bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stratification of Intermediate-Risk Endometrial Cancer Patients into Groups at High Risk or Low Risk for Recurrence Based on Tumor Gene Expression Profiles
Authors: Ferguson Sarah E. , Olshen Adam B. , Viale Agnès , Barakat Richard R. , Boyd Jeff 
Published: September 2005

Abstract
Purpose: Endometrial cancers classified as “intermediate risk” based on clinical and/or pathologic features are associated with a 15% to 20% risk of recurrence. Here, we test whether global gene expression profiling can distinguish intermediate-risk tumors into high-risk and low-risk subgroups.
Experimental Design: Tumor specimens were obtained from 75 intermediate-risk endometrial cancer patients, 13 who had recurred and 62 who had not recurred with a median follow-up of 24 months. Gene expression profiles were obtained using the Affymetrix U133A GeneChip oligonucleotide microarray. The genes most associated with risk of recurrence were used to create a risk score using a leave-one-out cross-validation method and the univariate Cox proportional hazards regression model. Time to recurrence curves for the high-risk and low-risk subgroups were estimated using the Kaplan-Meier method, and the difference in time to recurrence between these two subgroups was tested using the log-rank test.
Results: There was a significant difference in time to recurrence between high-risk and low-risk patients using risk scores as defined above (P = 0.04). The estimated hazard ratio (95% confidence interval) was 3.07 (1.00-9.43).
Conclusions: Patients with intermediate-risk endometrial cancers identified as high-risk for recurrence according to a gene expression–based risk score have a significantly increased risk for recurrence compared with those classified as low risk. These findings suggest that gene expression profiling can potentially contribute to the clinical classification and management of intermediate-risk endometrial cancers.
Regulation of Fibroblast Growth Factor-2 Activity by Human Ovarian Cancer Tumor Endothelium
Authors: Whitworth Melissa K. , Backen Alison C. , Clamp Andrew R. , Wilson Godfrey , McVey Rhona , Friedl Andreas , Rapraeger Alan C. , David Guido , McGown Alan , Slade Richard J. , Gallagher John T. , Jayson Gordon C. 
Published: September 2005

Abstract
Fibroblast growth factor-2 (FGF-2) is a potent angiogenic cytokine that is dependent on heparan sulfate for its biological activity. We have investigated the relationship among heparan sulfate, FGF-2, and the signal-transducing receptors in human, advanced-stage, serous ovarian adenocarcinoma. Using a unique molecular probe, FR1c-Ap, which consisted of a soluble FGF receptor 1 isoform lllc covalently linked to an alkaline phosphatase moiety, the distribution of heparan sulfate that had the ability to support the formation of a heparan sulfate/FGF-2/FGFR1 isoform IIIc alkaline phosphatase heparan sulfate construct complex was determined. This may be taken as a surrogate marker for the distribution of biologically active heparan sulfate and was distributed predominantly in endothelial cells and stroma but was absent from adenocarcinoma cells. In situ hybridization revealed the expression of FGFR1 mRNA in the endothelium and reverse transcription-PCR confirmed the presence of FGFR1 isoform IIIc but not isoform IIIb. The presence of FGF-2 around tumor endothelium was detected through immunohistochemistry. Double-staining techniques showed that heparan sulfate was found predominantly at the basal aspect of the endothelium and suggested that syndecan-3 might function as one of the proteoglycans involved in FGF-2 signaling in the endothelium. The data suggest that the entire extracellular signaling apparatus, consisting of FGF-2, biologically active heparan sulfate, and FGFRs capable of responding to FGF-2, is present in ovarian cancer endothelium, thereby highlighting the cytokine and its cognate receptor as potential targets for the antiangiogenic treatment of this disease.
A Phase I Study of α-Galactosylceramide (KRN7000)–Pulsed Dendritic Cells in Patients with Advanced and Recurrent Non–Small Cell Lung Cancer
Authors: Ishikawa Aki , Motohashi Shinichiro , Ishikawa Eiichi , Fuchida Hiroki , Higashino Kazuko , Otsuji Mizuto , Iizasa Toshihiko , Nakayama Toshinori , Taniguchi Masaru , Fujisawa Takehiko 
Published: September 2005

