bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor α2 Chain
Authors: Kawakami Koji , Terabe Masaki , Kawakami Mariko , Berzofsky Jay A. , Puri Raj K. 
Published: April 2006

AbstractThe interleukin (IL)-13 receptor α2 (IL-13Rα2) chain is a primary binding and internalization subunit for a Th2-derived immune regulatory cytokine, IL-13. Although extremely high levels of IL-13Rα2 chain are expressed on a variety of human tumor cells and specimens, its precise role in tumor immunology has not been defined. To investigate the role of IL-13Rα2 in tumor immunity, we used D5 melanoma cells stably transfected with the human IL-13Rα2 gene (D5α2) to assess the effect of an IL-13Rα2 DNA vaccine in immunocompetent animals. Prophylactic immunization of mice with the IL-13Rα2 DNA vaccine resulted in protection against D5α2 tumor development. In vivo depletion experiments in C57BL/6 and RAG-2 knockout mice indicated that both T and B cells, but not natural killer cells, were required for the tumor protection. In addition, antibody induced by the IL-13Rα2 DNA vaccine showed a modest but significant inhibitory effect on D5α2 cells in vitro, suggesting that the antibody is biologically functional. The IL-13Rα2 DNA vaccine also exhibited antitumor activity against established D5α2 tumors in mice. Histologic analysis of regressing tumors identified infiltration of CD4+ and CD8+ T cells and the expression of CXCL9 chemokine in tumors. Taken together, our results identify the human IL-13Rα2 chain as a novel tumor rejection antigen. (Cancer Res 2006; 66(8): 4434-42)
Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells
Authors: Afshar Golnar , Jelluma Nannette , Yang Xiaodong , Basila Daniel , Arvold Nils D. , Karlsson Amelia , Yount Garret L. , Dansen Tobias B. , Koller Erich , Haas-Kogan Daphne A. 
Published: April 2006

Abstract
Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation. (Cancer Res 2006; 66(8): 4223-32)
Discovery and Evaluation of Dual CDK1 and CDK2 Inhibitors
Authors: Payton Marc , Chung Grace , Yakowec Peter , Wong Andrew , Powers Dave , Xiong Ling , Zhang Nancy , Leal Juan , Bush Tammy L. , Santora Vincent , Askew Ben , Tasker Andrew , Radinsky Robert , Kendall Richard , Coats Steve 
Published: April 2006

Abstract
In eukaryotic cells, cyclin-dependent kinase (CDK) complexes regulate the temporal progression of cells through the cell cycle. Deregulation in the cell cycle is an essential component in the evolution of cancer. Here, we validate CDK1 and CDK2 as potential therapeutic targets using novel selective small-molecule inhibitors of cyclin B1/CDK1 and cyclin E2/CDK2 enzyme complexes (CDKi). Flow cytometry–based methods were developed to assess intracellular retinoblastoma (Rb) phosphorylation to show inhibition of the CDK pathway. Tumor cells treated with CDK inhibitors showed an overall decrease in cell proliferation, accumulation of cells in G1 and G2, and apoptosis in a cell line–specific manner. Although CDK inhibitors activate p53, the inhibitors were equipotent in arresting the cell cycle in isogenic breast and colon tumor cells lacking p53, suggesting the response is independent of p53. In vivo, the CDK inhibitors prevented the growth of colon and prostate tumors, blocked proliferation of tumor cells, and inhibited Rb phosphorylation. The discovery and evaluation of novel potent and selective CDK1 and CDK2 inhibitors will help delineate the role that CDK complexes play in regulating tumorigenesis. (Cancer Res 2006; 66(8): 4299-308)
Soluble Human LAG-3 Molecule Amplifies theIn vitroGeneration of Type 1 Tumor-Specific Immunity
Authors: Casati Chiara , Camisaschi Chiara , Rini Francesca , Arienti Flavio , Rivoltini Licia , Triebel Frédéric , Parmiani Giorgio , Castelli Chiara 
Published: April 2006

