bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the St. John's Wort Constituent Hyperforin on Docetaxel Metabolism by Human Hepatocyte Cultures
Authors: Komoroski Bernard J. , Parise Robert A. , Egorin Merrill J. , Strom Stephen C. , Venkataramanan Raman 
Published: March 2006

Abstract
Background and Purpose: St. John's wort is a commonly used herbal medication that increases cytochrome P450 3A (CYP3A) activity. Because docetaxel is inactivated by CYP3A, we studied the effects of the St. John's wort constituent hyperforin on docetaxel metabolism in a human hepatocyte model.
Experimental Design: Hepatocytes, isolated from three donor livers, were exposed to hyperforin (0.1, 0.5, or 1.5 μmol/L) or rifampin (10 μmol/L) for 48 hours. After 48 hours, hyperforin- or rifampin-containing medium was replaced with medium containing 100 μmol/L docetaxel. After 1 hour, docetaxel metabolism was characterized by liquid chromatography-tandem mass spectrometry. Subsequent incubations characterized the specific cytochrome P450s that produced the docetaxel metabolites observed in hepatocyte incubations.
Results: Rifampin induced docetaxel metabolism 6.8- to 32-fold above docetaxel metabolism in control cultures. Hyperforin induced docetaxel metabolism in all three hepatocyte preparations. Hyperforin induction was dose-dependent and, at maximum, was 2.6- to 7-fold greater than that in controls. Docetaxel metabolites identified in rifampin- and hyperforin-treated hepatocyte preparations included the previously described tert-butyl–hydroxylated metabolite and two previously unidentified metabolites involving hydroxylation on the baccatin ring. CYP3A4 produced the tert-butyl–hydroxylated metabolite and the two ring-hydroxylated metabolites. CYP2C8 produced one of the newly described ring-hydroxylated metabolites.
Conclusions: Exposure to the St. John's wort constituent hyperforin induces docetaxel metabolism in vitro. This implies that subtherapeutic docetaxel concentrations may result when docetaxel is administered to patients using St. John's wort on a chronic basis. The results also show induction of previously undescribed metabolic pathways for docetaxel, one of which may be analogous to the known 6-α-hydroxylation of paclitaxel by CYP2C8.
Absence of Adverse Effects in Cynomolgus Macaques Treated with CNTO 95, a Fully Human Anti-αv Integrin Monoclonal Antibody, Despite Widespread Tissue Binding
Authors: Martin Pauline L. , Jiao Qun , Cornacoff Joel , Hall William , Saville Bradley , Nemeth Jeffrey A. , Schantz Allen , Mata Marielena , Jang Haishan , Fasanmade Adedigbo A. , Anderson Lisa , Graham Martin A. , Davis Hugh M. , Treacy George 
Published: March 2006

Abstract
Purpose: CNTO 95 is a fully human anti-αv integrin monoclonal antibody that inhibits macaque and rodent angiogenesis and inhibits human tumor growth in rodents. The purpose of these studies was to evaluate the preclinical safety of long-term administration of CNTO 95 in cynomolgus macaques.
Experimental Design: The in vitro binding profiles of CNTO 95 to human and macaque tissues and the in vivo binding to macaque tissues was evaluated by immunohistochemistry. The preclinical safety of CNTO 95 (10 and 50 mg/kg, i.v.) was evaluated in macaques treated once per week for up to 6 months. Safety was evaluated by clinical observations, ophthalmic and physical examinations (including heart rate, blood pressure, and electrocardiogram), clinical pathology (including coagulation parameters), and comprehensive anatomic pathology. The effect of CNTO 95 (50 mg/kg, i.v.) on incisional wound healing was evaluated in macaques.
Results: The tissue binding studies showed that CNTO 95 bound with mild to moderate intensity to macaque and human endothelial cells, epithelial cells, and vascular smooth muscle cells in most normal tissues examined. CNTO 95 showed strong to intense staining to the positive control tissue, human placenta. Despite the widespread binding to normal tissues, treatment of cynomolgus macaques with CNTO 95 produced no signs of toxicity and no histopathologic changes in any of the tissues examined (including ovaries and bone growth plates). CNTO 95 did not impair wound healing.
Conclusion: These studies show that CNTO 95 is safe and, unlike some other angiogenesis inhibitors, does not seem to inhibit normal physiologic angiogenesis.
Evaluation of a Panel of Molecular Markers for the Diagnosis of Malignant Serous Effusions
Authors: Passebosc-Faure Karine , Li Guorong , Lambert Claude , Cottier Michèle , Gentil-Perret Anne , Fournel Pierre , Pérol Maurice , Genin Christian 
Published: March 2006