AbstractPurpose: Human Vα24 natural killer T (NKT) cells bearing an invariant Vα24JαQ antigen receptor, the counterpart of murine Vα14 NKT cells, are activated by a specific ligand, α-galactosylceramide (αGalCer, KRN7000), in a CD1d-dependent manner. I.v. administration of αGalCer-pulsed dendritic cells (DC) induces significant activation and expansion of Vα14 NKT cells in the lung and resulting potent antitumor activities in mouse tumor metastatic models. We did a phase I dose escalation study with αGalCer-pulsed DCs in lung cancer patients.Experimental Design: Patients with advanced non–small cell lung cancer or recurrent lung cancer received i.v. injections of αGalCer-pulsed DCs (level 1: 5 × 107/m2; level 2: 2.5 × 108/m2; and level 3: 1 × 109/m2) to test the safety, feasibility, and clinical response. Immunomonitoring was also done in all completed cases.Results: Eleven patients were enrolled in this study. No severe adverse events were observed during this study in any patient. After the first and second injection of αGalCer-pulsed DCs, dramatic increase in peripheral blood Vα24 NKT cells was observed in one case and significant responses were seen in two cases receiving the level 3 dose. No patient was found to meet the criteria for partial or complete responses, whereas two cases in the level 3 group remained unchanged for more than a year with good quality of life.Conclusions: In this clinical trial, αGalCer-pulsed DC administration was well tolerated and could be safely done even in patients with advanced disease.
SMAD4 as a Prognostic Marker in Colorectal Cancer
Authors: Alazzouzi Hafid , Alhopuro Pia , Salovaara Reijo , Sammalkorpi Heli , Järvinen Heikki , Mecklin Jukka-Pekka , Hemminki Akeseli , Schwartz Simo , Aaltonen Lauri A. , Arango Diego 
Published: September 2005

Abstract
More than 50% of patients with Dukes C colorectal cancer have disease recurrence and die within 5 years after surgical removal of their primary tumor. It is currently not possible to distinguish patients with good and bad prognosis. SMAD4 is an important tumor suppressor gene that mediates transforming growth factor-β superfamily signaling and is located in chromosome 18q21, a region with frequent genetic losses in these tumors. Allelic imbalance in 18q has been linked to poor prognosis in a subset of colorectal cancer patients. Therefore, we generated a tissue microarray containing triplicate tumor samples from 86 Dukes C patients and used immunohistochemistry to assess the relative expression level of SMAD4 and its value as a prognostic marker. In addition, SMAD4 was screened for mutations and two polymorphic microsatellite markers were used to assess the presence of allelic imbalance in these tumors. Patients with tumors expressing high SMAD4 levels had significantly better overall (P &lt; 0.025) and disease-free (P &lt; 0.013) survival than patients with low levels. This identifies SMAD4 as a prognostic marker for Dukes C colorectal cancer. Although all tumors with absent SMAD4 staining showed allelic imbalance in 18q21, tumors with 18q21 allelic imbalance as a group showed no difference in SMAD4 levels compared with tumors without allelic imbalance, suggesting that additional mechanisms of SMAD4 down-regulation exist. In addition, although SMAD4 mutations were found in five tumors, they were not associated with shorter survival. In conclusion, the level of expression of SMAD4 was found to be a more sensitive marker than 18q21 allelic imbalance and SMAD4 mutations, which were of no prognostic significance for these patients.
Evasion of a Single-Step, Chemotherapy-Induced Senescence in Breast Cancer Cells: Implications for Treatment Response
Authors: Elmore Lynne W. , Di Xu , Dumur Catherine , Holt Shawn E. , Gewirtz David A. 
Published: September 2005

AbstractPurpose: The purpose of this study is to define the mechanistic basis for recovery of proliferative capacity in breast tumor cells after chemotherapy. Here, we test the hypothesis that evasion of senescence confers resistance to chemotherapeutic drugs and ionizing radiation.Experimental Design: MCF-7 cells were treated with a single, clinically relevant dose (0.75-1.0 μmol/L) of Adriamycin. Two weeks following induction of senescence, clonal outgrowths were expanded and characterized in terms of senescence-associated β-galactosidase activity, gene expression profiles (Affymetrix U95 probe sets, Affymetrix, Santa Clara, CA) with confirmatory Western analyses, and telomerase activity following a second drug treatment. Levels of intracellular Adriamycin, as well as cross-resistance to other therapeutic agents, were also determined to define the resistance phenotype.Results: A senescence-resistant (SR) clone (clone 2) was identified that was largely refractory to both Adriamycin-induced and γ-irradiation–induced senescence. Clone 2 continued to proliferate and maintain high levels of telomerase activity following a second drug treatment, when treated parental cells expressed very low levels of telomerase and many positive cell cycle regulators. SR clone 2 also expressed substantially more cdc-2 than parental cells and undetectable levels of MDR1, showed an intact p53 checkpoint and only a modestly lower level of intracellular drug accumulation, while exhibiting cross-resistance to other topoisomerase inhibitors.Conclusions: SR clone 2 is intrinsically resistant to DNA damage–induced senescence perhaps through an ability to prevent down-regulation of cdc-2. Telomerase is a marker of proliferative recovery for breast cancer cells after chemotherapy exposure. Evasion or escape from a single-step, drug-induced senescence may represent a unique and previously unrecognized drug-resistance phenotype.
Caspase Regulation in Non–Small Cell Lung Cancer and its Potential for Therapeutic Exploitation
Authors: Fennell Dean A. 
Published: September 2005

