectiveness of Tumor Necrosis Factor-Related Apoptosis–Inducing Ligand Receptor Agonists in a Xenograft Model of Ewing’s Sarcoma
Authors: Merchant Melinda S. , Yang Xuezhong , Melchionda Fraia , Romero Maria , Klein Ruth , Thiele Carol J. , Tsokos Maria , Kontny H. Udo , Mackall Crystal L. 
Published: September 2005

AbstractTumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces selective apoptosis in a variety of tumors, including most cell lines derived from Ewing’s sarcoma family of tumors, an aggressive sarcoma that afflicts children and young adults. To determine the in vivo efficacy of TRAIL receptor agonists in Ewing’s sarcoma family of tumors, mice with orthotopic xenografts were treated with anti-TRAIL-R2 monoclonal antibody or TRAIL/Apo2L in a model that can identify effects on both primary tumors and metastases. Administration of either agonist slowed tumor growth in 60% of animals and induced durable remissions in 11 to 19% but did not alter the incidence of metastatic disease. Response rates were not improved by concurrent doxorubicin treatment. Cells recovered from both TRAIL receptor agonist–treated and nontreated tumors were found to be resistant to TRAIL-induced death in vitro unless pretreated with interferon (IFN) γ. This resistance coincided with a selective down-regulation of TRAIL receptor expression on tumor cells. In vivo treatment with IFNγ increased tumor expression of TRAIL receptors and caspase 8, but did not increase the antitumor effect of TRAIL receptor agonists on primary tumors. However, IFNγ treatment alone or in combination with a TRAIL receptor agonist significantly decreased the incidence of metastatic disease and the combination of TRAIL receptor agonist therapy with IFNγ-mediated impressive effects on both primary tumors and metastatic disease. These data demonstrate that in vivo growth favors TRAIL resistance but that TRAIL receptor agonists are active in Ewing’s sarcoma family of tumors and that the combination of TRAIL receptor agonists with IFNγ is a potent regimen in this disease capable of controlling both primary and metastatic tumors.
The Novel Sequence-Specific DNA Cross-Linking Agent SJG-136 (NSC 694501) Has Potent and Selective
In vitro
Cytotoxicity in Human B-Cell Chronic Lymphocytic Leukemia Cells with Evidence of a p53-Independent Mechanism of Cell Kill
Authors: Pepper Christopher J. , Hambly Rachel M. , Fegan Christopher D. , Delavault Patrick , Thurston David E. 
Published: September 2005

Abstract
SJG-136 (NSC 694501) is a novel DNA cross-linking agent that binds in a sequence-selective manner in the minor groove of the DNA helix. It is structurally novel compared with other clinically used DNA cross-linking agents and has exhibited a unique multilog differential pattern of activity in the NCI 60-cell line screen (i.e., is COMPARE negative to other cross-linking agents). Given this profile, we undertook a preclinical evaluation of SJG-136 in primary tumor cells derived from 34 B-cell chronic lymphocytic leukemia (B-CLL) patients. SJG-136 induced apoptosis in all of the B-CLL samples tested with a mean LD50 value (the concentration of drug required to kill 50% of the cells) of 9.06 nmol/L. Its cytotoxicity was undiminished in B-CLL cells derived from patients treated previously, those with unmutated VH genes, and those with p53 mutations (P = 0.17; P = 0.63; P = 0.42, respectively). SJG-136-induced apoptosis was associated with the activation of caspase-3 that could be partially abrogated by the caspase-9 inhibitor Z-LEHD-FMK. Furthermore, SJG-136 did not trigger the phosphorylation of p53 or the up-regulation of GADD45 expression in B-CLL cells whereas the cross-linking agent chlorambucil elicited both of these effects. This suggests that SJG-136 cross-linking adducts are not subject to p53-mediated DNA excision repair mechanisms in B-CLL cells. Taken together, these data demonstrate a novel mechanism of action for SJG-136 that appears to circumvent the effects of poor prognostic markers. This unique cytotoxicity profile warrants further investigation and supports the evaluation of this agent in Phase I clinical trials for patients with B-CLL.
Homeobox D10 Induces Phenotypic Reversion of Breast Tumor Cells in a Three-Dimensional Culture Model
Authors: Carrio Meritxell , Arderiu Gemma , Myers Connie , Boudreau Nancy J. 
Published: September 2005