Abstract
Purpose: Our main goal was to evaluate a panel of molecular markers for the detection of cancer cells in serous effusions and to determine their value as an adjunctive reverse transcription-PCR (RT-PCR) test to cytologic examination.
Experimental Design: One hundred fourteen serous effusions from 71 patients with tumors and 43 patients with benign diseases were subjected to RT-PCR for expression of carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (Ep-CAM), E-cadherin, mammaglobin, mucin 1 (MUC1) isoforms MUC1/REP, MUC1/Y, and MUC1/Z, calretinin, and Wilms' tumor 1 susceptibility gene.
Results: CEA, Ep-CAM, E-cadherin, and mammaglobin were specifically expressed in malignant effusions. The sensitivity of RT-PCR in cytologically negative malignant effusions was 63.1% combining CEA and Ep-CAM (with 100% specificity) and reached 78.9% adding MUC1/Y or MUC1/Z (with 93% specificity). In the whole population of effusions, the combination of cytology with RT-PCR of CEA and Ep-CAM yielded a 90.1% sensitivity, a specificity and a positive predictive value of 100%, and a 86% negative predictive value for malignancy. Adding MUC1/Y or MUC1/Z to the panel, the sensitivity was 94.5% with 93% specificity, 95.7% PPV, and 90.9% negative predictive value. Moreover, CEA and mammaglobin were specifically expressed in epithelial malignancies, and mammaglobin was mainly expressed in effusions from breast carcinoma (97.3% of specificity).
Conclusions: A combination of cytology and RT-PCR analysis of CEA and Ep-CAM significantly improved the detection sensitivity of tumor cells in serous effusions. RT-PCR analysis of CEA, Ep-CAM, and mammaglobin in serous effusions could be a beneficial adjunct to cytology for the diagnosis of malignancy.
Thomsen-Friedenreich and Tn Antigens in Nipple Fluid: Carbohydrate Biomarkers for Breast Cancer Detection
Authors: Kumar Senthil R. , Sauter Edward R. , Quinn Thomas P. , Deutscher Susan L. 
Published: March 2006

AbstractPurpose: Novel biomarkers would facilitate early and accurate diagnosis of breast cancer. The Thomsen-Freidenreich (TF) and Tn antigens are aberrantly glycosylated carbohydrate cancer-associated antigens found in ∼80% of adenocarcinomas. Both TF and Tn are expressed on cell-surface glycoproteins and glycolipids. Nipple aspirate fluid (NAF) is concentrated in secreted proteins and lipids from cells that give rise to cancer. The objective of this study was to determine if NAF from breasts with cancer contains elevated levels of TF and Tn compared with NAF from normal breasts. A sensitive and specific antigen capture immunoassay for TF and Tn detection in NAF was developed for this purpose.Experimental Design: Fifty NAF samples, 25 from breasts with cancer and 25 from normal breasts, were examined. Antigen capture immunoassays were done on the samples using monoclonal antibodies that specifically recognized either TF or Tn antigen in NAF. These antibodies captured serially diluted NAF samples, and the concentration of TF or Tn was determined by comparing absorbance values against a standard curve generated from standard sources of TF or Tn.Results: TF and Tn were detected in 19 of 25 and 20 of 25 NAF samples from breasts with cancer, respectively, compared with 0 of 25 and 1 of 25 NAF samples from breasts without cancer (P &lt; 0.001 for both TF and Tn). In 92% of the cancerous breast NAF samples tested, either TF or Tn was found.Conclusions: Simultaneous measurement of TF and Tn in NAF may facilitate the noninvasive detection of breast cancer and warrants further study.
Phosphatidylinostol 3-Kinase Mediates Angiogenesis and Vascular Permeability Associated with Ovarian Carcinoma
Authors: Hu Limin , Hofmann Judith , Jaffe Robert B. 
Published: March 2006