Abstract
Metastatic non–small cell lung cancer (NSCLC, stages IIIB/IV) is one of the most common and rapidly lethal causes of cancer related mortality worldwide. Efficacy of chemotherapy, the mainstay of treatment, is limited due to resistance in the vast majority of patients. NSCLC cells exhibit intrinsic apoptosis resistance. Understanding the molecular basis of this phenotype is critical, if therapy is to move beyond the therapeutic plateau that has been reached with conventional chemotherapy. Caspases occupy a pivotal position in the final common pathway of apoptosis. Increasing evidence suggests that these proteases are constitutively inhibited in NSCLC. This review discusses current knowledge relating to caspase regulation in NSCLC and highlights novel strategies for reversing the apoptosis resistant phenotype, with potential to accelerate development of effective therapy.
Severe Drug Toxicity Associated with a Single-Nucleotide Polymorphism of the Cytidine Deaminase Gene in a Japanese Cancer Patient Treated with Gemcitabine plus Cisplatin
Authors: Yonemori Kan , Ueno Hideki , Okusaka Takuji , Yamamoto Noboru , Ikeda Masafumi , Saijo Nagahiro , Yoshida Teruhiko , Ishii Hiroshi , Furuse Junji , Sugiyama Emiko , Kim Su-Ryang , Kikura-Hanajiri Ruri , Hasegawa Ryuichi , Saito Yoshiro , Ozawa Shogo , Kaniwa Nahoko , Sawada Jun-ichi 
Published: September 2005

Abstract
Purpose: We investigated single-nucleotide polymorphisms of the cytidine deaminase gene (CDA), which encodes an enzyme that metabolizes gemcitabine, to clarify the relationship between the single-nucleotide polymorphism 208G&gt;A and the pharmacokinetics and toxicity of gemcitabine in cancer patients treated with gemcitabine plus cisplatin.
Experimental Design: Six Japanese cancer patients treated with gemcitabine plus cisplatin were examined. Plasma gemcitabine and its metabolite 2′,2′-difluorodeoxyuridine were measured using an high-performance liquid chromatography method, and the CDA genotypes were determined with DNA sequencing.
Results: One patient, a 45-year-old man with pancreatic carcinoma, showed severe hematologic and nonhematologic toxicities during the first course of chemotherapy with gemcitabine and cisplatin. The area under the concentration-time curve value of gemcitabine in this patient (54.54 μg hour/mL) was five times higher than the average value for five other patients (10.88 μg hour/mL) treated with gemcitabine plus cisplatin. The area under the concentration-time curve of 2′,2′-difluorodeoxyuridine in this patient (41.58 μg hour/mL) was less than the half of the average value of the five patients (106.13 μg hour/mL). This patient was found to be homozygous for 208A (Thr70) in the CDA gene, whereas the other patients were homozygous for 208G (Ala70).
Conclusion: Homozygous 208G&gt;A alteration in CDA might have caused the severe drug toxicity experienced by a Japanese cancer patient treated with gemcitabine plus cisplatin.
In vivo Generation of Angiostatin Isoforms by Administration of a Plasminogen Activator and a Free Sulfhydryl Donor: A Phase I Study of an Angiostatic Cocktail of Tissue Plasminogen Activator and Mesna
Authors: Soff Gerald A. , Wang Hao , Cundiff Deborah L. , Jiang Keyi , Martone Brenda , Rademaker Alfred W. , Doll Jennifer A. , Kuzel Timothy M. 
Published: September 2005

