bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Endothelial Growth Factor Messenger RNA Expression Level Is Preserved in Liver Metastases Compared with Corresponding Primary Colorectal Cancer
Authors: Kuramochi Hidekazu , Hayashi Kazuhiko , Uchida Kazumi , Miyakura Satoru , Shimizu Daisuke , Vallböhmer Daniel , Park Seongjin , Danenberg Kathleen D. , Takasaki Ken , Danenberg Peter V. 
Published: March 2006

Abstract
Purpose: Increased vascular endothelial growth factor (VEGF) expression is associated with colorectal cancer liver metastases. It is reasonable to expect that measurement of VEGF in liver metastases would provide the best prediction of therapy benefit for VEGF-targeted drugs, such as bevacizumab (Avastin). In this study, we evaluated how VEGF mRNA level in primary colorectal cancer was related to that in corresponding liver metastases. Thirty-one pairs of primary colorectal cancer and corresponding liver metastases were analyzed.
Experimental Design: Formalin-fixed, paraffin-embedded tumor specimens were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse transcription. Quantitation of VEGF and internal reference gene (β-actin) was done using real-time PCR (Taqman PCR).
Results: There was no difference between median VEGF mRNA levels of primary colorectal cancer and liver metastases (median value 3.79 versus 3.97: P = 0.989). On an individual basis, there was a significant correlation in VEGF mRNA expression between primary colorectal cancer and corresponding liver metastases (rs = 0.6627, P &lt; 0.0001). In addition, the VEGF mRNA levels of the patients who had two or more liver metastatic tumors were significantly higher than those of the patient who had solitary liver metastatic tumor in both primary cancer (5.02 versus 3.34: P = 0.0483) and liver metastases (4.38 versus 3.25: P = 0.0358).
Conclusion: Good prediction of VEGF mRNA levels in liver metastases can be obtained by measuring those of primary colorectal cancer. The risk of multiple liver metastatic tumors might be predictable by measuring VEGF mRNA expression in primary colorectal cancer. Further study is required to confirm these preliminary results.
T-Cell Responses Directed against Multiple HLA-A*0201-Restricted Epitopes Derived from Wilms' Tumor 1 Protein in Patients with Leukemia and Healthy Donors: Identification, Quantification, and Characterization
Authors: Rezvani Katayoun , Brenchley Jason M. , Price David A. , Kilical Yasemin , Gostick Emma , Sewell Andrew K. , Li Jongming , Mielke Stephan , Douek Daniel C. , Barrett A. John 
Published: March 2006

AbstractPurpose: Antigens derived from the Wilms' tumor (WT1) protein, which is overexpressed in leukemias, are attractive targets for immunotherapy. Four HLA-A*0201-restricted WT1-derived epitopes have been identified: WT37, WT126, WT187, and WT235. We determined the natural immunogenecity of these antigens in patients with hematologic malignancies and healthy donor.Experimental Design: To detect very low frequencies of WT1-specific CD8+ T cells, we used quantitative reverse transcription-PCR to measure IFN-γ mRNA production by WT1 peptide–pulsed CD8+ T cells from 12 healthy donors, 8 patients with chronic myelogenous leukemia, 6 patients with acute myelogenous leukemia, and 8 patients with acute lymphoblastic leukemia.Results: Responses were detected in 5 of 8 chronic myelogenous leukemia patients, 4 of 6 patients with acute myelogenous leukemia, and 7 of 12 healthy donors. No responses were detected in patients with acute lymphoblastic leukemia. The magnitude and extent of these CD8+ T-cell responses was greater in patients with myeloid leukemias than in healthy donors. Clonotypic analysis of WT1-specific CD8+ T cells directly ex vivo in one case showed that this naturally occurring population was oligoclonal. Using fluorescent peptide-MHC class I tetramers incorporating mutations in the α3 domain (D227K/T228A) that abrogate binding to the CD8 coreceptor, we were able to confirm the presence of high-avidity T-cell clones within the antigen-specific repertoire.Conclusion: The natural occurrence of high-avidity WT1-specific CD8+ T cells in the periphery could facilitate vaccination strategies to expand immune responses against myeloid leukemias.
Epigenetic Inactivation of Wnt Inhibitory Factor-1 Plays an Important Role in Bladder Cancer through Aberrant Canonical Wnt/β-Catenin Signaling Pathway
Authors: Urakami Shinji , Shiina Hiroaki , Enokida Hideki , Kawakami Toshifumi , Tokizane Takashi , Ogishima Tatsuya , Tanaka Yuichiro , Li Long-Cheng , Ribeiro-Filho Leopoldo A. , Terashima Masaharu , Kikuno Nobuyuki , Adachi Hiroyuki , Yoneda Tatsuaki , Kishi Hirofumi , Shigeno Kazushi , Konety Badrinath R. , Igawa Mikio , Dahiya Rajvir 
Published: March 2006

