bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosome Instability and Risk of Squamous Cell Carcinomas of Head and Neck
Authors: Wang Li-E , Xiong Ping , Zhao Hui , Spitz Margaret R. , Sturgis Erich M. , Wei Qingyi 
Published: June 2008

Abstract
In 895 subjects with squamous cell carcinoma of the head and neck (SCCHN) and 898 cancer-free controls matched by age, sex, and ethnicity, we validated our previous finding that mutagen sensitivity as measured by the frequency of chromatid breaks in vitro induced by benzo[a]pyrene diol epoxide (BPDE) is an independent risk factor for SCCHN. Using a previously established concentration of 4 μmol/L BPDE to treat short-term cultured primary lymphocytes for 5 hours, we evaluated chromatid breaks in 50 well-spread metaphases for each blood sample. The mean frequency of BPDE-induced chromatid breaks was significantly higher in cases than in controls in non-Hispanic Whites (P = 0.0003) but not in other ethnic groups (P = 0.549 for Hispanic Americans and 0.257 for African Americans). The odds ratio associated with risk of SCCHN for the frequency of chromatid breaks greater than median value of controls was 1.56 (95% confidence interval, 1.27–1.91) in non-Hispanic Whites (767 cases and 763 controls) after adjustment for age, sex, smoking status, and drinking status. When the quartiles of the controls were used as the cutoff values, there was a dose response between the degree of mutagen sensitivity and risk of SCCHN in non-Hispanic Whites (Ptrend = 0.0001). However, none of these associations in non-Hispanic Whites was identified in Hispanic Americans (69 cases and 70 controls) or African Americans (59 cases and 65 controls), possibly because of the small samples of these ethnic groups or ethnic difference in genetic variation, which needs to be confirmed in future studies. [Cancer Res 2008;68(11):4479–85]
WL-276, an Antagonist against Bcl-2 Proteins, Overcomes Drug Resistance and Suppresses Prostate Tumor Growth
Authors: Wang Liangyou , Sloper Daniel T. , Addo Sadiya N. , Tian Defeng , Slaton Joel W. , Xing Chengguo 
Published: June 2008

AbstractPatients with hormone-refractory prostate cancer (HRPC) have an estimated median survival of only 10 months because of acquired drug resistance, urging the need to develop therapies against the drug-resistant HRPC phenotype. Accumulating evidence suggests that overexpressing antiapoptotic Bcl-2 family proteins is at least partially responsible for the development of drug resistance among HRPC patients. Antagonizing the antiapoptotic Bcl-2 family proteins, therefore, is one potential approach to circumventing drug resistance in HRPC. WL-276 was developed as a small-molecule antagonist against antiapoptotic Bcl-2 family proteins, with binding potency comparable to (−)-gossypol. Overexpressing Bcl-2 or Bcl-XL failed to confer resistance to WL-276. WL-276 also effectively induced apoptosis in PC-3 cells. In addition, three PC-3 cell lines with acquired drug resistance against standard cancer chemotherapies were more sensitive to WL-276 than the parent PC-3 cell line. The increased cytotoxicity toward drug-resistant PC-3 cells shows the clinical potential of WL-276 against HRPC that is resistant to conventional therapies. The anticancer activity of WL-276 was manifested in its suppression of PC-3–induced prostate tumor growth in vivo. The selective toxicity of WL-276 against drug-resistant PC-3 cells and its in vivo suppression of PC-3 prostate tumor growth suggest that WL-276 is a promising lead candidate for the development of Bcl-2 antagonists against drug-resistant HRPC. [Cancer Res 2008;68(11):4377–83]
Guggulsterone, a Farnesoid X Receptor Antagonist, Inhibits Constitutive and Inducible STAT3 Activation through Induction of a Protein Tyrosine Phosphatase SHP-1
Authors: Ahn Kwang Seok , Sethi Gautam , Sung Bokyung , Goel Ajay , Ralhan Ranju , Aggarwal Bharat B. 
Published: June 2008

