bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of Nuclear Factor-κB, Urokinase-Type Plasminogen Activator, and HBx and Their Clinicopathological Significance in Hepatocellular Carcinoma
Authors: Chan Chun-Fung , Yau Tai-On , Jin Dong-Yan , Wong Chun-Ming , Fan Sheung-Tat , Ng Irene Oi-Lin 
Published: September 2005

Abstract
Purpose: Nuclear factor κB (NF-κB) signaling pathway is an important regulating pathway in human diseases and cancers. One of its downstream target genes is urokinase plasminogen activator (uPA), which is involved in cancer invasion and metastasis. The purpose of this study was to evaluate NF-κB activation, uPA up-regulation, and hepatitis B viral X protein (HBx) expression in human hepatocellular carcinoma (HCC) and to assess their clinicopathological significance.
Experimental Design: We evaluated NF-κB activation, expression of uPA, and presence of HBx in 32 human HCCs. Their clinicopathological significance was assessed by correlation with the clinicopathological features. Aberrant NF-κB signaling pathway and uPA up-regulation mediated by HBx were also analyzed in vitro.
Results: We found that NF-κB activation and uPA up-regulation were frequently (56% and 59%, respectively) observed in HCCs, and particularly in HBx-positive HCCs. NF-κB activation and uPA overexpression were closely associated with one another (P &lt; 0.0001). Furthermore, both activation of NF-κB and up-regulation of uPA were significantly associated with a more aggressive tumor behavior in terms of venous invasion, direct liver invasion, and absence of tumor encapsulation. In vitro, NF-κB activation was induced by HBx transfection in HepG2 cells through inhibitor of nuclear factor-κB kinase β (IKKβ). HBx also up-regulated uPA and enhanced cell invasion synergistically with IKKβ.
Conclusions: The data indicate that NF-κB dysregulation and uPA overexpression may lead to a more aggressive tumor behavior in HCC. In addition, our data suggest that IKKβ plays a critical role in the HBx-activated NF-κB signaling pathway.
Pilot Trial Evaluating an 123I-Labeled 80-Kilodalton Engineered Anticarcinoembryonic Antigen Antibody Fragment (cT84.66 Minibody) in Patients with Colorectal Cancer
Authors: Wong Jeffrey Y. C. , Chu David Z. , Williams Lawrence E. , Yamauchi Dave M. , Ikle David N. , Kwok Cheuk S. , Liu An , Wilczynski Sharon , Colcher David , Yazaki Paul J. , Shively John E. , Wu Anna M. , Raubitschek Andrew A. 
Published: September 2005

AbstractPurpose: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (VL-linker-VH-CH3; 80 kDa) that demonstrates bivalent and high affinity (4 × 1010 m−1) binding to carcinoembryonic antigen (CEA). The variable regions (VL and VH) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the CH3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab′)2 fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether 123I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer.Experimental Design: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5–10 mCi (1 mg) of 123I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48–72 h. Surgery was performed immediately after the last nuclear scan.Results: Tumor imaging was observed with 123I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. 123I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9–65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed.Conclusion: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as 111In.
Loss of
WWOX
Expression in Gastric Carcinoma
Authors: Aqeilan Rami I. , Kuroki Tamotsu , Pekarsky Yuri , Albagha Omar , Trapasso Francesco , Baffa Raffaele , Huebner Kay , Edmonds Pamela , Croce Carlo M. 
Published: September 2005