AbstractPurpose: Aberrant activation of the Wingless-type (Wnt) pathway plays a significant role in the pathogenesis of several human cancers. Wnt inhibitory factor-1 (Wif-1) was identified as one of the secreted antagonists that can bind Wnt protein. We hypothesize that Wif-1 plays an important role in bladder cancer pathogenesis.Experimental Design: To test this hypothesis, epigenetic and genetic pathways involved in the Wif-1 gene modulation and expression of Wnt/β-catenin-related genes were analyzed in 4 bladder tumor cell lines and 54 bladder tumor and matched normal bladder mucosa.Results: Wif-1 mRNA expression was significantly enhanced after 5-aza-2′-deoxycytidine treatment in bladder tumor cell lines. Wif-1 promoter methylation level was significantly higher and Wif-1 mRNA expression was significantly lower in bladder tumor samples than in bladder mucosa samples. In the total bladder tumor and bladder mucosa samples, an inverse correlation was found between promoter methylation and Wif-1 mRNA transcript levels. However, loss-of-heterozygosity at chromosome 12q14.3 close to the Wif-1 gene loci was a rare event (3.7%). Nuclear accumulation of β-catenin was significantly more frequent in bladder tumor than in bladder mucosa and inversely correlated with Wif-1 expression. In addition, known targets of the canonical Wnt/β-catenin signaling pathway, such as c-myc and cyclin D1, were up-regulated in bladder tumor compared with bladder mucosa, and this up-regulation was associated with reduced Wif-1 expression at both mRNA and protein levels. Furthermore, transfection of Wif-1 small interfering RNA into bladder tumor cells expressing Wif-1 mRNA transcripts had increased levels of c-myc and cyclin D1 and accelerated cell growth.Conclusion: This is the first report showing that CpG hypermethylation of the Wif-1 promoter is a frequent event in bladder tumor and may contribute to pathogenesis of bladder cancer through aberrant canonical Wnt/β-catenin signaling pathway. The present study elucidates novel pathways that are involved in the pathogenesis of bladder cancer.
Chemokine C Receptor 7 Expression and Protection of Circulating CD8+ T Lymphocytes from Apoptosis
Authors: Kim Jeong-Whun , Ferris Robert L. , Whiteside Theresa L. 
Published: March 2006