AbstractHomeobox (Hox) genes are master regulatory genes that direct organogenesis and maintain differentiated tissue function. We previously reported that HoxD10 helps to maintain a quiescent, differentiated phenotype in endothelial cells by suppressing expression of genes involved in remodeling the extracellular matrix and cell migration. Here we investigated whether HoxD10 could also promote or maintain a differentiated phenotype in epithelial cells. We observed that HoxD10 expression is progressively reduced in epithelial cells as malignancy increases in both breast and endometrial tumors. Retroviral gene transfer to restore expression of HoxD10 in the malignant breast tumor cells MDA-MB-231 significantly impaired migration, and when these cells were cultured in a three-dimensional laminin-rich basement membrane (3DlrBM) model, they formed polarized, acinar structures. This phenotypic reversion was accompanied by decreased α3 integrin expression and reduced proliferation. Importantly, expression of HoxD10 in the MDA-MB-231 cells inhibited their ability to form tumors in mouse xenografts. Taken together, our results suggest that HoxD10 has tumor-suppressive functions for mammary epithelial cells.
Invasive Potential Induced under Long-Term Oxidative Stress in Mammary Epithelial Cells
Authors: Mori Kazunori , Shibanuma Motoko , Nose Kiyoshi 
Published: September 2005

Abstract
Although the causal relationship between chronic inflammation and carcinogenesis has long been discussed, the molecular basis of the relation is poorly understood. In the present study, we focused on reactive oxygen species (ROS) and their signals under inflammatory conditions leading to the carcinogenesis of epithelial cells and found that repeated treatment with a low dose of H2O2 (0.2 mmol/L) for periods of 2 to 4 days caused a phenotypic conversion of mouse NMuMG mammary epithelial cells from epithelial to fibroblast-like as in malignant transformation. The phenotypic conversion included the dissolution of cell-cell contacts, redistribution of E-cadherin in the cytoplasm, and up-regulation of a set of integrin family members (integrin α2, α6, and β3) and matrix metalloproteinases (MMPs; MMP-3, -10, and -13), as analyzed using Northern blot analysis and quantitative reverse transcription-PCR. Gelatin zymography indicated post-transcriptional activation of gelatinases, including MMP-2 and -9. In parallel, p38 mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 were activated, which contributed to the induction of MMP-13, and a glutathione S-transferase pull-down assay showed the activation of a small GTPase, Rac1. Surprisingly, the prolonged oxidative treatment was sufficient to induce all of the aforementioned events. Most importantly, depending on the MMP activities, the epithelial cells exposed to oxidative conditions eventually acquired invasiveness in a reconstituted model system with a Matrigel invasion chamber containing normal fibroblasts at the bottom, providing the first substantial evidence supporting the direct role of ROS signals in the malignant transformation of epithelial cells.
Membrane-Associated and Secreted Genes in Breast Cancer
Authors: Stitziel Nathan O. , Mar Brenton G. , Liang Jie , Westbrook Carol A. 
Published: September 2005

