bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular Endothelial Growth Factor Gene Polymorphisms Are Associated with Prognosis in Ovarian Cancer
Authors: Hefler Lukas A. , Mustea Alexander , Könsgen Dominique , Concin Nicole , Tanner Berno , Strick Reiner , Heinze Georg , Grimm Christoph , Schuster Eva , Tempfer Clemens , Reinthaller Alexander , Zeillinger Robert 
Published: February 2007

Abstract
Purpose: Vascular endothelial growth factor (VEGF), an important regulator of angiogenesis and vascular permeability, is involved in various steps of ovarian carcinogenesis. Gene polymorphisms within the gene encoding VEGF were shown to be independently associated with an adverse outcome in various malignancies. No data are available for ovarian cancer.
Experimental Design: In the present multicenter study, we examined three common polymorphisms within the VEGF gene (−634G/C, −1154G/A, and −2578C/A) known to be associated with an increased VEGF production in 563 Caucasian patients with ovarian cancer from Austria and Germany using pyrosequencing. Results were correlated with clinical data.
Results: The three investigated polymorphisms did not correlate with any of the investigated clinicopathologic variables. In univariate and multivariate models, no significant correlations between any polymorphism and patients' overall survival were ascertained. Simultaneous carriage of the three homozygous genotypes (i.e., VEGF −634C/C, VEGF −1154G/G, VEGF −2578C/C) known to be associated with increased VEGF expression in an individual patient, however, was independently associated with a shortened overall survival (hazard ratio, 2.1; 95% confidence interval, 1.1-3.9; P = 0.02).
Conclusions: We present the first data on VEGF gene polymorphisms in ovarian cancer. Simultaneous carriage of the three investigated homozygous genotypes was shown to be an independent adverse prognosticator of overall survival.
Suberoylanilide Hydroxamic Acid, a Histone Deacetylase Inhibitor: Effects on Gene Expression and Growth of Glioma Cells In vitro and In vivo
Authors: Yin Dong , Ong John M. , Hu Jinwei , Desmond Julian C. , Kawamata Norihiko , Konda Bindu M. , Black Keith L. , Koeffler H. Phillip 
Published: February 2007

Abstract
Purpose: Histone acetylation is one of the main mechanisms involved in regulation of gene expression. During carcinogenesis, tumor-suppressor genes can be silenced by aberrant histone deacetylation. This epigenetic modification has become an important target for tumor therapy. The histone deacetylation inhibitor, suberoylanilide hydroxamic acid (SAHA), can induce growth arrest in transformed cells. The aim of this study is to examine the effects of SAHA on gene expression and growth of glioblastoma multiforme (GBM) cells in vitro and in vivo.
Experimental Design: The effect of SAHA on growth of GBM cell lines and explants was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Changes of the cell cycle and relative gene expression were detected by fluorescence-activated cell sorting, real-time reverse transcription-PCR, and Western blotting. After glioma cells were implanted in the brains of mice, the ability of SAHA to decrease tumor growth was studied.
Results: Proliferation of GBM cell lines and explants were inhibited in vitro by SAHA (ED50, 2 × 10−6 to 2 × 10−5 mol/L, 5 days). SAHA exposure of human U87 and T98G glioma cell lines, DA66 and JM94 GBM explants, as well as a murine GL26 GBM cell line resulted in an increased accumulation of cells in G2-M of the cell cycle. Many proapoptotic, antiproliferative genes increased in their expression (DR5, TNFα, p21WAF1, p27KIP1), and many antiapoptotic, progrowth genes decreased in their levels (CDK2, CDK4, cyclin D1, cyclin D2) as measured by real-time reverse transcription-PCR and/or Western blot after these GBM cells were cultured with SAHA (2.5 × 10−6 mol/L, 1 day). Chromatin immunoprecipitation assay found that acetylation of histone 3 on the p21WAF1 promoter was markedly increased by SAHA. In vivo murine experiments suggested that SAHA (10 mg/kg, i.v., or 100 mg/kg, i.p.) could cross the blood-brain barrier as shown by prominent increased levels of acetyl-H3 and acetyl-H4 in the brain tissue. Furthermore, the drug significantly (P &lt; 0.05) inhibited the proliferation of the GL26 glioma cells growing in the brains of mice and increased their survival.
Conclusions: Taken together, SAHA can slow the growth of GBM in vitro and intracranially in vivo. SAHA may be a welcome addition for the treatment of this devastating disease.
Chimmitecan, a Novel 9-Substituted Camptothecin, with Improved Anticancer Pharmacologic ProfilesIn vitroandIn vivo
Authors: Huang Min , Gao Heyong , Chen Yi , Zhu Hong , Cai Yujun , Zhang Xiongwen , Miao Zehong , Jiang Hualiang , Zhang Jian , Shen Hongwu , Lin Liping , Lu Wei , Ding Jian 
Published: February 2007

