bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Receptor for Advanced Glycation End Products by EBV Latent Membrane Protein 1 and Its Correlation with Angiogenesis and Cervical Lymph Node Metastasis in Nasopharyngeal Carcinoma
Authors: Tsuji Akira , Wakisaka Naohiro , Kondo Satoru , Murono Shigeyuki , Furukawa Mitsuru , Yoshizaki Tomokazu 
Published: September 2008

Abstract
Purpose: The EBV oncoprotein, latent membrane protein 1 (LMP1), contributes to the metastasis of nasopharyngeal carcinoma (NPC) by inducing factors to promote tumor invasion and angiogenesis. The receptor for advanced glycation end products (RAGE) is associated with abnormal angiogenesis in diabetic microangiopathies. Moreover, some papers have suggested the association of RAGE overexpression with tumor metastasis; thus, the associations of RAGE with LMP1 and angiogenesis in NPC were examined.
Experimental Design: Forty-two patients with NPC were evaluated for expressions of LMP1, RAGE, and S100 proteins and for microvessel counts by immunohistochemistry. Then, the RAGE induction by LMP1 was examined with Western blotting and luciferase reporter assay.
Results: The microvessel counts were significantly higher in patients with high LMP1 expression or high RAGE expression compared with cases with low expressions (P = 0.0049 and P &lt; 0.0001), respectively. Patients with advanced N classification were also significantly increased in these groups (P = 0.0484 and P = 0.0005). The expressions of LMP1 and RAGE proteins were clearly correlated in NPC tissues (P = 0.0093). Transient transfection with LMP1 expression plasmid induced RAGE protein in Ad-AH cells. The expression of LMP1 transactivated the RAGE promoter as shown by luciferase reporter assay. Mutation of the reporter at nuclear factor-κB binding site (−671 to −663) abolished transactivation of the RAGE promoter by LMP1.
Conclusion: These results suggest that LMP1-induced RAGE enhances lymph node metastasis through the induction of angiogenesis in NPC. Nuclear factor-κB binding site (−671 to −663) is essential for transactivation of the RAGE promoter by LMP1.
TMTP1, a Novel Tumor-Homing Peptide Specifically Targeting Metastasis
Authors: Yang Wanhua , Luo Danfeng , Wang Shixuan , Wang Rui , Chen Rui , Liu Yan , Zhu Tao , Ma Xiangyi , Liu Ronghua , Xu Gang , Meng Li , Lu Yunping , Zhou Jianfeng , Ma Ding 
Published: September 2008

AbstractPurpose: Tumor metastasis continues to be the major obstacle to cancer therapy and the leading cause of cancer-related death. Methods used to detect metastasis, especially occult metastases, have received a great deal attention. In this study, a novel selective peptide was assessed for its specific binding to metastasis.Methods: The FliTrx bacterial peptide display system, an alternative to phage peptide display, was used to identify a 5-amino acid peptide termed TMTP1 (NVVRQ), which binds to the highly metastatic prostate cancer cell line PC-3M-1E8. The synthetic TMTP1 was tested in vitro for its binding specificity and affinity to highly metastatic cancer cells. The tumor targeting assays were done in vivo by i.v. injection of FITC-conjugated TMTP1 into tumor-bearing mice.Results: TMTP1 specifically bound to a series of highly metastatic tumor cells, including prostate cancer PC-3M-1E8, breast cancer MDA-MB-435S, lung cancer PG-BE1, and gastric cancer MKN-45sci, in vitro and in vivo but not to the poorly metastatic or nonmetastatic cell line, including prostate cancer PC-3M-2B4, breast cancer MCF-7, lung cancer PG-LH7, or murine fibroblast cell NIH/3T3. FITC-TMTP1 strongly and specifically targeted the metastasis foci in tumor-bearing mice 24 h after i.v. peptide injection. Moreover, the occult metastases were specifically detected by FITC-TMTP1.Conclusion: Our results suggest that TMTP1 is a potential strategy for the development of new diagnostic tracers or alternative anticancer agents for tumor metastasis.
Magnetic Resonance Imaging–Measured Blood Flow Change after Antiangiogenic Therapy with PTK787/ZK 222584 Correlates with Clinical Outcome in Metastatic Renal Cell Carcinoma
Authors: de Bazelaire Cedric , Alsop David C. , George Daniel , Pedrosa Ivan , Wang Yongyu , Michaelson M. Dror , Rofsky Neil M. 
Published: September 2008