AbstractThe adjuvant activities of the human lymphocyte activation gene-3 (LAG-3) molecule have been evaluated in a human setting by investigating the ability of a soluble recombinant human LAG-3 protein (hLAG-3Ig) to enhance the in vitro induction of viral- and tumor-specific CTLs. We found that soluble human LAG-3 significantly sustained the generation and expansion of influenza matrix protein Melan-A/MART-1 and survivin-specific CD8+ T lymphocytes in peripheral blood mononuclear cells (PBMC) of both cancer patients and healthy donors, showing its ability to boost CD8+ T-cell memory response or to prime naive T cells in vitro. The peptide-specific T cells generated in the presence of hLAG-3Ig were endowed with cytotoxic activity and enhanced release of type 1 cytotoxic T (Tc1) cytokines and were able to recognize tumor cells expressing their nominal antigen. Phenotype and cytokine/chemokines produced by antigen-presenting cells (APC) of PBMCs exposed in vitro for 2 days to peptide and hLAG-3Ig indicate that the LAG-3–mediated adjuvant effect may depend on a direct activation of circulating APCs. Our data revealed the activity of hLAG-3Ig in inducing tumor-associated, antigen-specific CD8+ T-cell responses in a human setting and strongly support the conclusion that this recombinant protein is a potential candidate adjuvant for cancer vaccines. (Cancer Res 2006; 66(8): 4450-60)
Multiple Adaptive Mechanisms to Chronic Liver Disease Revealed at Early Stages of Liver Carcinogenesis in the Mdr2-Knockout Mice
Authors: Katzenellenbogen Mark , Pappo Orit , Barash Hila , Klopstock Naama , Mizrahi Lina , Olam Devorah , Jacob-Hirsch Jasmine , Amariglio Ninette , Rechavi Gidi , Mitchell Leslie Ann , Kohen Ron , Domany Eytan , Galun Eithan , Goldenberg Daniel 
Published: April 2006

Abstract
Molecular events preceding the development of hepatocellular carcinoma were studied in the Mdr2-knockout (Mdr2-KO) mice. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by hepatocellular carcinoma development after the age of 1 year. Liver tissue samples of Mdr2-KO mice in the early and late precancerous stages of liver disease were subjected to histologic, biochemical, and gene expression profiling analysis. In an early stage, multiple protective mechanisms were found, including induction of many anti-inflammatory and antioxidant genes and increase of total antioxidant capacity of liver tissue. Despite stimulation of hepatocyte DNA replication, their mitotic activity was blocked at this stage. In the late stage of the disease, although the total antioxidant capacity of liver tissue of Mdr2-KO mice was normal, and inflammation was less prominent, many protective genes remained overexpressed. Increased mitotic activity of hepatocytes resulted in multiple dysplastic nodules, some of them being steatotic. Expression of many genes regulating lipid and phospholipid metabolism was distorted, including up-regulation of choline kinase A, a known oncogene. Many other oncogenes, including cyclin D1, Jun, and some Ras homologues, were up-regulated in Mdr2-KO mice at both stages of liver disease. However, we found no increase of Ras activation. Our data suggest that some of the adaptive mechanisms induced in the early stages of hepatic disease, which protect the liver from injury, could have an effect in hepatocarcinogenesis at later stages of the disease in this hepatocellular carcinoma model. (Cancer Res 2006; 66(8): 4001-10)
Altered Expression of c-IAP1, Survivin, and Smac Contributes to Chemotherapy Resistance in Thyroid Cancer Cells
Authors: Tirrò Elena , Consoli Maria Letizia , Massimino Michele , Manzella Livia , Frasca Francesco , Sciacca Laura , Vicari Luisa , Stassi Giorgio , Messina Luigi , Messina Angelo , Vigneri Paolo 
Published: April 2006

Abstract
Resistance to chemotherapy predicts an unfavorable outcome for patients with radioiodine-insensitive thyroid cancer. To investigate the mechanisms underlying this resistance, we evaluated the expression of four different inhibitor of apoptosis proteins, and their antagonist, Smac, in thyroid cancer cells that survived 48 hours of exposure to cisplatin, doxorubicin, or taxol. We found high levels of c-IAP1 after cisplatin treatment and increased expression of survivin following exposure to doxorubicin. Cells that endured treatment with taxol showed reduced expression of Smac and released minimal amounts of this protein from the mitochondria. Down-regulation of c-IAP1 and survivin increased the cytotoxicity of cisplatin and doxorubicin, whereas overexpression of Smac improved the efficacy of taxol. Finally, thyroid cancer cells permanently resistant to doxorubicin or cisplatin showed increased expression of c-IAP1 and survivin, respectively. However, silencing of these proteins by RNA interference restored sensitivity to doxorubicin and cisplatin. Thus, in thyroid cancer cells, early resistance to chemotherapeutic agents requires high levels of c-IAP1 and survivin and low levels of Smac. Furthermore, increased expression of c-IAP1 and survivin contributes to the acquisition of permanent resistance to cytotoxic compounds. (Cancer Res 2006; 66(8): 4263-72)
Colony-Stimulating Factor-1 Antibody Reverses Chemoresistance in Human MCF-7 Breast Cancer Xenografts
Authors: Paulus Patrick , Stanley E. Richard , Schäfer Romana , Abraham Dietmar , Aharinejad Seyedhossein 
Published: April 2006