AbstractPurpose: This study aimed to evaluate antitumor activities and pharmacologic profiles of chimmitecan, a novel 9-small-alkyl–substituted lipophilic camptothecin, in comparison with irinotecan (CPT-11) and topotecan.Experimental Design: The in vitro cytotoxities of chimmitecan in human tumor cell lines and multidrug resistance (MDR) cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and sulforhodamin B assays. DNA relaxation, cleavage assays, and cellular band depletion assay were combined to delineate its effects on topoisomerase I. DNA damage, cell cycle arrest, and apoptosis were assessed using comet assay, flow cytometry, and DNA ladder analysis, respectively. The in vivo antitumor activities were measured in nude mice bearing human tumor xenografts.Results: Chimmitecan displayed more potent cytotoxicity than SN38 and topotecan. Neither a cross-resistance to chimmitecan in MDR cells nor an influence of human serum albumin in its cytotoxity was observed. Chimmitecan exhibited comparable effects on topoisomerase I compared with the reference drugs, including inhibiting topoisomerase I catalytic activity and trapping and stabilizing covalent topoisomerase I-DNA complexes. Furthermore, nanomolar levels of chimmitecan caused impressive DNA damage, G2-M phase arrest, and apoptosis in human leukemia HL60 cells. I.v. administration of chimmitecan inhibited the growth of HCT-116, MDA-MB-435, BEL-7402, and A549 human carcinoma xenografts in nude mice, with greater potency than CPT-11 against the latter two tumors models. Chimmitecan presented potent efficacy in A549 tumor model when given orally.Conclusions: Chimmitecan is a potent inhibitor of topoisomerase I and displays outstanding activity in vitro and in vivo. The substitution at the 9-position benefits chimmitecan a salient anti-MDR activity, stability in human serum albumin, improved solubility, and oral availability, which might favorably promise its therapeutic potential in clinical settings.
α1-Antitrypsin Precursor in Gastric Juice Is a Novel Biomarker for Gastric Cancer and Ulcer
Authors: Hsu Ping-I , Chen Chung-Hsuan , Hsieh Chieu-Shia , Chang Wei-Chao , Lai Kwok-Hung , Lo Gin-Ho , Hsu Ping-Ning , Tsay Feng-Woei , Chen Yu-Shan , Hsiao Michael , Chen Hui-Chun , Lu Pei-Jung 
Published: February 2007