Abstract
Purpose: WW domain-containing oxidoreductase (WWOX) is a tumor suppressor gene that maps to the common fragile site FRA16D on chromosome 16q23.3–24.1. To investigate the role of the WWOX gene in the development of gastric carcinoma, we examined a large series of primary adenocarcinomas and nine gastric cancer cell lines for the expression of Wwox.
Experimental Design: Loss of heterozygosity, reverse-transcription-PCR, and immunohistochemistry were used to assess the role of WWOX in stomach cancer. A total of 81 primary gastric adenocarcinoma were analyzed.
Results: Loss of heterozygosity was observed in 31% of the cases and loss of Wwox protein expression was found in 65% of gastric adenocarcinoma primary specimens and 33% of gastric cancer cell lines. In addition, we found a high correlation between Wwox and Fhit protein expression.
Conclusions: Our results indicate that alterations of the WWOX gene may be involved quite frequently in gastric tumorigenesis. Our data could be used in future studies to develop diagnostic and targeted therapy of stomach cancer.
Association between Expression of Transcription Factor Sp1 and Increased Vascular Endothelial Growth Factor Expression, Advanced Stage, and Poor Survival in Patients with Resected Gastric Cancer
Authors: Yao James C. , Wang Liwei , Wei Daoyan , Gong Weida , Hassan Manal , Wu Tsung-Teh , Mansfield Paul , Ajani Jaffer , Xie Keping 
Published: September 2005

Abstract
The biological and clinical behaviors of cancer are affected by multiple molecular pathways that are under the control of transcription factors. Improved understanding of how transcription factors affect cancer biology may lead to improved ability to predict clinical outcome and discovery of novel therapeutic strategies. We evaluated the relationship between Sp1 and vascular endothelial growth factor (VEGF) expression, as well as their effect on survival in 86 cases of resected human gastric cancer. The degree of VEGF expression correlated highly with Sp1 expression (P &lt; 0.01). Patients with high Sp1 expression were 98 times more likely to have high VEGF expression compared with those with negative Sp1 expression. Clinically, negative or weak Sp1 expression was associated with early stage (IA) in gastric cancer. Strong Sp1 expression was more frequently observed among patients with stage IB–IV disease (P = 0.035). Similarly, whereas strong Sp1 expression was uncommonly observed among patients with N0 or N1 disease (19 and 16%), N2/N3 gastric cancer was associated with strong Sp1 expression (48%; P = 0.034). Strong Sp1 expression was also associated with inferior survival. The median survival duration in patients who had a tumor with a negative, weak, and strong Sp1 expression was 44, 38, and 8 months (P = 0.0075), respectively, whereas patients with strong VEGF expression had a shorter survival duration; the difference was not statistically significant. When Sp1 and VEGF expression, stage, completeness of resection, histology, and patient age were entered in a Cox proportional hazards model, strong Sp1 expression (P = 0.021) and an advanced disease stage (P &lt; 0.001) were independently prognostic of poor survival. Given the importance of Sp1 in the expression of VEGF, our data suggest that dysregulated Sp1 expression and activation play important roles in VEGF overexpression and, thus, gastric cancer development and progression.
CXCR4 and CXCL12 (SDF-1) in Prostate Cancer
Authors: Vaday Gayle G. , Hua Shao-Bing , Peehl Donna M. , Pauling Michelle H. , Lin Yu-Huei , Zhu Li , Lawrence Diana M. , Foda Hussein D. , Zucker Stanley 
Published: September 2005

AbstractPurpose: Metastasis is a major cause of morbidity in prostate cancer (PCa). Several studies have shown that the chemokine receptor CXCR4 and its ligand, CXCL12 (stromal cell-derived factor-1), regulate tumor cell metastasis to specific organs. Recently, it was demonstrated that CXCL12 enhances PCa cell adhesion, migration, and invasion, implicating CXCR4 in PCa metastasis. In this study, we examined the inhibitory effects of anti-CXCR4 antibodies on CXCL12-mediated PCa cell activities.Experimental Design: We developed fully human single chain Fv antibodies (scFv), Ab124 and Ab125, against CXCR4 using the yeast two-hybrid system. We performed immunofluorescent staining, flow cytometry, and ELISA-binding assays to measure scFv binding to PCa cells. We also examined the effects of scFv on CXCL12-mediated calcium mobilization, cell migration, and invasion.Results: Our results confirmed that PCa cell lines express cell-surface CXCR4. Real-time quantitative reverse transcription-PCR and immunohistochemical staining also verified that CXCR4 is expressed in primary cultures of prostate epithelial cells from adenocarcinomas and in human prostate tissues. Ab124 and Ab125 demonstrated specific binding to PCa cell lines by flow cytometry and in binding assays. Preincubation with scFv resulted in significant reduction of CXCL12-induced calcium mobilization in PC-3 and LNCaP cells. Ab124 and Ab125 also inhibited PCa cell migration toward CXCL12, as well as invasion through extracellular matrix gels.Conclusions: Ab124 and Ab125 inhibit CXCL12-mediated cellular activities by binding the receptor CXCR4. Recombinant scFv are an efficient mode of targeting tumor antigens. Considering the high incidence of PCa, the development of fully human scFv may be a useful therapeutic approach in the prevention and treatment of PCa metastasis.
A Phase I Trial of a Potent P-Glycoprotein Inhibitor, Zosuquidar Trihydrochloride (LY335979), Administered Intravenously in Combination with Doxorubicin in Patients with Advanced Malignancy
Authors: Sandler Alan , Gordon Michael , de Alwis Dinesh P. , Pouliquen Isabelle , Green Lisa , Marder Phil , Chaudhary Ajai , Fife Karen , Battiato Linda , Sweeney Christopher , Jordan Christopher , Burgess Michael , Slapak Christopher A. 
Published: September 2005