Abstract
Signal transducers and activator of transcription 3 (STAT3) is a transcription factor that has been associated with survival, proliferation, chemoresistance, and angiogenesis of tumor cells. Whether the apoptotic, antiproliferative, and antimetastatic effects of guggulsterone (GS), a farnesoid X receptor antagonist, are linked to its ability to suppress STAT3 activation was investigated. We found that the Z but not the E stereoisomer of GS inhibited both constitutive and interleukin-6–induced STAT3 activation in human multiple myeloma cells. The suppression of STAT3 was mediated through the inhibition of activation of protein tyrosine kinases Janus-activated kinase 2 and c-Src. Vanadate treatment reversed the GS-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that GS induced the expression of both the protein and mRNA for tyrosine protein phosphatase SHP-1 that was not due to demethylation of the SHP-1 promoter previously implicated in the epigenetic silencing of SHP-1. Moreover, knockdown of SHP-1 by small interfering RNA suppressed the effect of GS on induction of SHP-1 and on the inhibition of STAT3 activation, thereby implicating SHP-1 in the action of GS. Finally, GS down-regulated the expression of STAT3-regulated antiapoptotic (Bcl-2, Bcl-xL, and Mcl-1), proliferative (cyclin D1), and angiogenic (VEGF) gene products; and this correlated with suppression of proliferation, the accumulation of cells in sub-G1 phase of cell cycle, and induction of apoptosis. Overall, these results suggest that GS is a novel blocker of STAT3 activation and thus may have a potential in regulation of growth and metastasis of tumor cells. [Cancer Res 2008;68(11):4406–15]
Vascular Endothelial Growth Factor Receptor 2 Mediates Macrophage Infiltration into Orthotopic Pancreatic Tumors in Mice
Authors: Dineen Sean P. , Lynn Kristi D. , Holloway Shane E. , Miller Andrew F. , Sullivan James P. , Shames David S. , Beck Adam W. , Barnett Carlton C. , Fleming Jason B. , Brekken Rolf A. 
Published: June 2008

Abstract
Macrophages are an abundant inflammatory cell type in the tumor microenvironment that can contribute to tumor growth and metastasis. Macrophage recruitment into tumors is mediated by multiple cytokines, including vascular endothelial growth factor (VEGF), which is thought to function primarily through VEGF receptor (VEGFR) 1 expressed on macrophages. Macrophage infiltration is affected by VEGF inhibition. We show that selective inhibition of VEGFR2 reduced macrophage infiltration into orthotopic pancreatic tumors. Our studies show that tumor-associated macrophages express VEGFR2. Furthermore, peritoneal macrophages from tumor-bearing animals express VEGFR2, whereas peritoneal macrophages from non–tumor-bearing animals do not. To our knowledge, this is the first time that tumor-associated macrophages have been shown to express VEGFR2. Additionally, we found that the cytokine pleiotrophin is sufficient to induce VEGFR2 expression on macrophages. Pleiotrophin has previously been shown to induce expression of endothelial cell markers on macrophages and was present in the microenvironment of orthotopic pancreatic tumors. Finally, we show that VEGFR2, when expressed by macrophages, is essential for VEGF-stimulated migration of tumor-associated macrophages. In summary, tumor-associated macrophages express VEGFR2, and selective inhibition of VEGFR2 reduces recruitment of macrophages into orthotopic pancreatic tumors. Our results show an underappreciated mechanism of action that may directly contribute to the antitumor activity of angiogenesis inhibitors that block the VEGFR2 pathway. [Cancer Res 2008;68(11):4340–6]
Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression
Authors: Karp Cristina M. , Tan Ting Ting , Mathew Robin , Nelson Deidre , Mukherjee Chandreyee , Degenhardt Kurt , Karantza-Wadsworth Vassiliki , White Eileen 
Published: June 2008

Abstract
Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. [Cancer Res 2008;68(11):4105–15]
Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth
Authors: Montgomery R. Bruce , Mostaghel Elahe A. , Vessella Robert , Hess David L. , Kalhorn Thomas F. , Higano Celestia S. , True Lawrence D. , Nelson Peter S. 
Published: June 2008