Abstract
Purpose: To search for novel disease-specific markers in gastric juice by investigating the protein concentrations and components in gastric juice from patients with various gastroduodenal diseases.
Experimental Design: Protein concentrations and pH values in fasting gastric juice were examined in 120 healthy subjects and 39 gastric ulcer, 38 duodenal ulcer, and 31 gastric cancer patients. The protein components in gastric juice were studied by two-dimensional PAGE and mass spectrometric analysis.
Results: Protein concentrations in gastric juice of patients with gastric ulcers and gastric cancer were significantly higher than those in healthy subjects (1.06 and 2.61 mg/mL versus 0.48 mg/mL; P = 0.001 and P &lt; 0.001, respectively), and duodenal ulcer patients had lower gastric juice protein concentrations compared with healthy subjects (0.26 versus 0.48 mg/mL; P &lt; 0.05). Gastric hypoacidity and advanced age were independent factors affecting the protein concentrations in gastric juice with odds ratios of 32.9 (95% confidence interval, 11.8-90.9) and 3.2 (95% confidence interval, 1.3-8.3), respectively. Each electrophoresis images of gastric juice could be classified into one of three patterns: basic band, specific band, or nonspecific band. The frequencies of specific band pattern in healthy subjects, gastric ulcer, duodenal ulcer, and gastric cancer patients were 6%, 42%, 6%, and 93%, respectively. Proteomic analysis revealed that α1-antitrypsin precursor was the principal peptide in the specific band.
Conclusions: α1-antitrypsin precursor in gastric juice is a novel biomarker for gastric cancer and ulcer. A noninvasive method to obtain gastric juice followed by proteomic analysis may serve as a new tool to screen for gastric malignancies.
NF-Y–Dependent Cyclin B2 Expression in Colorectal Adenocarcinoma
Authors: Park Seon-Hwa , Yu Gyung-Ran , Kim Woo-Ho , Moon Woo-Sung , Kim Jong-Hun , Kim Dae-Ghon 
Published: February 2007

Abstract
Purpose: Cyclin B2, a G2-M cyclin, is overexpressed in colorectal adenocarcinomas compared with the normal mucosa. This study examined the level of cyclin B2 overexpression according to the histologic findings and investigated the mechanism(s) and clinical implications of cyclin B2 overexpression in colorectal adenocarcinomas.
Experimental Design: The immunoreactivity of the polyclonal antibodies to cyclin B2 was determined in colorectal cancer cells. The transcriptional regulation of cyclin B2 by NF-Y was analyzed using an in vitro transfection assay and an in vivo chromatin immunoprecipitation assay. The proliferative activity of the colorectal cancer cells in relation to cyclin B2 overexpression was further examined.
Results: The cytoplasmic distribution of cyclin B2 immunoreactivity was positive in 42 of 65 (64.6%) cases of colorectal adenocarcinoma, and the level was similar regardless of the histologic type. A dominant-negative form of NF-YA effectively inhibited the cyclin B2 promoter activity, and NF-Y was found to bind three conserved CCAAT boxes in the cyclin B2 promoter in colorectal adenocarcinoma cells. Tumor cells with a higher functional cyclin B2 activity grew faster than those with a lower activity. Furthermore, there was a correlation between the cells showing immunoreactivity to cyclin B2 and those containing the proliferating cell nuclear antigen, a G1-S cyclin, which is also downstream of NF-Y in colorectal adenocarcinoma cells.
Conclusions: Cyclin B2 seems to be a molecular marker of a colorectal adenocarcinoma and that its up-regulation and coordinate expression of the other cell cycle–related genes by NF-Y might contribute to tumor cell proliferation by accelerating cell cycle progression.
Class III β-Tubulin Expression and Benefit from Adjuvant Cisplatin/Vinorelbine Chemotherapy in Operable Non–Small Cell Lung Cancer: Analysis of NCIC JBR.10
Authors: Sève Pascal , Lai Raymond , Ding Keyue , Winton Timothy , Butts Charles , Mackey John , Dumontet Charles , Dabbagh Laith , Aviel-Ronen Sarit , Seymour Lesley , Whitehead Marlo , Tsao Ming-Sound , Shepherd Frances A. , Reiman Tony 
Published: February 2007