Abstract
Purpose: Our intention was to (a) to investigate the safety and tolerability of a potent P-glycoprotein modulator, zosuquidar trihydrochloride (LY335979), when administered i.v. alone or in combination with doxorubicin, (b) to determine the pharmacokinetics of zosuquidar and correlate exposure to inhibition of P-glycoprotein function in a surrogate assay, and (c) to compare the pharmacokinetics of doxorubicin in the presence and absence of zosuquidar.
Patients and Methods: Patients with advanced malignancies who provided written informed consent received zosuquidar and doxorubicin administered separately during the first cycle of therapy and then concurrently in subsequent cycles. Zosuquidar was given i.v. over 48 h in a cohort-dose escalation manner until the occurrence of dose-limiting toxicity or protocol specified maximum exposure. Doxorubicin doses of 45, 60, 75 mg/m2 were administered during the course of the trial.
Results: Dose escalation proceeded through 9 cohorts with a total of 40 patients. The maximal doses administered were 640 mg/m2 of zosuquidar and 75 mg/m2 of doxorubicin. No dose-limiting toxicity of zosuquidar was observed. Pharmacokinetic analysis revealed that, in the presence of zosuquidar at doses that exceeded 500 mg, there was a modest decrease in clearance (17–22%) and modest increase in area under the curve (15–25%) of doxorubicin. This change was associated with an enhanced leukopenia and thrombocytopenia but was without demonstrable clinical significance. The higher doses of zosuquidar were associated with maximal P-glycoprotein inhibition in natural killer cells.
Conclusion: Zosuquidar can be safely coadministered with doxorubicin using a 48 h i.v. dosing schedule.
The A3 Adenosine Receptor Is Highly Expressed in Tumor
versus
Normal Cells
Authors: Madi Lea , Ochaion Avivit , Rath-Wolfson Lea , Bar-Yehuda Sara , Erlanger Abigail , Ohana Gil , Harish Arie , Merimski Ofer , Barer Faina , Fishman Pnina 
Published: September 2005