Abstract
The identification of membrane-associated and secreted genes that are differentially expressed is a useful step in defining new targets for the diagnosis and treatment of cancer. Extracting information on the subcellular localization of genes represented on DNA microarrays is difficult and is limited by the incomplete sequence and annotation that is available in existing databases. Here we combine a biochemical and bioinformatic approach to identify membrane-associated and secreted genes expressed in the MCF-7 breast cancer cell line. Our approach is based on the analysis of differential hybridization levels of RNAs that have been physically separated by virtue of their association with polysomes on the endoplasmic reticulum. This approach is specifically applicable to oligonucleotide microarrays such as Affymetrix, which use single-color hybridization instead of dual-color competitive hybridizations. Assignment to membrane-associated and secreted class membership is based on both the differential hybridization levels and an expression threshold, which are calculated empirically from data collected on a reference set of known cytoplasmic and membrane proteins. This method enabled the identification of 755 membrane-associated and secreted probe sets expressed in MCF-7 cells for which this annotation did not previously exist. The data were used to filter a previously reported expression dataset to identify membrane-associated and secreted genes which are associated with poor prognosis in breast cancer and represent potential targets for diagnosis and treatment. The approach reported here should provide a useful tool for the analysis of gene expression patterns, identifying membrane-associated or secreted genes with biological relevance that have the potential for clinical applications in diagnosis or treatment.
A Recurrent Chromosome Breakpoint in Breast Cancer at the
NRG1
/
Neuregulin 1
/
Heregulin
Gene
Authors: Huang Huai-En , Chin Suet-Feung , Ginestier Christophe , Bardou Valérie-Jeanne , Adélaïde José , Iyer N. Gopalakrishna , Garcia Maria J. , Pole Jessica C. , Callagy Grace M. , Hewitt Stephen M. , Gullick William J. , Jacquemier Jocelyne , Caldas Carlos , Chaffanet Max , Birnbaum Daniel , Edwards Paul A. W. 
Published: September 2005

Abstract
Most studies of genomic rearrangements in common cancers have focused on regional gains and losses, but some rearrangements may break within specific genes. We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression. NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB/epidermal growth factor-receptor family, which includes ErbB2/HER2. We have now screened for breaks at NRG1 in paraffin sections of breast tumors. Tissue microarrays were screened by fluorescence in situ hybridization, with hybridization probes proximal and distal to the expected breakpoints. This screen detects breaks but does not distinguish between translocation or deletion breakpoints. The screen was validated with array-comparative genomic hybridization on a custom 8p12 high-density genomic array to detect a lower copy number of the sequences that were lost distal to the breaks. We also precisely mapped the breaks in five tumors with different hybridization probes. Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers. In an unselected series of 213 cases with follow-up, breast cancers where the break was detected tended to be high-grade (65% grade III compared with 28% of negative cases). They were, like breast tumors in general, mainly ErbB2 low (11 of 13 were low) and estrogen receptor positive (11 of 13 positive).
Gene-Environment Interaction Signatures by Quantitative mRNA Profiling in Exfoliated Buccal Mucosal Cells
Authors: Spivack Simon D. , Hurteau Gregory J. , Jain Ritu , Kumar Shalini V. , Aldous Kenneth M. , Gierthy John F. , Kaminsky Laurence S. 
Published: September 2005

AbstractExfoliated cytologic specimens from mouth (buccal) epithelium may contain viable cells, permitting assay of gene expression for direct and noninvasive measurement of gene-environment interactions, such as for inhalation (e.g., tobacco smoke) exposures. We determined specific mRNA levels in exfoliated buccal cells collected by cytologic brush, using a recently developed RNA-specific real-time quantitative reverse transcription-PCR strategy. In a pilot study, metabolic activity of exfoliated buccal cells was verified by 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium assay in vitro. Transcriptional activity was observed, after timed in vivo exposure to mainstream tobacco smoke resulted in induction of CYP1B1 in serially collected buccal samples from the one subject examined. For a set of 11 subjects, mRNA expression of nine genes encoding carcinogen- and oxidant-metabolizing enzymes qualitatively detected in buccal cells was then shown to correlate with that in laser-microdissected lung from the same individuals (χ2 = 52.91, P &lt; 0.001). Finally, quantitative real-time reverse transcription-PCR assays for seven target gene (AhR, CYP1A1, CYP1B1, GSTM1, GSTM3, GSTP1, and GSTT1) and three reference gene [glyceraldehyde-3-phosphate dehydrogenase (GAPDH), β-actin, and 36B4] transcripts were performed on buccal specimens from 42 subjects. In multivariate analyses, gender, tobacco smoke exposure, and other factors were associated with the level of expression of CYP1B1, GSTP1, and other transcripts on a gene-specific basis, but substantial interindividual variability in mRNA expression remained unexplained. Within the power limits of this pilot study, gene expression signature was not clearly predictive of lung cancer case or control status. This noninvasive and quantitative method may be incorporated into high-throughput human applications for probing gene-environment interactions associated with cancer.
Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy
Authors: Stagg John , Wu Jian Hui , Bouganim Nathaniel , Galipeau Jacques 
Published: September 2005