Abstract
Purpose: To measure changes in tumor blood flow following treatment with PTK787/ZK 222584, a pan–vascular endothelial growth factor receptor tyrosine kinase inhibitor, and their association with clinical response in patients with metastatic renal cell carcinoma.
Experimental Design: In 10 patients with metastatic renal cell carcinoma treated with PTK787/ZK 222584, tumor blood flow was evaluated by arterial spin labeling (ASL) magnetic resonance imaging before and 1 month on treatment. Changes in blood flow after 1 month of treatment were compared with bidimensional tumor response at 4 months of treatment using the Mann-Whitney test.
Results: Changes in blood flow at 1 month and changes in tumor size measured at 4 months or at time of disease progression were significantly correlated (P = 0.01). Patients with progressive disease within 4 months on treatment (n = 4) had a nonsignificant increase in tumor blood flow at 1 month (+25 ± 33%; P = 0.43), whereas patients with stable disease or partial response at 4 months (n = 6) had a significant decrease in tumor blood flow at 1 month (−42 ± 22%; P = 0.02).
Conclusion: These results suggest that decreasing tumor blood flow with PTK787/ZK 222584 therapy, as shown as soon as 1 month on therapy by ASL, may predict for a favorable clinical outcome. These data are consistent with a hypothetical functional role for tumor ischemia in the mechanism of response to anti–vascular endothelial growth factor therapy. ASL blood flow magnetic resonance imaging shows promise as an early predictor of clinical response to antiangiogenic therapies.
Genetic Clustering of Clear Cell Renal Cell Carcinoma Based on Array-Comparative Genomic Hybridization: Its Association with DNA Methylation Alteration and Patient Outcome
Authors: Arai Eri , Ushijima Saori , Tsuda Hitoshi , Fujimoto Hiroyuki , Hosoda Fumie , Shibata Tatsuhiro , Kondo Tadashi , Imoto Issei , Inazawa Johji , Hirohashi Setsuo , Kanai Yae 
Published: September 2008

Abstract
Purpose: The aim of this study was to clarify genetic and epigenetic alterations occurring during renal carcinogenesis.
Experimental Design: Copy number alterations were examined by array-based comparative genomic hybridization analysis using an array harboring 4,361 bacterial artificial chromosome clones, and DNA methylation alterations on CpG islands of the p16, human MutL homologue 1, von Hippel-Lindau, and thrombospondin 1 genes and the methylated in tumor (MINT-1, MINT-2, MINT-12, MINT-25, and MINT-31) clones were examined in 51 clear cell renal cell carcinomas (RCC).
Results: By unsupervised hierarchical clustering analysis based on copy number alterations, clear cell RCCs were clustered into the two subclasses, clusters A (n = 34) and B (n = 17). Copy number alterations were accumulated in cluster B. Loss of chromosome 3p and gain of 5q and 7 were frequent in both clusters A and B, whereas loss of 1p, 4, 9, 13q, and 14q was frequent only in cluster B. The average number of methylated CpG islands in cluster B was significantly higher than those in cluster A. Clear cell RCCs showing higher histologic grades, vascular involvement, renal vein tumor thrombi, and higher pathologic stages were accumulated in cluster B. The recurrence-free and overall survival rates of patients in cluster B were significantly lower than those of patients in cluster A. Multivariate analysis revealed that genetic clustering was a predictor of recurrence-free survival and was independent of histologic grade and pathologic stage.
Conclusions: This genetic clustering of clear cell RCC is significantly associated with regional DNA hypermethylation and may become a prognostic indicator for patients with RCC.
Overexpression of the Zinc Uptake Transporter hZIP1 Inhibits Nuclear Factor-κB and Reduces the Malignant Potential of Prostate Cancer CellsIn vitroandIn vivo
Authors: Golovine Konstantin , Makhov Peter , Uzzo Robert G. , Shaw Tavis , Kunkle David , Kolenko Vladimir M. 
Published: September 2008