Abstract
Chemokine C receptor 7 (CCR7) expression is important for lymphocyte homing to tissues. We hypothesized that CCR7 also plays a role in CD8+ T-cell protection from apoptosis. Its expression was determined on circulating T cells in patients with cancer and related to that of molecules responsible for lymphocyte susceptibility/resistance to apoptosis. Peripheral blood mononuclear cells were obtained from 36 patients with squamous cell carcinoma of the head and neck and 16 normal controls. Multicolor flow cytometry was used to evaluate CCR7, Fas, Bax, and Bcl-2 expression in CD8+ T cells. Annexin V binding to CD8+CCR7+ and CD8+CCR7− T-cell subsets was compared. Fewer CD8+CCR7+ T cells bound Annexin V than CD8+CCR7− T cells in normal control and patients (P &lt; 0.0001). CCR7 expression correlated with higher Bcl-2 but lower Bax and Fas expression levels in CD8+ T cells in both normal control and patients (P &lt; 0.0001). In patients, the CD8+CCR7+ subset was reduced relative to normal control (P = 0.008) and replaced with an excess of apoptosis-sensitive CD8+CCR7− T cells. To study CCR7 signaling, CD8+ T cells were stimulated with CCR7 ligands, chemokine C ligands 19 or 21. Ligand binding to CCR7 resulted in phosphorylation of Akt and increased Bcl-2 expression in CD8+CCR7+ T cells, suggesting that CCR7 protects effector T cells from apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. The absence of CCR7 expression on the majority of CD8+ T cells in the peripheral circulation of patients with squamous cell carcinoma of the head and neck contributes to apoptosis and a rapid turnover of these effector cells.
Expression of Hepatoma-Derived Growth Factor Is Correlated with Lymph Node Metastasis and Prognosis of Gastric Carcinoma
Authors: Yamamoto Shinji , Tomita Yasuhiko , Hoshida Yoshihiko , Takiguchi Shuji , Fujiwara Yoshiyuki , Yasuda Takushi , Doki Yuichiro , Yoshida Kenya , Aozasa Katsuyuki , Nakamura Hideji , Monden Morito 
Published: March 2006

Abstract
Purpose: Hepatoma-derived growth factor (HDGF) is a unique nuclear/growth factor and might play an important role in the development and progression of carcinomas. In the present study, association of HDGF expression with recurrence and prognosis of gastric carcinoma was examined.
Patients and Methods: HDGF expression in 317 patients with gastric carcinoma (233 males and 84 females) with ages ranging from 26 to 81 years (median, 60 years) was analyzed by immunohistochemistry. Samples with &gt;90% of tumor cells to express positive immunoreactivity similar to or stronger than that in endothelial cells both for nucleus and cytoplasm were regarded as HDGF index level 2, and others as HDGF index level 1.
Results: One hundred and eighty-two cases showed level 1 HDGF expression, whereas 135 cases showed level 2 HDGF expression. Patients with level 2 expression showed higher rates of proximal tumor location (P &lt; 0.0001), large tumor size (P &lt; 0.0001), infiltrative tumor growth (P &lt; 0.0001), presence of vascular and lymphatic invasion (P &lt; 0.0001 for both), presence of lymph node metastasis (P &lt; 0.0001), deep tumor invasion (P &lt; 0.0001), and poorer disease-free and overall survival (P &lt; 0.0001 for both) compared to those with level 1 expression. Multivariate analysis revealed HDGF expression level as an independent prognosticator for disease-free and overall survival.
Conclusion: HDGF expression level was shown to be a prognostic factor for gastric carcinoma.
Effect of Repetitive Administration of Doxorubicin-Containing Liposomes on Plasma Pharmacokinetics and Drug Biodistribution in a Rat Brain Tumor Model
Authors: Arnold Robert D. , Mager Donald E. , Slack Jeanine E. , Straubinger Robert M. 
Published: March 2006