AbstractGenetic engineering of tumor cells to express both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-2 can induce synergistic immune antitumor effects. Paradoxically, the combination has also been reported to down-regulate certain immune functions, highlighting the unpredictability of dual cytokine use. We hypothesized that a GM-CSF and IL-2 fusion transgene (GIFT) could circumvent such limitations yet preserve synergistic features. We designed a fusion cDNA of murine GM-CSF and IL-2. Protein structure computer modeling of GIFT protein predicted for intact ligand binding domains for both cytokines. B16 mouse melanoma cells were gene modified to express GIFT (B16GIFT), and these cells were unable to form tumors in C57bl/6 mice. Irradiated B16GIFT whole-cell tumor vaccine could also induce absolute protective immunity against challenge by live B16 cells. In mice with established melanoma, B16GIFT therapeutic cellular vaccine significantly improved tumor-free survival when compared with B16 expressing both IL-2 and GM-CSF. We show that GIFT induced a significantly greater tumor site recruitment of macrophages than combined GM-CSF and IL-2 and that macrophage recruitment arises from novel chemotactic feature of GIFT. In contrast to suppression by GM-CSF of natural killer (NK) cell recruitment despite coexpression of IL-2, GIFT leads to significant functional NK cell infiltration as confirmed in NK-defective beige mice. In conclusion, we demonstrated that a fusion between GM-CSF and IL-2 can invoke greater antitumor effect than both cytokines in combination, and novel immunobiological properties can arise from such chimeric constructs.
Large-Scale Association Study Identifies
ICAM
Gene Region as Breast and Prostate Cancer Susceptibility Locus
Authors: Kammerer Stefan , Roth Richard B. , Reneland Richard , Marnellos George , Hoyal Carolyn R. , Markward Nathan J. , Ebner Florian , Kiechle Marion , Schwarz-Boeger Ulrike , Griffiths Lyn R. , Ulbrich Christian , Chrobok Korbinian , Forster Gerhard , Praetorius Georg M. , Meyer Peter , Rehbock Joachim , Cantor Charles R. , Nelson Matthew R. , Braun Andreas 
Published: September 2005

Abstract
We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using a collection of German cases and matched controls and &gt;25,000 single nucleotide polymorphisms located within 16,000 genes. One of the candidate loci identified was located on chromosome 19p13.2 [odds ratio (OR) = 1.5, P = 0.001]. The effect was substantially stronger in the subset of cases with reported family history of breast cancer (OR = 3.4, P = 0.001). The finding was subsequently replicated in two independent collections (combined OR = 1.4, P &lt; 0.001) and was also associated with predisposition to prostate cancer in an independent sample set of prostate cancer cases and matched controls (OR = 1.4, P = 0.002). High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5. Although genetic variants in ICAM5 showed the strongest association with disease status, ICAM1 is expressed at highest levels in normal and tumor breast tissue. A variant in ICAM5 was also associated with disease progression and prognosis. Because ICAMs are suitable targets for antibodies and small molecules, these findings may not only provide diagnostic and prognostic markers but also new therapeutic opportunities in breast and prostate cancer.
Cyclooxygenase-2 Is Expressed in Neuroblastoma, and Nonsteroidal Anti-Inflammatory Drugs Induce Apoptosis and Inhibit Tumor Growth
In vivo
Authors: Johnsen John I. , Lindskog Magnus , Ponthan Frida , Pettersen Ingvild , Elfman Lotta , Orrego Abiel , Sveinbjörnsson Baldur , Kogner Per 
Published: September 2005