Abstract
Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription–PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59–0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03–0.44; P &lt; 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P &lt; 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment. [Cancer Res 2008;68(11):4447–54]
RET/PTC-Induced Cell Growth Is Mediated in Part by Epidermal Growth Factor Receptor (EGFR) Activation: Evidence for Molecular and Functional Interactions between RET and EGFR
Authors: Croyle Michelle , Akeno Nagako , Knauf Jeffrey A. , Fabbro Doriano , Chen Xu , Baumgartner Jacqueline E. , Lane Heidi A. , Fagin James A. 
Published: June 2008

Abstract
RET/PTC rearrangements are one of the genetic hallmarks of papillary thyroid carcinomas. RET/PTC oncoproteins lack extracellular or transmembrane domains, and activation takes place through constitutive dimerization mediated through coiled-coil motifs in the NH2 terminus of the chimeric protein. Based on the observation that the epidermal growth factor receptor (EGFR) kinase inhibitor PKI166 decreased RET/PTC kinase autophosphorylation and activation of downstream effectors in thyroid cells, despite lacking activity on the purified RET kinase, we proceeded to examine possible functional interactions between RET/PTC and EGFR. Conditional activation of RET/PTC oncoproteins in thyroid PCCL3 cells markedly induced expression and phosphorylation of EGFR, which was mediated in part through mitogen-activated protein kinase signaling. RET and EGFR were found to coimmunoprecipitate. The ability of RET to form a complex with EGFR was not dependent on recruitment of Shc or on their respective kinase activities. Ligand-induced activation of EGFR resulted in phosphorylation of a kinase-dead RET, an effect that was entirely blocked by PKI166. These effects were biologically relevant, as the EGFR kinase inhibitors PKI166, gefitinib, and AEE788 inhibited cell growth induced by various constitutively active mutants of RET in thyroid cancer cells as well as NIH3T3 cells. These data indicate that EGFR contributes to RET kinase activation, signaling, and growth stimulation and may therefore be an attractive therapeutic target in RET-induced neoplasms. [Cancer Res 2008;68(11):4183–91]
TIP30 Induces Apoptosis under Oxidative Stress through Stabilization of p53 Messenger RNA in Human Hepatocellular Carcinoma
Authors: Zhao Jian , Chen Jingjing , Lu Bin , Dong Li , Wang Huajing , Bi Chongshan , Wu Guobin , Guo Huaizu , Wu Mengchao , Guo Yajun 
Published: June 2008

Abstract
Reactive oxygen species (ROS) and cellular oxidant stress have long been associated with cancer. Here, we show that TIP30, also called CC3, regulates p53 mRNA stability and induces apoptosis by sensing of intracellular oxidative stress in human hepatocellular carcinoma (HCC) cells. Introduction of TIP30 induced more cell death in HepG2 cells with a high level of intracellular ROS than that in normal liver cell line, HL7702, which had low level of intracellular ROS. Treatment with an antioxidant agent attenuated TIP30-induced cell death in HepG2 cells, whereas oxidant H2O2 augmented TIP30-induced cell death in HL7702 cells. The conformation of TIP30 was altered with the formation of an intermolecular disulfide bridge under oxidative stress. TIP30 greatly enhanced p53 expression and its transcriptional activity under oxidative stress, which was probably through stabilization of p53 mRNA. TIP30 induced apoptosis and mitochondrial dysfunction were blocked by silencing of p53 expression. The nuclear import of mRNA-binding protein HuR was blocked upon TIP30 introduction, which might be due to the interruption of the association of HuR with importin β2. The elevated cytoplasmic HuR bound to p53 mRNA 3′-untranslated region, resulting in prolonged half-life of p53 mRNA. Our results suggest that TIP30 is involved in cellular oxidative stress surveillance and induces apoptosis through stabilization of p53 mRNA in HCC cells. [Cancer Res 2008;68(11):4133–41]
Protein Phosphatase-2A Is a Target of Epigallocatechin-3-Gallate and Modulates p53-Bak Apoptotic Pathway
Authors: Qin Jichao , Chen He-Ge , Yan Qin , Deng Mi , Liu Jinping , Doerge Stephan , Ma Weiya , Dong Zigang , Wan-Cheng Li David 
Published: June 2008