Abstract
Purpose: To assess the role of phosphatidylinositol-3 kinase (PI3K) inhibition in vascular permeability, angiogenesis, and vascular remodeling in tumor vessels and peritoneal lining in an athymic mouse model of i.p. human ovarian carcinoma.
Experimental Design: Mice were inoculated i.p. with cells from the human ovarian cancer cell line, OVCAR-3. Fourteen days after inoculation, mice were treated with or without the PI3K inhibitor LY294002, 3 days weekly for 4 weeks. At the end of the experiment, some mice were anesthetized and injected via the tail vein with FITC-labeled lycopersicon lectin and perfused through the aorta before sacrifice. The peritoneal wall and tumor from all mice were removed and embedded in 10% agarose. Tumor sections were visualized by fluorescence microscopy.
Results: Ascites in the LY294002-treated group (0.69 ± 0.27 mL) was reduced by 72.4% compared with the control group (2.5 ± 1.2 mL). Tumor burden in the LY294002-treated group (0.62 ± 0.32 g) was reduced by 47.3% compared with the control group (1.18 ± 0.41 g). LY294002 inhibited peritoneal and tumor vascularization resulting in numerous leaky, irregular, tortuous vessels in scant, straight, relatively impermeable vessels.
Conclusions: The data indicate that LY294002 inhibits ascites formation in our mouse model of human ovarian cancer by inhibiting tumor and peritoneal neovascularization as well as vascular permeability. The data also show that LY294002 directly inhibits vascular endothelial growth factor (VEGF) protein expression and release from ovarian carcinoma and suggest that LY294002 blocks the VEGF signaling pathway involved in angiogenesis and vascular permeability.
A Physiologic Imaging Pilot Study of Breast Cancer Treated with AZD2171
Authors: Miller Kathy D. , Miller Michael , Mehrotra Sanjana , Agarwal Beamon , Mock Bruce H. , Zheng Qi-Huang , Badve Sunil , Hutchins Gary D. , Sledge George W. 
Published: March 2006

Abstract
Background: This pilot study combined physiologic imaging, microcomputed tomography, and histologic tumor evaluation with a xenograft model of breast cancer to identify surrogates likely to correlate with response to AZD2171, an inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinases.
Experimental Design: MCF-7 cells transfected with vector (MCF-7neo) or VEGF (MCFVEGF) were implanted in the right and left mammary fat pads of 75 athymic mice. Treatment with AZD2171 (5 mg/kg/d) or vehicle control was initiated once tumors were established. Positron emission tomography with [11C]carbon monoxide to measure blood volume, [18F]fluoromethane to measure perfusion, and [18F]fluorodeoxyglucose to measure glucose utilization was done at baseline, and after 24 hours, 72 hours, and 4 weeks of treatment. After imaging, tumors were analyzed for microvessel density, proliferation, and VEGF expression.
Results: AZD2171 induced significant inhibition of tumor growth in established MCF-7neo xenografts and regression of established MCF-7VEGF xenografts. An acute decrease in blood flow was detected in MCF-7VEGF tumors at 24 hours (P = 0.05). Tumor blood volume was increased in the MCF-7VEGF tumors but correlated with tumor size; blood volume did not change with AZD2171 therapy. Glucose utilization correlated with tumor size and did not change with acute or chronic AZD2171 therapy. Unlike blood flow and blood volume, glucose utilization was similar in MCF-7neo and MCF-7VEGF tumors. Microvessel density and proliferation acutely decreased in MCF-7VEGF tumors but returned to baseline during chronic therapy.
Conclusions: [18F]Fluoromethane imaging may be a useful surrogate for biological activity of AZD2171 with changes identified within 24 hours of starting therapy.
Phase I Clinical Trial of a HER-2/neu Peptide (E75) Vaccine for the Prevention of Prostate-Specific Antigen Recurrence in High-Risk Prostate Cancer Patients
Authors: Hueman Matthew T. , Dehqanzada Zia A. , Novak Thomas E. , Gurney Jennifer M. , Woll Michael M. , Ryan Gayle B. , Storrer Catherine E. , Fisher Christine , McLeod David G. , Ioannides Constantine G. , Ponniah Sathibalan , Peoples George E. 
Published: March 2006