Abstract
Overexpression of colony-stimulating factor-1 (CSF-1) and its receptor in breast cancer is correlated with poor prognosis. Based on the hypothesis that blockade of CSF-1 would be beneficial in breast cancer treatment, we developed a murinized, polyethylene glycol–linked antigen-binding fragment (Fab) against mouse (host) CSF-1 (anti-CSF-1 Fab). Mice bearing human, chemoresistant MCF-7 breast cancer xenografts were treated with combination chemotherapy (CMF: cyclophosphamide, methotrexate, 5-fluorouracil; cycled twice i.p.), anti-CSF-1 Fab (i.p., cycled every 3 days for 14 days), combined CMF and anti-CSF-1 Fab, or with Ringer's solution as a control. Anti-CSF-1 Fab alone suppressed tissue CSF-1 and retarded tumor growth by 40%. Importantly, in combination with CMF, anti-CSF-1 Fab reversed chemoresistance of MCF-7 xenografts, suppressing tumor development by 56%, down-regulating expression of the chemoresistance genes breast cancer–related protein, multidrug resistance gene 1, and glucosylceramide synthase, and prolonging survival significantly. Combined treatment also reduced angiogenesis and macrophage recruitment and down-regulated tumor matrix metalloproteinase-2 (MMP-2) and MMP-12 expression. These studies support the paradigm of CSF-1 blockade in the treatment of solid tumors and show that anti-CSF-1 antibodies are potential therapeutic agents for the treatment of mammary cancer. (Cancer Res 2006; 66(8): 4349-56)
Inhibition of Cyclooxygenase-2 Disrupts Tumor Vascular Mural Cell Recruitment and Survival Signaling
Authors: Lee Alice , Frischer Jason , Serur Anna , Huang Jianzhong , Bae Jae-O , Kornfield Zev Noah , Eljuga Lucy , Shawber Carrie J. , Feirt Nikki , Mansukhani Mahesh , Stempak Diana , Baruchel Sylvain , Bender Julia Glade , Kandel Jessica J. , Yamashiro Darrell J. 
Published: April 2006

AbstractMuch evidence supports an important role for the inducible enzyme cyclooxygenase-2 (COX-2) in tumor angiogenesis. Previous studies have focused on the role of COX-2 in stimulating endothelial proliferation, with blockade of this enzyme impairing endothelial homeostasis. However, recent data suggest that COX-2 also regulates molecules implicated in endothelial trafficking with pericytes/vascular mural cells (VMC), an interaction crucial to vessel stability. We investigated the role of COX-2 in vascular assembly by testing the effect of the specific COX-2 inhibitor SC-236 in an orthotopic xenograft model of human Wilms' tumor. Tumor growth was significantly suppressed by SC-236 (78% at day 28, 55% at day 35). Perfusion studies and immunostaining showed a marked decrease in vasculature, particularly in small vessels. Specifically, SC-236 inhibited participation of VMC in xenograft vessels. SC-236–treated tumors developed segmentally dilated, architecturally erratic tumor vessels with decreased nascent pericytes and scant mature VMC. Although vascular endothelial growth factor expression was unchanged, expression of the chemokine receptor CXCR4 was decreased in tumor vessels, consistent with defective homing of vascular progenitor cells. Vascular expression of phosphorylated platelet-derived growth factor receptor-β was also diminished, indicating impaired VMC-endothelial trafficking. Consistent with the key role of this interaction in vessel homeostasis, vascular cells in SC-236–treated tumors displayed markedly diminished phosphorylated Akt, indicating disrupted survival signaling. These results show that SC-236 causes defective vascular assembly by attenuating incorporation of VMC into tumor vessels, impairing endothelial survival, and raise the possibility that blockade of COX-2 may provide therapeutic synergies with antiangiogenic molecules that more selectively target endothelial cells. (Cancer Res 2006; 66(8): 4378-84)
Serum IgE, Tumor Epidermal Growth Factor Receptor Expression, and Inherited Polymorphisms Associated with Glioma Survival
Authors: Wrensch Margaret , Wiencke John K. , Wiemels Joe , Miike Rei , Patoka Joe , Moghadassi Michelle , McMillan Alex , Kelsey Karl T. , Aldape Kenneth , Lamborn Kathleen R. , Parsa Andrew T. , Sison Jennette D. , Prados Michael D. 
Published: April 2006