AbstractPurpose: The incorporation of doxorubicin in long-circulating sterically stabilized liposomes (SSL-DXR) alters the pharmacokinetics and biodistribution of doxorubicin and therefore has the potential to alter the pharmacologic properties of doxorubicin. Previously, we showed that repetitive administration of SSL-DXR alters tumor vascular permeability.Experimental Design: Here, we investigated the effect of weekly i.v. injections of SSL-DXR on plasma pharmacokinetics and drug biodistribution in the orthotopic 9L rat brain tumor model.Results and Conclusions: The pharmacokinetics of free doxorubicin (5.67 mg/kg) did not change with repeat dosing. In contrast, drug concentrations in plasma and brain tumor increased and deposition in liver and spleen decreased after administration of the second of two weekly doses of SSL-DXR. Noncompartmental analysis and descriptive pharmacokinetic models were created to test hypotheses relating to the mechanisms responsible for alterations in SSL-DXR deposition. The analysis suggested that weekly administration of SSL-DXR significantly (P &lt; 0.05) decreased the plasma elimination rate of SSL-DXR (34%) and decreased drug deposition in liver (2-fold) and spleen (3.5-fold). The pharmacokinetic model that best captured the observed 2.5-fold increase in tumor uptake of SSL-DXR mediated by repeat dosing was one that hypothesized that the rates of drug influx/efflux into tumor were increased by the first dose of SSL-DXR. Models that accounted only for residual drug deposited in the tissue or blood by the first weekly injection provided inferior fits to the data. Thus, the effects of repetitive dosing on SSL-DXR deposition in tumor are consistent with a treatment-mediated alteration of tumor vascular permeability.
DNA Polymerase ζ Accounts for the Reduced Cytotoxicity and Enhanced Mutagenicity of Cisplatin in Human Colon Carcinoma Cells That Have Lost DNA Mismatch Repair
Authors: Lin Xinjian , Trang Julie , Okuda Tsuyoshi , Howell Stephen B. 
Published: March 2006

Abstract
The mutagenicity of cis-diamminedichloroplatinum(II) (DDP; cisplatin) and the rate at which resistance develops with repeated exposure to DDP are dependent on mutagenic translesional replication across DDP DNA adducts, mediated in part by DNA polymerase ζ, and on the integrity of the DNA mismatch repair (MMR) system. The aim of this study was to determine whether disabling Pol ζ by suppressing expression of its hREV3 subunit in human cancer cells can reduce the mutagenicity of DDP and whether loss of MMR facilitates mutagenic Pol ζ-dependent translesional bypass. The HCT116+ch3 (MMR+/REV3+) and HCT116 (MMR−/REV3+) human colon carcinoma cell lines were engineered to suppress hREV3 mRNA by stable expression of a short hairpin interfering RNA targeted to hREV3. The effect of knocking down REV3 expression was to completely offset the DDP resistance mediated by loss of MMR. Knockdown of REV3 also reduced the mutagenicity of DDP and eliminated the enhanced mutagenicity of DDP observed in the MMR−/REV3+ cells. Similar results were obtained when the ability of the cells to express luciferase from a platinated plasmid was measured. We conclude that Pol ζ plays a central role in the mutagenic bypass of DDP adducts and that the DDP resistance, enhanced mutagenicity, and the increased capacity of MMR−/REV3+ cells to express a gene burdened by DDP adducts are all dependent on the Pol ζ pathway.
Genetic characterization of fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma.
Authors: Yeh Shiou-Hwei , Wu Dai-Chen , Tsai Ching-Yi , Kuo Ti-Jung , Yu Wei-Che , Chang Yuan-Shau , Chen Chi-Ling , Chang Ching-Fang , Chen Ding-Shinn , Chen Pei-Jer 
Published: March 2006

Abstract
PURPOSE: Allelic loss at chromosome 4q21-23 occurs frequently in human hepatocellular carcinoma, and the putative tumor suppressor gene (TSG) has not yet been identified. We studied the Fas-associated phosphatase-1 (FAP-1) gene as a potential candidate TSG in this region. EXPERIMENTAL DESIGN: The expression level of FAP-1 RNA in hepatocellular carcinomas was evaluated by RNase protection and quantitative PCR. Sodium bisulfite modification and subsequent single-strand conformational polymorphism and sequence analyses were used to assay the methylation of CpGs at FAP-1 promoter. Direct sequencing of the FAP-1 coding region was conducted for detecting the genetic mutations. Two common single nucleotide polymorphisms of FAP-1 were selected for evaluating their association with the hepatocellular carcinoma trait in sporadic and familial hepatocellular carcinomas. Moreover, the functional effect of FAP-1 on cellular proliferation has been evaluated by small interfering RNA approach. RESULTS: Around 50% of hepatocellular carcinomas showed significantly decreased expression of FAP-1 compared with the corresponding nontumorous liver tissues. In most cases, the RNA level was well correlated with the methylation status of promoter CpGs, suggesting that the promoter methylation may contribute to the down-regulation. Several genetic mutations of FAP-1 have been identified in hepatocellular carcinomas. The G/G genotype of FAP-1 cSNP6304 was significantly associated with the increased risk of multiplex familial hepatocellular carcinomas (odds ratio, 2.44; 95% confidence interval, 1.19-5.01). Finally, knockdown expression of FAP-1 was shown to enhance the cellular proliferation in PLC5 cells. CONCLUSIONS: FAP-1 could be inactivated during hepatocarcinogenesis, mainly attributed by allelic loss and promoter methylation. The genetic mutations and polymorphisms may also confront with the higher hepatocellular carcinoma risk. These results first suggested FAP-1 as a putative TSG in hepatocarcinogenesis.
Docetaxel Followed by Castration Improves Outcomes in LNCaP Prostate Cancer–Bearing Severe Combined Immunodeficient Mice
Authors: Tang Yao , Khan Mohammad A. , Goloubeva Olga , Lee Dong I. , Jelovac Danijela , Brodie Angela M. , Hussain Arif 
Published: March 2006