Abstract
Purpose: A3 adenosine receptor (A3AR) activation was shown to inhibit the growth of various tumor cells via the down-regulation of nuclear factor κB and cyclin D1. To additionally elucidate whether A3AR is a specific target, a survey of its expression in tumor versus adjacent normal cells was conducted.
Experimental Design: A3AR mRNA expression in various tumor tissues was tested in paraffin-embedded slides using reverse transcription-PCR analysis. A comparison with A3AR expression in the relevant adjacent normal tissue or regional lymph node metastasis was performed. In addition, A3AR protein expression was studied in fresh tumors and was correlated with that of the adjacent normal tissue.
Results: Reverse transcription-PCR analysis of colon and breast carcinoma tissues showed higher A3AR expression in the tumor versus adjacent non-neoplastic tissue or normal tissue. Additional analysis revealed that the lymph node metastasis expressed even more A3AR mRNA than the primary tumor tissue. Protein analysis of A3AR expression in fresh tumors derived from colon (n = 40) or breast (n = 17) revealed that 61% and 78% had higher A3AR expression in the tumor versus normal adjacent tissue, respectively. The high A3AR expression level in the tumor tissues was associated with elevated nuclear factor κB and cyclin D1 levels. High A3AR mRNA expression was also demonstrated in other solid tumor types.
Conclusions: Primary and metastatic tumor tissues highly express A3AR indicating that high receptor expression is a characteristic of solid tumors. These findings and our previous data suggest A3AR as a potential target for tumor growth inhibition.
Reduced Expression of Metastasis Suppressor RhoGDI2 Is Associated with Decreased Survival for Patients with Bladder Cancer
Authors: Theodorescu Dan , Sapinoso L. M. , Conaway M. R. , Oxford G. , Hampton G. M. , Frierson H. F. 
Published: September 2005

Abstract
Purpose: RhoGDI2 was recently shown to be a metastasis suppressor gene in models of bladder cancer. We sought to further understand its importance in human cancer by determining the level of its expression and the distribution of its encoded protein in normal human tissues and cell lines and to evaluate whether its protein expression is a determinant of human bladder cancer progression.
Experimental Design: RhoGDI2 mRNA and protein expression was evaluated in cell lines and human tissues using Affymetrix and tissue microarrays, respectively. Tissue microarrays represented most human normal adult tissues and material from 51 patients that had undergone radical cystectomy for bladder cancer. In these 51 patients, the χ2 test was used to test for associations between RhoGDI2 and stage, grade of urothelial carcinoma, histological type, and disease-specific survival status. Cox proportional hazards regression analyses were used to estimate the effect of RhoGDI2 expression level on time to development of metastatic disease and disease-specific survival time, adjusting for grade, stage, and histological type.
Results: In normal tissues, there was strong RhoGDI2 protein expression in WBCs, endothelial cells, and transitional epithelium. RhoGDI2 mRNA expression was inversely related to the invasive and metastatic phenotype in human bladder cancer cell lines. In patients with bladder cancer, univariate analysis indicated that reduced tumor RhoGDI2 protein expression was associated with a lower actuarial 5-year disease-free and disease-specific survival (P = 0.01). In addition, patients with tumors that had low or absent RhoGDI2 had a shorter time to disease-specific death (P ≤ 0.01). When tumor grade, stage, histological type, and RhoGDI2 staining level were examined using multivariate analysis, RhoGDI2 expression was found to be an independent predictive factor for disease-specific death (P = 0.03).
Conclusions: These results suggest that RhoGDI2 is an independent predictor of prognosis for patients with bladder cancer and provide clinical evidence in support of its involvement in cancer metastasis.
The Membrane-Anchored Matrix Metalloproteinase (MMP) Regulator RECK in Combination with MMP-9 Serves as an Informative Prognostic Indicator for Colorectal Cancer
Authors: Takeuchi Taku , Hisanaga Michiyoshi , Nagao Mitsuo , Ikeda Naoya , Fujii Hisao , Koyama Fumikazu , Mukogawa Tomohide , Matsumoto Hiroshi , Kondo Shunya , Takahashi Chiaki , Noda Makoto , Nakajima Yoshiyuki 
Published: September 2005

Abstract
Purpose: RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue.
Experimental Design: The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically.
Results: RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P = 0.011). Moreover, RECK-dominant (RECK score ≥ MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P = 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P = 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression.
Conclusions: RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.
Simultaneous Expression of Furin and Vascular Endothelial Growth Factor in Human Oral Tongue Squamous Cell Carcinoma Progression
Authors: de Cicco Ricardo López , Watson James C. , Bassi Daniel E. , Litwin Samuel , Klein-Szanto Andrés J. 
Published: September 2005