AbstractIn population-based glioma patients, we examined survival in relation to potentially pertinent constitutive polymorphisms, serologic factors, and tumor genetic and protein alterations in epidermal growth factor receptor (EGFR), MDM2, and TP53. Subjects were newly diagnosed adults residing in the San Francisco Bay Surveillance Epidemiology and End Results Area during 1991 to 1994 and 1997 to 1999 with central neuropathology review (n = 873). Subjects provided blood for serologic studies of IgE and IgG to four herpes viruses and constitutive specimens for genotyping 22 polymorphisms in 13 genes (n = 471). We obtained 595 of 697 astrocytic tumors for marker studies. We determined treatments, vital status, and other factors using registry, interview, medical record, and active follow-up data. Cox regressions for survival were adjusted for age, gender, ethnicity, study series, resection versus biopsy only, radiation, and chemotherapy. Using a stringent P &lt; 0.001, glioma survival was associated with ERCC1 C8092A [hazard ratio (HR), 0.72; 95% confidence limits (95% CL), 0.60-0.86; P = 0.0004] and GSTT1 deletion (HR, 1.64; 95% CL, 1.25-2.16; P = 0.0004); glioblastoma patients with elevated IgE had 9 months longer survival than those with normal or borderline IgE levels (HR, 0.62; 95% CL, 0.47-0.82; P = 0.0007), and EGFR expression in anaplastic astrocytoma was associated with nearly 3-fold poorer survival (HR, 2.97; 95% CL, 1.70-5.19; P = 0.0001). Based on our and others' findings, we recommend further studies to (a) understand relationships of elevated IgE levels and other immunologic factors with improved glioblastoma survival potentially relevant to immunologic therapies and (b) determine which inherited ERCC1 variants or other variants in the 19q13.3 region influence survival. We also suggest that tumor EGFR expression be incorporated into clinical evaluation of anaplastic astrocytoma patients. (Cancer Res 2006; 66(8): 4531-41)
Two-Dimensional Transcriptome Profiling: Identification of Messenger RNA Isoform Signatures in Prostate Cancer from Archived Paraffin-Embedded Cancer Specimens
Authors: Li Hai-Ri , Wang-Rodriguez Jessica , Nair T. Murlidharan , Yeakley Joanne M. , Kwon Young-Soo , Bibikova Marina , Zheng Christina , Zhou Lixin , Zhang Kui , Downs Tracy , Fu Xiang-Dong , Fan Jian-Bing 
Published: April 2006

Abstract
The expression of specific mRNA isoforms may uniquely reflect the biological state of a cell because it reflects the integrated outcome of both transcriptional and posttranscriptional regulation. In this study, we constructed a splicing array to examine ∼1,500 mRNA isoforms from a panel of genes previously implicated in prostate cancer and identified a large number of cell type–specific mRNA isoforms. We also developed a novel “two-dimensional” profiling strategy to simultaneously quantify changes in splicing and transcript abundance; the results revealed extensive covariation between transcription and splicing in prostate cancer cells. Taking advantage of the ability of our technology to analyze RNA from formalin-fixed, paraffin-embedded tissues, we derived a specific set of mRNA isoform biomarkers for prostate cancer using independent panels of tissue samples for feature selection and cross-analysis. A number of cancer-specific splicing switch events were further validated by laser capture microdissection. Quantitative changes in transcription/RNA stability and qualitative differences in splicing ratio may thus be combined to characterize tumorigenic programs and signature mRNA isoforms may serve as unique biomarkers for tumor diagnosis and prognosis. (Cancer Res 2006; 66(8): 4079-88)
Identification of EZH2 as a Molecular Marker for a Precancerous State in Morphologically Normal Breast Tissues
Authors: Ding Lei , Erdmann Christine , Chinnaiyan Arul M. , Merajver Sofia D. , Kleer Celina G. 
Published: April 2006