Abstract
Purpose: Angiostatin4.5 (AS4.5), the endogenous human angiostatin, is derived from plasminogen in a two-step process. A plasminogen activator converts plasminogen to plasmin, then plasmin undergoes autoproteolysis to AS4.5. A free sulfhydryl donor can mediate plasmin autoproteolysis. To translate this process to human cancer therapy, we conducted a phase I trial of administration of a tissue plasminogen activator (tPA) with a free sulfhydryl donor (mesna).
Patients and Methods: Fifteen patients with advanced solid tumors were treated. The dose of tPA was escalated (cohorts; 1, 2, 3, 5, and 7.5 mg/h for 6 hours). Mesna was administered as a 240 mg/m2 bolus followed by an infusion of 50 mg/h, concurrent with tPA. Both tPA and mesna were administered 3 consecutive days every 14 days.
Results: No dose-limiting toxicity was observed. Two AS4.5 isoforms were generated, Lys-AS4.5 and Glu-AS4.5. Mean baseline Lys-AS4.5 level was 20.4 nmol/L (SE, 2.9). In the 5 mg/h tPA cohort, Lys-AS4.5 levels increased by an average of 143% or 24 nmol/L (SE, 4.9) above baseline. Glu-AS4.5 (Mr ∼ 62,000) was also generated (additional 77 amino acids at amino terminus compared with Lys-AS4.5). Glu-AS4.5 level at baseline was undetectable in four of five patients in the 5 mg/h tPA cohort, but at end of infusion, was ∼67 nmol/L (SE, 20). Two patients in the 5 mg/h tPA cohort experienced decreases in tumor markers with treatment, although no clinical objective responses were observed.
Conclusion: This study shows that in vivo generation of AS4.5 is safe in humans and may provide a practical approach to achieve antiangiogenic therapy.
Anti-Flt1 Peptide, a Vascular Endothelial Growth Factor Receptor 1–Specific Hexapeptide, Inhibits Tumor Growth and Metastasis
Authors: Bae Dong-Goo , Kim Tae-Dong , Li Ge , Yoon Wan-Hee , Chae Chi-Bom 
Published: September 2005

Abstract
Purpose: The purpose of this study was to develop antagonists specific for the vascular endothelial growth factor receptor 1 (VEGFR1) and to investigate the effects of the antagonists on the VEGF-induced endothelial cell functions and tumor progression.
Experimental Design: Hexapeptides that inhibit binding of VEGFR1 and VEGF were identified through screening of synthetic peptide library. A selected peptide, anti-Flt1, was investigated for binding specificity with various receptors and ligand peptides. Effects of the peptide on proliferation, cell migration, and fibrin gel–based angiogenesis of endothelial cells were also investigated. The activity of anti-Flt1, in vivo, was evaluated for inhibition of tumor growth and metastasis in VEGF-secreting cancer cell–implanted mice by s.c. injections of the peptide.
Results: Here, we report on a short peptide that binds to VEGFR1 and prevents binding of VEGF. A hexapeptide, anti-Flt1 (Gly-Asn-Gln-Trp-Phe-Ile or GNQWFI), was identified from peptide libraries. The anti-Flt1 peptide shows specificity toward binding to VEGFR1 and it inhibits binding of VEGF, placental growth factor (PlGF), and VEGF/PlGF heterodimer to VEGFR1. This peptide does not inhibit the proliferation of endothelial cells induced by VEGF and VEGF/PlGF heterodimer but it effectively blocks VEGF-induced migration of endothelial cells and their capacity to form capillary-like structures on fibrin gel–based in vitro angiogenesis system. Furthermore, growth and metastasis of VEGF-secreting tumor cells were also significantly inhibited by s.c. injections of anti-Flt1 peptide in nude mice. Accordingly, VEGF-induced migration and capillary formation are mediated through VEGFR1, and these processes may play an important role in the growth and metastasis of VEGF-secreting tumors.
Conclusions: We show that a peptide (anti-Flt1) specific for VEGFR1 inhibits growth and metastasis of tumor that secretes VEGF. The effects on endothelial cell functions, in vitro, indicate that the anticancer activity of anti-Flt1 peptide with reduced blood vessel density could also be due to the blocking of VEGFR1-mediated endothelial cell migration and tube formation. Although the effects of anti-Flt1 peptide still remain to be further characterized, the receptor 1–specific peptide antagonist, anti-Flt1, has potential as a therapeutic agent for various angiogenesis-related diseases, especially cancer.
In vivo Effects of the Human Type I Insulin-Like Growth Factor Receptor Antibody A12 on Androgen-Dependent and Androgen-Independent Xenograft Human Prostate Tumors
Authors: Wu Jennifer D. , Odman Austin , Higgins Lily M. , Haugk Kathy , Vessella Robert , Ludwig Dale L. , Plymate Stephen R. 
Published: September 2005