Abstract
Purpose: The E75 peptide is an immunogenic peptide from the HER-2/neu protein that is substantially expressed in prostate cancer. We are conducting a clinical trial of an E75/granulocyte macrophage colony-stimulating factor vaccine to prevent post-prostatectomy prostate-specific antigen (PSA) recurrences in high-risk prostate cancer (HRPC) patients.
Experimental Design: Prostate cancer patients at high risk for recurrence were prospectively evaluated and identified by the validated Center for Prostate Disease Research (CPDR)/CaPSURE high-risk equation. From these high-risk equation patients, 27 HER-2/neu-expressing prostate cancer patients were enrolled. HLA-A2+ patients (n = 17) were vaccinated, whereas HLA-A2− patients (n = 10) were followed as clinical controls. Local/systemic toxicities, immunologic responses, and time to recurrence were measured.
Results: This vaccine is safe with only minor toxicities observed. Additionally, the vaccine is immunogenic with all patients showing both in vivo and in vitro phenotypic and functional immune responses, although variable. HLA-A2+ patients were found to have larger tumors, higher postoperative Gleason scores, and more high-risk CPDR scores than HLA-A2− patients. Despite these differences, disease-free survival was not different between the vaccinated HLA-A2+ patients and the HLA-A2− controls at a median follow up of 23 months. Three of the four vaccinated patients that recurred had rising PSAs at the initiation of the trial. Ex vivo phenotypic assays were predictive of recurrences and correlated in general with functional assays.
Conclusions: The E75 vaccine strategy is safe and effective in eliciting an immune response against the HER-2/neu protein in HRPC patients and may be useful as a preventive strategy against disease recurrence. Vaccination in response to a rising PSA may be too late.
A Phase II Trial of Pemetrexed in Advanced Breast Cancer: Clinical Response and Association with Molecular Target Expression
Authors: Gomez Henry L. , Santillana Sergio L. , Vallejos Carlos S. , Velarde Raul , Sanchez Juvenal , Wang Xinpeng , Bauer Nancy L. , Hockett Richard D. , Chen Victor J. , Niyikiza Clet , Hanauske Axel R. 
Published: March 2006

Abstract
Purpose: This phase II trial of pemetrexed explored potential correlations between treatment outcome (antitumor activity) and molecular target expression.
Experimental Design: Chemonaïve patients with advanced breast cancer received up to three cycles of pemetrexed 500 mg/m2 (10-minute i.v. infusion) on day 1 of a 21-day cycle, with folic acid and vitamin B12 supplementation. Tumors were surgically removed after the last cycle of pemetrexed as clinically indicated. Biopsies were taken at baseline, 24 hours after infusion in cycle 1, and after cycle 3.
Results: Sixty-one women (median age, 46 years; range, 32-72 years) were treated and were evaluable for response. Objective response rate was 31%. Simple logistic regression suggested a potential relationship between mRNA expression of thymidylate synthase (TS) and pemetrexed response (P = 0.103). Based on threshold analysis, patients with “low” baseline TS (≤71) were more likely to respond to pemetrexed than patients with “high” baseline TS (&gt;71). Expression of baseline dihydrofolate reductase and glycinamide ribonucleotide formyl transferase tended to be higher in responders but this association was not significant (P &gt; 0.311). TS expression increased significantly between baseline and biopsy 2 (P = 0.004) and dropped to near baseline levels at biopsy 3. Conversely, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase decreased after pemetrexed chemotherapy.
Conclusions: Our results suggest a potential association between “low” pretreatment TS expression levels and response to pemetrexed chemotherapy. Future trials examining expression levels of other genes important to the folate pathway and/or breast cancer may identify a more robust multigene profile that can better predict response to this novel antifolate.
Complete Tumor Response Following Intratumoral 32P BioSilicon on Human Hepatocellular and Pancreatic Carcinoma Xenografts in Nude Mice
Authors: Zhang Kai , Loong Susan L.E. , Connor Steve , Yu Sidney W.K. , Tan Soo-Yong , Ng Robert T.H. , Lee Khai Mun , Canham Leigh , Chow Pierce K.H. 
Published: March 2006