Abstract
Purpose: Androgen ablation is the standard initial treatment for advanced prostate cancer; however, tumors eventually develop androgen independence and become incurable. Chemotherapy is commonly used after hormone treatment fails but has not shown significant survival benefit. Studies suggest that androgen ablation can select for a population of hormone-independent cells that are also relatively chemotherapy resistant. Thus, it may be therapeutically advantageous to target prostate cancer with chemotherapy before hormone ablation. This study was undertaken to determine the relative efficacy of such an approach in a preclinical model of prostate cancer.
Experimental Design: Severe combined immunodeficient mice bearing human LNCaP prostate tumors were treated with docetaxel and/or surgical castration applied singly, concurrently, or in different sequences. Treatment efficacy was determined by tumor volume and growth delay measurements. The extent of apoptosis in tumors in response to treatments was assessed via terminal deoxynucleotidyl transferase–mediated nick-end labeling (TUNEL) assays. In addition, Western blots were done to study the relative expression of Bcl-2 and Bax in the tumors.
Results: Docetaxel followed by castration showed the most potent antitumor effects. In contrast, with the exception of castration alone, castration followed by docetaxel produced the least antitumor activity. TUNEL assays confirmed that the density of apoptotic tumor cells was significantly greater for docetaxel followed by castration than for any other treatment. In tumors of mice treated with single modality therapies, Bax to Bcl-2 ratios decreased significantly after castration, whereas this ratio remained high after docetaxel treatment.
Conclusion: A treatment sequence of docetaxel followed by hormone ablation may be more effective in treating prostate cancer than concurrent docetaxel/hormone therapy or hormone ablation followed by docetaxel.
Increased MDR1 Expression in Normal and Malignant Peripheral Blood Mononuclear Cells Obtained from Patients Receiving Depsipeptide (FR901228, FK228, NSC630176)
Authors: Robey Robert W. , Zhan Zhirong , Piekarz Richard L. , Kayastha Ganesh L. , Fojo Tito , Bates Susan E. 
Published: March 2006