Abstract
Purpose: The type I insulin-like growth factor receptor (IGF-IR) and its ligands have been shown to play a critical role in prostate carcinoma development, growth, and metastasis. Targeting the IGF-IR may be a potential treatment for prostate cancer. A fully human monoclonal antibody, A12, specific to IGF-IR, has shown potent antitumor effects in breast, colon, and pancreatic cancers in vitro and in vivo. In this study, we tested the in vivo effects of A12 on androgen-dependent and androgen-independent prostate tumor growth.
Experimental Design: Androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate tumors were implanted s.c. into intact and castrated severe combined immunodeficient mice, respectively. When tumor volume reached about 150 to 200 mm3, A12 was injected at 40 mg/kg body weight thrice a week for up to 5 weeks.
Results: We find that A12 significantly inhibits growth of androgen-dependent LuCaP 35 and androgen-independent LuCaP 35V prostate xenografts, however, by different mechanisms. In LuCaP 35 xenografts, A12 treatment induces tumor cell apoptosis or G1 cycle arrest. In LuCaP 35V xenografts, A12 treatment induces tumor cell G2-M cycle arrest. Moreover, we find that blocking the function of IGF-IR down-regulates androgen-regulated gene expression in androgen-independent LuCaP 35V tumor cells.
Conclusions: Our findings suggest that A12 is a therapeutic candidate for both androgen-dependent and androgen-independent prostate cancer. Our findings also suggest an IGF-IR–dependent activity of the androgen receptor in androgen-independent prostate cancer cells.
Green Tea Extract Modulates Actin Remodeling via Rho Activity in an In vitro Multistep Carcinogenic Model
Authors: Lu Qing-Yi , Jin Yu-Sheng , Pantuck Allan , Zhang Zuo-Feng , Heber David , Belldegrun Arie , Brooks Mai , Figlin Robert , Rao JianYu 
Published: September 2005

Abstract
Alteration of actin polymerization and loss of actin filaments is a marker of cellular dedifferentiation and early malignant transformation. To study this phenomenon, an in vitro human urothelial model consisting of two cell lines, HUC-PC and MC-T11, were incorporated into the study design. These two cell lines have different malignant transformation potential. The effect of green tea extract (GTE), a potential anticancer agent, on actin remodeling was investigated. Upon exposure to the carcinogen 4-aminobiphenyl (4-ABP), the untransformed HUC-PC undergoes malignant transformation whereas the transformed MC-T11 progresses from noninvasive to invasive tumor. GTE induces actin polymerization in MC-T11 cells in a dose-responsive manner, but this effect is less obvious in the untransformed, more differentiated HUC-PC cells, which natively have higher actin polymerization status. In contrast, GTE antagonizes carcinogen 4-ABP induced actin depolymerization and stress fiber disruption in HUC-PC cells. In MC-T11 cells, GTE inhibits 4-ABP induced motility by increasing cell adhesion and focal adhesion complex formation. The effect of GTE on actin remodeling seems to be mediated by the stimulation of small GTP-binding protein Rho activity, because C3 exoenzyme, a specific inhibitor for Rho, blocks GTE-mediated Rho activation and stress fiber formation in MC-T11 cells. This study shows that GTE exerts an effect on cytoskeletal actin remodeling and provides further support for the use of GTE as a chemopreventive agent.
Endocrine Effects of Tamoxifen Plus Exemestane in Postmenopausal Women with Breast Cancer
Authors: Love Richard R. , Hutson Paul R. , Havighurst Thomas C. , Cleary James F. 
Published: September 2005

Abstract
Purpose: In some specific circumstances, combined hormonal therapies for breast cancer seem to be more effective than single maneuvers. In two laboratory mammary cancer models, the combination of the aromatase inactivator exemestane plus tamoxifen gives a higher response rate than is found with either agent alone.
To evaluate the endocrine effects of the combination of exemestane and tamoxifen, we studied 33 postmenopausal women disease-free following primary treatments for breast cancer who were taking tamoxifen for at least 3 months.
Design: After observation for symptoms on tamoxifen for 4 weeks, blood samples were taken and patients were begun additionally on exemestane 25 mg p.o. qd. Eight weeks later, blood samples were again taken, and exemestane was discontinued.
Results: A decrease in alkaline phosphatase was found with exemestane treatment (P = 0.06), whereas no change in osteocalcin level was observed. A decrease in high-density lipoprotein cholesterol level was found (P = 0.0025), whereas total cholesterol, low-density lipoprotein cholesterol and triglyceride levels showed no changes with exemestane treatment. Estradiol, estrone, and estrone sulfate levels decreased to immeasurable or very low levels with exemestane treatment (all P &lt; 0.001). No significant changes in frequencies of common drug-associated side effects, such as vasomotor symptoms or weight change, were found.
Conclusions: Based on the absence of adverse endocrine effects with the addition of exemestane to tamoxifen therapy observed in this study, further clinical evaluation of the efficacy of this combination is warranted.