Abstract(-)-Epigallocatechin-3-gallate (EGCG) is a well-known chemoprevention factor. Recent studies have revealed that EGCG triggers cancer cells undergoing apoptosis through p53-dependent pathway. How EGCG activates p53-dependent apoptosis is not fully understood. In the present study using JB6 cell as a model system, we have shown that EGCG can negatively regulate protein serine/threonine phosphatase-2A (PP-2A) to positively regulate p53-dependent apoptosis. First, EGCG at physiologic levels down-regulates PP-2A at the protein and enzyme activity levels. Second, EGCG induces apoptosis of JB6 cells, which is associated with hyperphosphorylation of p53 and up-regulation of the proapoptotic gene, Bak. DNA sequence analysis, gel mobility shifting, chromatin immunoprecipitation, and reporter gene activity assays revealed that p53 directly controls Bak in JB6 cells. Knockdown of p53 and Bak expression with RNAi substantially inhibits EGCG-induced apoptosis. Third, PP-2A directly interacts with p53 and dephosphorylates p53 at Ser-15 in vitro and in vivo. Fourth, overexpression of the catalytic subunit for PP-2A down-regulates p53 phosphorylation at Ser15, attenuates expression of the downstream proapoptotic gene, Bak, and antagonizes EGCG-induced apoptosis. Inhibition of PP-2A activity enhances p53 phosphorylation at Ser-15 and up-regulates Bak expression to promote EGCG-induced apoptosis. Finally, in the p53−/− H1299 and p53+/+ H1080 cells, EGCG down-regulates PP-2A similarly but induces differential apoptosis. In summary, our results show that (a) PP-2A directly dephosphorylates p53 at Ser-15; (b) P53 directly controls Bak expression; and (c) EGCG negatively regulates PP-2A. Together, our results show that EGCG-mediated negative regulation of PP-2A is an important molecular event for the activation of p53-dependent apoptosis during its chemoprevention. [Cancer Res 2008;68(11):4150–62]
A Phase 1 Study of Mapatumumab (Fully Human Monoclonal Antibody to TRAIL-R1) in Patients with Advanced Solid Malignancies
Authors: Hotte Sébastien J. , Hirte Hal W. , Chen Eric X. , Siu Lillian L. , Le Lyly H. , Corey Alfred , Iacobucci Anne , MacLean Martha , Lo Larry , Fox Norma Lynn , Oza Amit M. 
Published: June 2008

AbstractPurpose: Mapatumumab (TRM-1, HGS-ETR1) is a fully human agonistic monoclonal antibody that targets and activates tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4). Mapatumumab functions like the natural receptor ligand, TRAIL, a tumor necrosis factor superfamily member that is an important mediator of apoptosis in cancer cell lines. Promising preclinical activity with mapatumumab has been observed.Experimental Design: This phase I, open-label, dose-escalation study assessed the tolerability and toxicity profile of ≥2 doses of mapatumumab administered i.v. in patients with advanced solid tumors. Patients received mapatumumab every 28 days until progression or dose-limiting toxicity.Results: There were escalation levels from 0.01 to 20.0 mg/kg. Forty-one patients, 27 female, with a median age of 55 years (range, 23-81) were entered into the study and received 143 courses. The most common diagnoses were colorectal (10 patients) and ovarian cancer (9 patients). Patients received a median of two cycles (range, 1-33). Mapatumumab was well tolerated. Adverse events considered at least possibly related to mapatumumab that occurred most frequently included fatigue (36.2%), hypotension (34.1%), nausea (29.3%), and pyrexia (12.2%). The majority of adverse events were grade 1 or 2. The maximum tolerated dose was not reached. Linear pharmacokinetics was observed for doses up to 0.3 mg/kg and for the 20 mg/kg level, whereas exposure at 3 and 10 mg/kg increased less than proportionally. No objective responses were observed, but 12 patients had stable disease for 1.9 to 29.4 months.Conclusions: Mapatumumab is well tolerated and further evaluation of this TRAIL-R1 targeting agent is warranted.
Protein Expression of Platelet-Derived Growth Factor Receptor Correlates with Malignant Histology and PTEN with Survival in Childhood Gliomas
Authors: Thorarinsdottir Halldora K. , Santi Mariarita , McCarter Robert , Rushing Elisabeth J. , Cornelison Robert , Jales Alessandra , MacDonald Tobey J. 
Published: June 2008