Abstract
The increased expression of markers associated with a differentiated phenotype, such as P-glycoprotein (Pgp), follows treatment with histone deacetylase inhibitors. Because depsipeptide (FR901228, FK228, NSC630176) is a substrate for Pgp, up-regulation of the gene that encodes it, MDR1, would mean that depsipeptide induces its own mechanism of resistance. To examine the effect of depsipeptide on expression of ATP-binding cassette transporters associated with multidrug resistance, the kidney cancer cell lines 108, 121, 127, and 143 were treated with depsipeptide and evaluated by quantitative reverse transcription-PCR. Increased levels of MDR1 (1.3- to 6.3-fold) and ABCG2 (3.2- to 11.1-fold) but not MRP1 (0.9- to 1.3-fold) were observed. The induced Pgp transported the fluorescent substrates rhodamine 123, bisantrene, calcein-AM, BODIPY-vinblastine, and BODIPY-paclitaxel. In normal peripheral blood mononuclear cells (PBMC) and circulating tumor cells obtained from patients receiving depsipeptide, increased levels of histone H3 acetylation were found. We next examined MDR1 levels in normal and malignant PBMCs obtained from 15 patients enrolled in clinical trials with depsipeptide and detected up to a 6-fold increase in normal PBMCs and up to an 8-fold increase in circulating tumor cells after depsipeptide administration. In one patient with Sézary syndrome, increased MDR1 gene expression was accompanied by increased cell surface Pgp expression in circulating Sézary cells as determined by measurement of MRK-16 staining by flow cytometry. These studies suggest that depsipeptide induces its own mechanism of resistance and thus provide a basis for clinical trials evaluating depsipeptide in combination with a Pgp inhibitor.
Activation of Neutrophils in Cutaneous T-Cell Lymphoma
Authors: Goddard Deborah S. , Yamanaka Kei-ichi , Kupper Thomas S. , Jones David A. 
Published: March 2006

Abstract
Purpose: Cutaneous T-cell lymphoma (CTCL) is a spectrum of disease of unknown etiology defined by infiltrates of activated and malignant T cells in the skin. In working with blood from CTCL patients, we noticed frequent activation of neutrophils; therefore, we tested the hypothesis that neutrophils are activated in CTCL subjects compared with normal healthy controls.
Experimental Design: Using peripheral blood of 44 subjects with CTCL and 15 normal controls, we examined three measures of neutrophil activation. These are the presence of neutrophils of reduced buoyant density, the presence of primed neutrophils in a stimulated chemiluminescence assay, and changes in surface markers by flow cytometry. In addition, we tested plasma interleukin-8 (IL-8) and leukotriene B4 (LTB4) levels using ELISA.
Results: A significantly larger fraction of hypodense neutrophils was observed in CTCL subjects compared with normals (10.6 ± 1.7% versus 1.5 ± 0.4%). Stimulated chemiluminescence was also significantly increased in CTCL, and analysis of neutrophil surface markers using flow cytometry showed significantly increased CD11b and CD66b and decreased CD62L, consistent with neutrophil activation. These changes were present even in early stages of CTCL. We further found that plasma IL-8 and LTB4 levels are elevated in CTCL, which could form a feedback loop contributing to disease pathophysiology.
Conclusions: CTCL is associated with systemic neutrophil activation, even in early disease, and a feedback loop between neutrophils and T cells mediated by IL-8 and LTB4 is a potential contribution to the pathophysiology of CTCL.
Celecoxib Decreases Ki-67 Proliferative Index in Active Smokers
Authors: Mao Jenny T. , Fishbein Michael C. , Adams Bradley , Roth Michael D. , Goodglick Lee , Hong Longsheng , Burdick Marie , Strieter E. Robert M. , Holmes Carmack , Tashkin Donald P. , Dubinett Steven M. 
Published: March 2006

Abstract
Purpose: This study evaluated the feasibility of cyclooxygenase-2 (COX-2) inhibition for lung cancer chemoprevention. We hypothesized that treatment with oral Celecoxib, a selective COX-2 inhibitor, would favorably alter the biomarkers of lung cancer risk as measured by the Ki-67 proliferative labeling index (Ki-67 LI).
Experimental Design: Twenty active heavy smokers were enrolled into a pilot study and treated with Celecoxib for 6 months. Bronchoscopies with bronchial biopsies were done before and after 6 months of Celecoxib treatment. H&E stain for histologic grading and immunohistochemical examination for Ki-67 LI, COX-2, and survivin were carried out on serially matched biopsy samples to determine responses to treatment.
Results: Treatment with Celecoxib significantly reduced Ki-67 LI in smokers by 35% (P = 0.016), and increased the expression of nuclear survivin by 23% (P = 0.036) without significantly changing that of cytoplasmic survivin.
Conclusions: Our findings suggest that oral Celecoxib may be capable of modulating the proliferation indices and apoptotic balance in bronchial tissue of active smokers.