AbstractPurpose: Intracellular zinc levels and expression of the zinc uptake transporter, hZIP1, are markedly down-regulated in prostate adenocarcinomatous tissue compared with normal prostate tissue. Our previous studies have shown that zinc inhibits nuclear factor-κB (NF-κB) activity and reduces the malignant potential of prostate cancer cells in vitro. In this study, we investigate the functional effect of hZIP1 overexpression on NF-κB activity and tumorigenic potential in human prostate cancer cells in vitro and in vivo.Experimental Design: NF-κB activity in PC-3 prostate cancer cells was examined by Western blotting and luciferase assay. ELISA was used to examine the expression of tumorigenic cytokines. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, adhesion, and invasiveness assays were used to assess the malignant potential of tumor cells. The effect of hZIP1 overexpression on prostate tumor progression in vivo was assessed using a xenograft model.Results: Overexpression of the hZIP1 transporter in PC-3 cells results in significant inhibition of NF-κB activity in the presence of physiologic levels of zinc. NF-κB inhibition coincides with a reduction in expression of several NF-κB controlled prometastatic and antiapoptotic factors as well as sensitization of the cells to etoposide and tumor necrosis factor-mediated apoptosis-inducing ligand-mediated cell death. Moreover, overexpression of the hZIP1 transporter induces regression of prostate tumor growth in a xenograft model.Conclusions: Our results show that hZIP1 overexpression has a functional effect on the malignant potential of prostate cancer cells via inhibition of NF-κB-dependent pathways and support the concept that hZIP1 may function as a tumor suppressor gene in prostate cancer.
Combination of Quantitative IMP3 and Tumor Stage: A New System to Predict Metastasis for Patients with Localized Renal Cell Carcinomas
Authors: Jiang Zhong , Chu Peigou G. , Woda Bruce A. , Liu Qin , Balaji K.C. , Rock Kenneth L. , Wu Chin-Lee 
Published: September 2008

Abstract
Purpose: To create an easily applicable system based on a combination of the quantitative level of IMP3 (an oncofetal protein) and tumor stage to more accurately predict postoperative metastasis of localized renal cell carcinoma.
Experimental Design: Three hundred sixty nine patients with localized renal cell carcinoma (without metastasis during nephrectomy) were investigated by the use of survival analysis. The expression of IMP3 was evaluated by immunohistochemistry and quantitated with a computerized image analyzer. Based on combining quantitative IMP3 results with tumor staging (QITS system), patients were divided into four distinct risk groups for the development of metastasis.
Results: The four groups of patients in the QITS system showed significant differences in their metastasis-free (P &lt; 0.0001) and overall survivals (P &lt; 0.0001). Almost all patients of group IV with localized renal cell carcinomas developed metastasis and died after nephrectomy. The 5- and 10-year metastasis-free survival rates for the QITS groups were as follows: for group I, 97% and 91%; II, 62% and 55%; III, 46% and 19%; and IV, 17% and 4%, respectively. The 5- and 10-year overall survival rates for the QITS groups were as follows: for group I, 89% and 72%; II, 58% and 41%; III, 38% and 17%; and IV, 14% and 4%, respectively.
Conclusions: The QITS is a simple and accurate system for the prediction of tumor metastasis. This system not only provides important prognostic information but also can be used at initial diagnosis of localized renal cell carcinoma to identify high-risk patients who may benefit from early systematic therapy.
CpG Oligodeoxynucleotides Alter Lymphocyte and Dendritic Cell Trafficking in Humans
Authors: Haining W. Nicholas , Davies Jeffrey , Kanzler Holger , Drury Linda , Brenn Thomas , Evans John , Angelosanto Jill , Rivoli Steven , Russell Kate , George Suzanne , Sims Paul , Neuberg Donna , Li Xiaochun , Kutok Jeffrey , Morgan Jeffrey , Wen Patrick , Demetri George , Coffman Robert L. , Nadler Lee M. 
Published: September 2008