AbstractPurpose: High class III β-tubulin (bTubIII) expression in advanced non–small cell lung cancer is known to correlate with reduced response rates and inferior survival with anti-microtubule agents. JBR.10 showed a 12% and 15% improvement in 5-year recurrence-free survival (RFS) and overall survival (OS), respectively, with the addition of cisplatin and vinorelbine following resection of stage IB-II non–small cell lung cancer. We sought to determine the effect of bTubIII on patient outcome and benefit from adjuvant chemotherapy in the JBR.10 trial.Experimental Design: We did a semiquantitative immunohistochemical assay for bTubIII on primary tumor tissue available from 265 of the 482 patients in JBR.10. Tumors were classified as bTubIII “low” or “high” using a validated method. We examined the prognostic effect of bTubIII in patients treated with or without chemotherapy and the survival benefit from chemotherapy in low versus high bTubIII subgroups.Results: High bTubIII expression was associated with poorer RFS and OS in patients treated with surgery alone but not in patients treated with adjuvant chemotherapy. The RFS and OS benefits of adjuvant chemotherapy were greater in high versus low tubulin expressors. However, with Cox regression, the interaction between bTubIII status and chemotherapy treatment in predicting RFS or OS did not reach statistical significance.Conclusions: Chemotherapy seemed to overcome the negative prognostic effect of high bTubIII expression. Greater benefit from adjuvant chemotherapy was seen in patients with high bTubIII expression. This is contrary to what has been seen in the setting of advanced disease; possible reasons for this difference are being explored.
Flaxseed and Its Lignans Inhibit Estradiol-Induced Growth, Angiogenesis, and Secretion of Vascular Endothelial Growth Factor in Human Breast Cancer Xenografts In vivo
Authors: Bergman Jungeström Malin , Thompson Lilian U. , Dabrosin Charlotta 
Published: February 2007

Abstract
Purpose: Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis, which is crucial in cancer progression. We have previously shown that estradiol (E2) increases VEGF in breast cancer. Phytoestrogens are potential compounds in breast cancer prevention and treatment by poorly understood mechanisms. The main phytoestrogens in Western diet are lignans, and flaxseed is a rich source of the mammalian lignans enterodiol and enterolactone.
Experimental Design: In the present study, ovariectomized mice were treated with continuous release of E2. MCF-7 tumors were established and mice were fed with basal diet or 10% flaxseed, and two groups that were fed basal diet received daily injections with enterodiol or enterolactone (15 mg/kg body weight).
Results: We show that flaxseed, enterodiol, and enterolactone counteracted E2-induced growth and angiogenesis in solid tumors. Extracellular VEGF in vivo, sampled using microdialysis, in all intervention groups was significantly decreased compared with tumors in the basal diet group. Our in vivo findings were confirmed in vitro. By adding enterodiol or enterolactone, E2-induced VEGF secretion in MCF-7 cells decreased significantly without agonistic effects. The increased VEGF secretion by E2 in MCF-7 cells increased the expression of VEGF receptor-2 in umbilical vein endothelial cells, suggesting a proangiogenic effect by E2 by two different mechanisms, both of which were inhibited by the addition of lignans.
Conclusions: Our results suggest that flaxseed and its lignans have potent antiestrogenic effects on estrogen receptor–positive breast cancer and may prove to be beneficial in breast cancer prevention strategies in the future.
Proteomic Signature Corresponding to the Response to Gefitinib (Iressa, ZD1839), an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma
Authors: Okano Tetsuya , Kondo Tadashi , Fujii Kiyonaga , Nishimura Toshihide , Takano Toshimi , Ohe Yuichiro , Tsuta Koji , Matsuno Yoshihiro , Gemma Akihiko , Kato Harbumi , Kudoh Shoji , Hirohashi Setsuo 
Published: February 2007

Abstract
Purpose: We aimed to identify candidate proteins for tumor markers to predict the response to gefitinib treatment.
Experimental Design: We did two-dimensional difference gel electrophoresis to create the protein expression profile of lung adenocarcinoma tissues from patients who showed a different response to gefitinib treatment. We used a support vector machine algorithm to select the proteins that best distinguished 31 responders from 16 nonresponders. The prediction performance of the selected spots was validated by an external sample set, including six responders and eight nonresponders. The results were validated using specific antibodies.
Results: We selected nine proteins that distinguish responders from nonresponders. The predictive performance of the nine proteins was validated examining an additional six responders and eight nonresponders, resulting in positive and negative predictive values of 100% (six of six) and 87.5% (seven of eight), respectively. The differential expression of one of the nine proteins, heart-type fatty acid–binding protein, was successfully validated by ELISA. We also identified 12 proteins as a signature to distinguish tumors based on their epidermal growth factor receptor gene mutation status.
Conclusions: Study of these proteins may contribute to the development of personalized therapy for lung cancer patients.
Detection of Circulating Tumor Cells in Peripheral Blood of Patients with Metastatic Breast Cancer: A Validation Study of the CellSearch System
Authors: Riethdorf Sabine , Fritsche Herbert , Müller Volkmar , Rau Thomas , Schindlbeck Christian , Rack Brigitte , Janni Wolfgang , Coith Cornelia , Beck Katrin , Jänicke Fritz , Jackson Summer , Gornet Terrie , Cristofanilli Massimo , Pantel Klaus 
Published: February 2007