Abstract
Purpose: We previously showed that overexpression of epidermal growth factor receptor (EGFR) is associated with malignant grade in childhood glioma. The objective of this study was to determine whether protein expression of EGFR or platelet-derived growth factor receptor (PDGFR) and their active signaling pathways are related to malignant histology, progression of disease, and worse survival.
Experimental Design: Tissue microarrays were prepared from untreated tumors from 85 new glioma patients [22 high-grade gliomas (HGG) and 63 low-grade gliomas (LGG)] diagnosed at this institution from 1989 to 2004. Immunohistochemistry was used to assess total expression of EGFR, PDGFRβ, and PTEN and expression of phosphorylated EGFR, phosphorylated PDGFRα (p-PDGFRα), phosphorylated AKT, phosphorylated mitogen-activated protein kinase, and phosphorylated mammalian target of rapamycin. These results were correlated with clinicopathologic data, including extent of initial tumor resection, evidence of dissemination, tumor grade, proliferation index, and survival, as well as with Affymetrix gene expression profiles previously obtained from a subset of these tumors.
Results: High expression of p-PDGFRα, EGFR, PDGFRβ, and phosphorylated EGFR was seen in 85.7%, 80.0%, 78.9%, and 47.4% of HGG and 40.0%, 87.1%, 41.7%, and 30.6% of LGG, respectively. However, high expression of p-PDGFRα and PDGFRβ was the only significant association with malignant histology (P = 0.031 and 0.005, respectively); only the loss of PTEN expression was associated with worse overall survival. None of these targets, either alone or in combination, was significantly associated with progression-free survival in either LGG or HGG.
Conclusions: High PDGFR protein expression is significantly associated with malignant histology in pediatric gliomas, but it does not represent an independent prognostic factor. Deficient PTEN expression is associated with worse overall survival in HGG.
Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents in Patients with Cancer
Authors: Juneja Vinni , Keegan Patricia , Gootenberg Joseph E. , Rothmann Mark D. , Shen Yuan Li , Lee Kyung Y. , Weiss Karen D. , Pazdur Richard 
Published: June 2008

Abstract
Purpose: Erythropoiesis-stimulating agents (ESA) are approved for the treatment of anemia in patients with nonmyeloid malignancies whose anemia is due to the effect of concomitantly administered chemotherapy. Since the 1993 approval of epoetin alfa in patients with cancer, the risk of thrombovascular events, decreased survival, and poorer tumor control have been increasingly recognized. The risks of ESAs in patients with cancer and the design of trials to assess these risks have been the topic of discussion at two Oncologic Drugs Advisory Committees in 2004 and 2007.
Experimental Design: Evaluation of randomized clinical trials comparing use of ESAs to transfusion support alone in patients with active cancer.
Results: Six studies (Breast Cancer Erythropoeitin Survival Trial, Evaluation of NeoRecormon on outcome in Head And Neck Cancer in Europe, Danish Head and Neck Cancer, Lymphoid Malignancy, CAN-20, and Anemia of Cancer) investigating ESAs in oncology patients showed decreased survival, decreased duration of locoregional tumor control, and/or increased risk of thrombovascular events. In these six studies, ESA dosing was targeted to achieve and maintain hemoglobin values in excess of current recommendations, and in three of the six studies, ESAs were administered to patients not receiving chemotherapy.
Conclusions: ESAs increase the risk of thrombovascular events and result in decreased survival and poorer tumor control when administered to achieve hemoglobin levels of ≥12 g/dL in patients with nonmyeloid malignancies. No completed or ongoing randomized, controlled trial has addressed safety issues of ESAs in patients with chemotherapy-associated anemia using currently approved dosing regimens in an epidermal tumor type. Additional studies are needed to better characterize these risks.