AbstractPurpose: CpG oligodeoxynucleotides (CpG-ODN) are being investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (PDC) into potent antigen-presenting cells. CpG-ODN also induce PDC to secrete chemokines that alter lymphocyte migration. Whether CpG-ODN TLR signals enhance antigen-specific immunity and/or trafficking in humans is unknown.Experimental Design: We conducted a phase I study of CpG-ODN (1018 ISS) given as a vaccine adjuvant with granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce T-cell immunity to a peptide vaccine from the tumor-associated antigen hTERT.Results: The adjuvant effect was limited; only 1 of 16 patients showed a high-frequency hTERT-specific tetramer CD8+ T-cell response. However, CpG-ODN induced marked, transient peripheral blood lymphopenia. Biopsies showed dense lymphocytic infiltration at the vaccine site clustered around activated PDC. In vitro, CpG-ODN-treated PDC induced T-cell migration, showing that CpG-ODN stimulation of human PDC was sufficient to chemoattract T cells.Conclusions: Our results show that (a) CpG-ODN with GM-CSF may not be an effective adjuvant strategy for hTERT peptide vaccines but (b) GM-CSF/CpG-ODN causes a PDC-mediated chemokine response that recruits T-cell migration to the peripheral tissues. These findings suggest a novel therapeutic role for targeted injections of CpG-ODN to direct lymphocyte migration to specific sites such as the tumor bed.
A Multigene Assay Is Prognostic of Survival in Patients with Early-Stage Lung Adenocarcinoma
Authors: Raz Dan J. , Ray M. Roshni , Kim Jae Y. , He Biao , Taron Miquel , Skrzypski Marcin , Segal Mark , Gandara David R. , Rosell Rafael , Jablons David M. 
Published: September 2008

Abstract
Purpose: Clinical staging does not adequately risk stratify patients with early stage non–small cell lung cancer. We sought to generate a real-time PCR (RT-PCR)–based prognostic model in patients with early stage lung adenocarcinoma, the dominant histology of lung cancer in the United States.
Experimental Design: We studied gene expression of 61 candidate genes in 107 patients with completely surgically resected lung adenocarcinoma using RT-PCR. We used crossvalidation methods to select and validate a prognostic model based on the expression of a limited number of genes. A risk score was generated based on model coefficients, and survival of patients with high- and low-risk scores were analyzed.
Results: We generated a four-gene model based on expression of WNT3a, ERBB3, LCK, and RND3. Risk score predicted mortality better than clinical stage or tumor size (adjusted hazard ratio, 6.7; 95% confidence interval, 1.6-28.9; P = 0.001). Among 70 patients with stage I disease, 5-year overall survival was 87% among patients with low-risk scores, and 38% among patients with high-risk scores (P = 0.0002). Among all patients, 5-year overall survival was 62% and 41%, respectively (P = 0.0054). Disease-free survival was also significantly different among low- and high-risk score patients.
Conclusions: This multigene assay predicts overall and disease-free survival significantly better than clinical stage and tumor size in patients with early stage lung adenocarcinoma and performs especially well in patients with stage I disease. Prospective clinical trials are needed to determine whether high-risk patients with stage I disease benefit from adjuvant chemotherapy.
Association of an Extracellular Matrix Gene Cluster with Breast Cancer Prognosis and Endocrine Therapy Response
Authors: Helleman Jozien , Jansen Maurice P.H.M. , Ruigrok-Ritstier Kirsten , van Staveren Iris L. , Look Maxime P. , Meijer-van Gelder Marion E. , Sieuwerts Anieta M. , Klijn Jan G.M. , Sleijfer Stefan , Foekens John A. , Berns Els M.J.J. 
Published: September 2008