Abstract
Purpose: The CellSearch system (Veridex, Warren, NJ) is designed to enrich and enumerate circulating tumor cells (CTCs) from peripheral blood. Here, we validated the analytic performance of this system for clinical use in patients with metastatic breast cancer.
Experimental Design: This prospective multicenter study conducted at three independent laboratories involved samples from 92 patients with metastatic breast cancer. Intra- and inter-assay variability using controls containing defined numbers of cells (average, 50 and 1,000, respectively), cell stability based on varying storage and shipment conditions, recovery precision from samples spiked with 4 to 12 tumor cells, inter-instrument variability, and positivity of samples from metastatic breast cancer patients were tested.
Results: Intra- and inter-assay precision for two sites were high: All eight positive controls analyzed in the same run and &gt;95% of the run to run control values (n = 299) were within the specified ranges. Recovery rate of spiked samples averaged between 80% and 82%. CTCs were detected in ∼70% of metastatic breast cancer patients. CTC values of identical samples processed either immediately after blood drawing or after storage for 24, 48, or 72 h at room temperature or at 4°C did not differ significantly. Shipment of samples had no influence on CTC values. When analyzing identical samples in different centers, inter-instrument accordance was high.
Conclusions: The CellSearch system enables the reliable detection of CTCs in blood and is suitable for the routine assessment of metastatic breast cancer patients in the clinical laboratory. Blood samples should be shipped at room temperature and CTC counts are stable for at least 72 h.
CD8+ T cells Reactive to Survivin Antigen in Patients with Multiple Myeloma
Authors: Grube Matthias , Moritz Stephanie , Obermann Ellen C. , Rezvani Katayoun , Mackensen Andreas , Andreesen Reinhard , Holler Ernst 
Published: February 2007

AbstractPurpose: Survivin is a member of the inhibitors of apoptosis family and is overexpressed in different types of malignancies. Cytotoxic T cells recognizing survivin epitopes can be elicited in vitro and by vaccination in patients with leukemia, breast cancer, and melanoma. We did this study to investigate whether survivin-specific CD8+ T cells occur in patients with multiple myeloma.Experimental Design: An HLA-A2.1–binding survivin peptide was used to detect peptide-specific T cells by a quantitative real-time PCR to measure antigen-specific IFN-γ mRNA expression in 23 patients with myeloma and 21 healthy volunteers. T cells producing IFN-γ in response to survivin were further analyzed for expression of CD45RA and CCR7 to determine phenotypic characterization. Additional immunohistochemical analyses of survivin antigen expression in bone marrow specimens of patients was done.Results: T cells recognizing HLA-A2.1–binding survivin peptide were detected in 9 of 23 patients and in 1 of 21 healthy volunteers. Survivin-reactive T cells were identified as terminally differentiated effector T cells (CD8+, CD45RA+, and CCR7−). Positive survivin expression of myeloma cells in bone marrow specimens was shown in 7 of 11 patients.Conclusion: We provide, for the first time, evidence of T cell reactivity against survivin antigen in patients with multiple myeloma. Our data suggest the immunogenicity of survivin antigen in multiple myeloma and that immunotherapeutic strategies using survivin as a target antigen might be an option for patients with this disease.
Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo
Authors: Ponthan Frida , Wickström Malin , Gleissman Helena , Fuskevåg Ole M. , Segerström Lova , Sveinbjörnsson Baldur , Redfern Christopher P.F. , Eksborg Staffan , Kogner Per , Johnsen John I. 
Published: February 2007

Abstract
Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2–specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo.
Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection.
Results: Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin, etoposide, irinotecan or vincristine in vitro. In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans.
Conclusions: Celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. Celecoxib could also be a potential drug for treatment of minimal residual disease.