Abstract
Neuroblastoma is the single most common and deadly tumor of childhood and is often associated with therapy resistance. Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to prostaglandins. COX-2 is up-regulated in several adult epithelial cancers and is linked to proliferation and resistance to apoptosis. We detected COX-2 expression in neuroblastoma primary tumors and cell lines but not in normal adrenal medullas from children. Treatment of neuroblastoma cells with nonsteroidal anti-inflammatory drugs, inhibitors of COX, induced caspase-dependent apoptosis via the intrinsic mitochondrial pathway. Treatment of established neuroblastoma xenografts in nude rats with the dual COX-1/COX-2 inhibitor diclofenac or the COX-2–specific inhibitor celecoxib significantly inhibited tumor growth in vivo (P &lt; 0.001). In vitro, arachidonic acid and diclofenac synergistically induced neuroblastoma cell death. This effect was further pronounced when lipooxygenases were simultaneously inhibited. Proton magnetic resonance spectroscopy (1H MRS) of neuroblastoma cells treated with COX inhibitors demonstrated accumulation of polyunsaturated fatty acids and depletion of choline compounds. Thus, 1H MRS, which can be performed with clinical magnetic resonance scanners, is likely to provide pharmacodynamic markers of neuroblastoma response to COX inhibition. Taken together, these data suggest the use of nonsteroidal anti-inflammatory drugs as a novel adjuvant therapy for children with neuroblastoma.
p73
G4C14-to-A4T14 Polymorphism and Risk of Lung Cancer
Authors: Li Guojun , Wang Li-E , Chamberlain Robert M. , Amos Christopher I. , Spitz Margaret R. , Wei Qingyi 
Published: September 2005

Abstract
Genetic variants in genes controlling cellular processes such as cell cycle, DNA repair, and apoptosis may modulate lung cancer risk. p73 has some p53-like activity and plays an important role in modulating these processes. The noncoding region of exon 2 of the p73 gene has two polymorphisms that are in complete linkage disequilibrium with one another, which may alter translation efficiency of the p73 protein. To test the hypothesis that this p73 polymorphism plays a role in the etiology of lung cancer, we conducted a hospital-based case-control study of 1054 patients newly diagnosed with lung cancer and 1139 cancer-free controls and evaluated the association between the p73 variant AT allele and risk of lung cancer. Cancer-free controls were frequency matched to the cases by age (±5 years), sex, and smoking status, and all subjects were non-Hispanic whites. The variant AT allele and genotypes were more common among the cases than among the controls (P = 0.0007 and P &lt; 0.001, respectively). Compared with the GC/GC genotype, the variant GC/AT and AT/AT genotypes were associated with a statistically significantly increased risk for lung cancer [adjusted odds ratio (OR) = 1.32, 95% confidence interval (CI), 1.10–1.59 and OR = 1.54, 95% CI, 1.05–2.26, respectively] in an allele dose-effect relationship (trend test: P &lt; 0.001). The risk associated with the AT allele (GC/AT+AT/AT) was more pronounced in younger (≤50 years) individuals (OR = 1.53, 95% CI, 1.00–2.37), men (OR = 1.61, 95% CI, 1.26–2.06), light smokers (OR = 1.58, 95% CI, 1.17–2.14), and squamous cell lung carcinoma (OR = 1.79, 95% CI, 1.32–2.42). These results suggest that this p73 polymorphism may be a marker for susceptibility to lung cancer.
Adhesion-Independent α6β4 Integrin Clustering Is Mediated by Phosphatidylinositol 3-Kinase
Authors: Gilcrease Michael Z. , Zhou Xiao , Welch Kristin 
Published: September 2005

Abstract
Clustering of cell-surface integrins is known to augment integrin-mediated signal transduction, but mechanisms of integrin clustering are poorly understood. Here we report that adhesion-independent clustering of α6β4 integrin, known to be important in mediating tumor cell motility, is driven by phosphatidylinositol 3-kinase (PI3K) but does not require activation of the PI3K-Akt pathway. We observed clustering of α6β4 in breast carcinoma cells after adhesion-independent cross-linking of the β4 integrin subunit. Clustering was significantly blocked when cross-linking was performed in the presence of PI3K inhibitors LY294002 and wortmannin. In contrast, no significant inhibition of clustering was observed with protein kinase C inhibitor GF109203X, rapamycin, or heparin. Although α6β4 clustering was blocked by PI3K inhibitors, clustering was not associated with increased PI3K lipid kinase activity or increased phosphorylation of Akt. A novel role for PI3K in α6β4 integrin clustering is proposed.