Abstract
Purpose: We previously discovered an extracellular matrix (ECM) gene cluster associated with resistance to first-line tamoxifen therapy of patients with metastatic breast cancer. In this study, we determined whether the six individual ECM genes [collagen 1A1 (COL1A1), fibronectin 1 (FN1), lysyl oxidase (LOX), secreted protein acidic cysteine-rich (SPARC), tissue inhibitor of metalloproteinase 3 (TIMP3), and tenascin C (TNC)] were associated with treatment response, prognosis, or both.
Experimental Design: In 1,286 primary breast tumors, mRNA expression (quantitative real-time PCR) was related to clinicopathologic factors and disease outcome in univariate and multivariate analysis including traditional factors.
Results: TIMP3, FN1, LOX, and SPARC expression levels (continuous variables) were significantly associated with distant metastasis-free survival (MFS) in 680 lymph node–negative untreated patients (P &lt; 0.03). Using a calculated linear prognostic score, these patients were evenly divided into five prognostic groups with a significant difference in 10-year MFS of ∼40% between the two extreme prognostic groups. Furthermore, high TNC expression as continuous variable was associated with (a) shorter MFS in 139 estrogen receptor–positive and lymph node–positive patients who received adjuvant tamoxifen therapy (hazard ratio, 1.53; P = 0.001), and (b) no clinical benefit (odds ratio, 0.81; P = 0.035) and shorter progression-free survival (hazard ratio, 1.19; P = 0.002) in 240 patients in whom recurrence was treated with tamoxifen as first-line monotherapy. These results were also significant in multivariate analyses.
Conclusion: FN1, LOX, SPARC, and TIMP3 expression levels are associated with the prognosis of patients with breast cancers, whereas TNC is associated with resistance to tamoxifen therapy. Further validation and functional studies are necessary to determine the use of these ECM genes in decisions regarding treatment and whether they can serve as targets for therapy.
Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma
Authors: Ren Wenhong , Korchin Borys , Lahat Guy , Wei Caimiao , Bolshakov Svetlana , Nguyen Theresa , Merritt William , Dicker Adam , Lazar Alexander , Sood Anil , Pollock Raphael E. , Lev Dina 
Published: September 2008

Abstract
Purpose: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment.
Experimental Design: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us).
Results: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis.
Conclusions: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.
ABCB1(MDR 1) Polymorphisms and Progression-Free Survival among Women with Ovarian Cancer following Paclitaxel/Carboplatin Chemotherapy
Authors: Johnatty Sharon E. , Beesley Jonathan , Paul Jim , Fereday Sian , Spurdle Amanda B. , Webb Penelope M. , Byth Karen , Marsh Sharon , McLeod Howard ,   AOCS Study Group, Harnett Paul R. , Brown Robert , deFazio Anna , Chenevix-Trench Georgia 
Published: September 2008

AbstractPurpose: The human ABCB1 gene encodes P-glycoprotein, which transports a broad range of anticancer drugs, including paclitaxel. Although the functional consequences of ABCB1 polymorphisms have been the subject of numerous studies, few have assessed the association with clinical outcome.Experimental Design: We assessed the association between the 2677G&gt;T/A, 3435C&gt;T, and 1236C&gt;T ABCB1 polymorphisms and progression-free and overall survival in 309 patients from the Australian Ovarian Cancer Study treated with paclitaxel/carboplatin and subsequently tested significant observations in an independent validation set.Results: Women who carried the minor T/A alleles at the 2677G&gt;T/A polymorphism were significantly less likely to relapse following treatment compared with homozygote GG carriers (PLog-rank = 0.001) in the Australian Ovarian Cancer Study cohort. Subgroup analyses showed that this effect was limited to cases with residual disease ≤1 cm (PLog-rank = 0.0004), not for those with residual disease &gt;1 cm (PLog-rank = 0.3). This effect was not confirmed in an independent validation set of carboplatin/paclitaxel-treated patients (n = 278) using a higher residual disease cut point (≤2 cm). However, analysis of the unrestricted data set expanded to include docetaxel-treated patients (n = 914) did support an effect of the 2677T/A allele in patients with no macroscopic residual disease (hazard ratio, 0.70; 95% confidence interval, 0.46-1.04; Pone-sided = 0.039).Conclusion: Our findings indicate that there is an effect of the 2677G&gt;T/A polymorphism on progression-free survival in ovarian cancer patients who are treated with a taxane/carboplatin, which is dependent on the extent of residual disease, with a better prognosis for patients with the 2677T/A allele and minimal residual disease.