Abstract
The discovery of molecular markers to detect the precancerous state would have profound implications in the prevention of breast cancer. We report that the expression of the Polycomb group protein EZH2 increases in histologically normal breast epithelium with higher risk of developing cancer. We identify EZH2 as a potential marker for detecting preneoplastic lesions of the breast in vivo and as a possible target for preventative intervention. (Cancer Res 2006; 66(8): 4095-9)
Shh Pathway Activity Is Down-Regulated in Cultured Medulloblastoma Cells: Implications for Preclinical Studies
Authors: Sasai Ken , Romer Justyna T. , Lee Youngsoo , Finkelstein David , Fuller Christine , McKinnon Peter J. , Curran Tom 
Published: April 2006

Abstract
Gene expression profiling indicates that the Sonic Hedgehog (Shh) pathway is active in ∼30% of human medulloblastomas, suggesting that it could provide a useful therapeutic target. Previously, we showed that spontaneous medulloblastomas in Ptc1+/−p53−/− mice could be eradicated by treatment with a small-molecule inhibitor (HhAntag) of Smoothened (Smo). Here, we compared the responses of mouse medulloblastoma cells propagated in flank allografts, either directly or after culture in vitro, to HhAntag. We found that Shh pathway activity was suppressed in medulloblastoma cells cultured in vitro and it was not restored when these cells were transplanted into the flank of nude mice. The growth of these transplanted tumor cells was not inhibited by treatment of mice with doses of HhAntag that completely suppressed Smo activity. Interestingly, tumor cells transplanted directly into the flank maintained Smo activity and were sensitive to treatment with HhAntag. These findings indicate that propagation of tumor cells in culture inhibits Smo activity in a way that cannot be reversed by transplantation in vivo, and they raise concerns about the use of cultured tumor cells to test the efficacy of Shh pathway inhibitors as anticancer therapies. (Cancer Res 2006; 66(8): 4215-22)
The DNA Damage Response Arouses the Immune System
Authors: Gasser Stephan , Raulet David H. 
Published: April 2006

Abstract
Although there is considerable knowledge of how DNA damage triggers cell cycle arrest, DNA repair, and apoptosis, little was known about its potential role in immune responses. Recently, we showed that genotoxic stress and stalled DNA replication forks induce the expression of ligands for the NKG2D receptor found in natural killer cells and certain T cells, cell types that are able to attack tumor cells. Chronic activation of this response in tumor cells may contribute to immune recognition, but it also imposes a selection mechanism for immune escape and malignant progression. This unique arm of the DNA damage response may have implications for understanding therapeutic responses, many of which induce the DNA damage response, and for designing more effective regimens to treat cancer. (Cancer Res 2006; 66(8): 3959-62)
Characteristics of Tropical Convection over the Ocean near Kwajalein
Authors: Cetrone Jasmine , Houze Robert A. 
Published: April 2006

Abstract
Radar observations have been analyzed to determine characteristics of convection over the oceanic region around Kwajalein in the tropical western Pacific. Generally, the echo areas, heights, and durations exhibited lognormal distributions. Heights were greater under conditions of higher midtropospheric humidity and correlated with echo area, with a wide spread of values. Mergers and splits often truncated echo lifetimes.
The most surprising result was the distribution of orientation angles of echo lines, which statistically verify the shear-parallel and shear-normal modes of convective line organization seen elsewhere over tropical oceans. The two modes typically coexisted within the area of radar coverage, indicating a potential difficulty in predicting line orientation in terms of large-scale variables.
The largest members of the echo population were mesoscale convective systems (MCSs), which had large stratiform components. They occurred in environments of increased humidity and higher midlevel buoyancy associated with westward-propagating synoptic-scale disturbances. MCSs moved with the easterlies in low to midlevels and exhibited the jump updraft, overturning updraft, and subsiding midlevel inflow characteristic of tropical oceanic MCSs.
The Kwajalein Experiment (KWAJEX) radar echo population resembles that of the eastern tropical Atlantic in terms of the shapes of the distributions of area, height, and lifetime, the prevalence of echo mergers and splits, and the tendency to form shear-parallel and shear-normal lines. These characteristics appear to be endemic to oceanic convective populations. Large-scale conditions appear to modulate these basic population characteristics rather than qualitatively alter them.