Abstract
Purpose: Squamous cell carcinoma (SCC) of the tongue is a common malignancy of the oral cavity. Furin convertase activates several precursor matrix metalloproteinases involved in the degradation of the extracellular matrix. The pattern of expression of furin and vascular endothelial growth factor-C (VEGF-C), two key molecules in neoplasm development, was examined during the progression from normal epithelium to invasive SCC.
Experimental Design: We evaluated furin and VEGF-C expression and microvessel density (MVD) by immunohistochemistry in human tongue sections harboring normal epithelium, dysplastic epithelium, and/or SCC. Sections from 46 glossectomy specimens were assessed for furin expression. A selected group of 15 cases, each containing normal epithelium, precursor lesions, and invasive SCC, were further studied for furin and VEGF-C expression and MVD quantification. We also evaluated the pattern of furin expression and VEGF-C processing by Western blot analysis in three SCC cell lines with different degrees of aggressiveness.
Results: Furin and VEGF-C expression was notably higher in most precursor lesions and SCCs than in normal epithelia. Approximately 60% (n = 26) and 100% (n = 15) of the normal epithelia showed low-intensity staining for furin and VEGF-C, respectively. Intense staining for furin and VEGF-C was detected in ∼80% (n = 34) and 100% (n = 15) of the SCCs, respectively. A significant correlation was seen between the expression of these two markers (Spearman’s test, P &lt; 0.00002). We found a statistically significant increase in MVD when either dysplasia (432 ± 19.06; P &lt; 0.05) or SCC (546 ± 17.24) was compared with normal epithelium (315 ± 17.27; P &lt; 0.0001). SCC71, the most aggressive cell line analyzed, was the one with the highest furin expression. This cell line totally processed the VEGF-C proform, whereas the less aggressive line SCC9, exhibiting the least furin expression, did not. SCC15, of intermediate aggressiveness and furin expression, showed intermediate pro-VEGF-C processing.
Conclusions: These findings suggest that furin is a useful marker of tumor progression and is responsible for VEGF-C processing. This in turn would enhance angiogenesis, leading to increased MVD associated with preinvasive and invasive neoplasia.
Simultaneously Targeting Epidermal Growth Factor Receptor Tyrosine Kinase and Cyclooxygenase-2, an Efficient Approach to Inhibition of Squamous Cell Carcinoma of the Head and Neck
Authors: Chen Zhuo (Georgia) , Zhang Xin , Li Mengfeng , Wang Zhiqiang , Wieand H. Samuel , Grandis Jennifer R. , Shin Dong M. 
Published: September 2005

Abstract
Purpose: Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (Cox-2) contribute to development of squamous cell carcinoma of the head and neck (SCCHN). Simultaneously blocking both EGFR and Cox-2–mediated pathways may be an efficient means of inhibiting cancer cell growth in SCCHN.
Experimental Design: A combination of EGFR-selective tyrosine kinase inhibitors (TKIs) AG1478 or ZD1839 (Iressa or gefitinib) with a Cox-2 inhibitor (Cox-2I) celecoxib (Celebrex) was studied for its effects on cell growth, cell cycle progression, and apoptosis in SCCHN cell lines by cell growth assay, clonogenic assay, flow cytometric analysis, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A potential effect of EGFR TKIs and Cox-2I on angiogenesis was examined by endothelial capillary tube formation assay. Primary and secondary targets of EGFR TKIs and Cox-2I were also examined using immunoblotting and immunoprecipitation after the combined treatment.
Results: The combination of AG1478 or ZD1839 with celecoxib either additively or synergistically inhibited growth of the five SCCHN cell lines examined, significantly induced G1 arrest and apoptosis, and suppressed capillary formation of endothelium. Furthermore, the combination showed strong reductions of p-EGFR, p-extracellular signal-regulated kinase 1/2, and p-Akt in SCCHN cells as compared with the single agents. Both AG1478 and ZD1839 inhibited expression of Cox-2 protein, whereas celecoxib mainly blocked the production of prostaglandin E2.
Conclusions: These results suggest that cell growth inhibition induced by a combination of EGFR TKIs and Cox-2I is mediated through simultaneously blocking EGFR and Cox-2 pathways. This combination holds a great potential for the treatment and/or prevention of SCCHN.