Abstract
Purpose: 32P BioSilicon is a new, implantable, radiological medical device that comprises particles of highly pure silicon encapsulating 32phosphorus (32P) for the treatment of unresectable solid tumors. Prior to administration, the device particles are suspended in a formulant which provides an even suspension of the intended dose for implantation. The primary objective of this animal trial study was to investigate the effects of intratumoral injection of 32P BioSilicon on human hepatocellular (HepG2) and pancreatic carcinoma (2119) xenografts implanted in nude mice (BALB/c). A secondary objective was the histopathologic examination of the tumor foci and surrounding tissue during the study.
Methods: Cultured human carcinoma cells (HepG2 and 2119) were injected s.c. into the gluteal region of nude mice. When the implanted tumors were ∼1 cm in diameter, 32P BioSilicon (0.5, 1.0, and 2.0 MBq) or formulant was injected into the tumors. Implanted tumor size was measured once a week for 10 weeks. At study termination, the tumor and surrounding normal tissue were collected and fixed in 10% formalin and processed for histopathologic analysis.
Results: 32P BioSilicon produced a reduction in HepG2 tumor volume when compared with formulant control, and complete response was observed among tumors in the 1.0 and 2.0 MBq treatment groups after week 8. There was also significant reduction in 2119 tumor volume in all treated groups, with the complete response rate of 67% in the 2.0 MBq group.
Conclusion: 32P BioSilicon suppressed the growth of both human hepatocellular and pancreatic carcinoma xenografts implanted in nude mice and complete responses were also observed in tumors at higher radiation doses.
Reversal of Hypermethylation and Reactivation of p16INK4a, RARβ, and MGMT Genes by Genistein and Other Isoflavones from Soy
Authors: Fang Ming Zhu , Chen Dapeng , Sun Yi , Jin Zhe , Christman Judith K. , Yang Chung S. 
Published: March 2006

Abstract
Purpose: We have previously shown the reactivation of some methylation-silenced genes in cancer cells by (−)-epigallocatechin-3-gallate, the major polyphenol from green tea. To determine whether other polyphenolic compounds have similar activities, we studied the effects of soy isoflavones on DNA methylation.
Experimental Design: Enzyme assay was used to determine the inhibitory effect of genistein on DNA methyltransferase activity in nuclear extracts and purified recombinant enzyme. Methylation-specific PCR and quantitative real-time PCR were employed to examine the DNA methylation and gene expression status of retinoic acid receptor β (RARβ), p16INK4a, and O6-methylguanine methyltransferase (MGMT) in KYSE 510 esophageal squamous cell carcinoma cells treated with genistein alone or in combination with trichostatin, sulforaphane, or 2′-deoxy-5-aza-cytidine (5-aza-dCyd).
Results: Genistein (2-20 μmol/L) reversed DNA hypermethylation and reactivated RARβ, p16INK4a, and MGMT in KYSE 510 cells. Genistein also inhibited cell growth at these concentrations. Reversal of DNA hypermethylation and reactivation of RARβ by genistein were also observed in KYSE 150 cells and prostate cancer LNCaP and PC3 cells. Genistein (20-50 μmol/L) dose-dependently inhibited DNA methyltransferase activity, showing substrate- and methyl donor–dependent inhibition. Biochanin A and daidzein were less effective in inhibiting DNA methyltransferase activity, in reactivating RARβ, and in inhibiting cancer cell growth. In combination with trichostatin, sulforaphane, or 5-aza-dCyd, genistein enhanced reactivation of these genes and inhibition of cell growth.
Conclusions: These results indicate that genistein and related soy isoflavones reactivate methylation-silenced genes, partially through a direct inhibition of DNA methyltransferase, which may contribute to the chemopreventive activity of dietary isoflavones.
Meta-analysis of the p53 Mutation Database for Mutant p53 Biological Activity Reveals a Methodologic Bias in Mutation Detection
Authors: Soussi Thierry , Asselain Bernard , Hamroun Dalil , Kato Shunsuke , Ishioka Chikashi , Claustres Mireille , Béroud Christophe 
Published: March 2006

Abstract
Purpose: Analyses of the pattern of p53 mutations have been essential for epidemiologic studies linking carcinogen exposure and cancer. We were concerned by the inclusion of dubious reports in the p53 databases that could lead to controversial analysis prejudicial to the scientific community.
Experimental Design: We used the universal mutation database p53 database (21,717 mutations) combined with a new p53 mutant activity database (2,300 mutants) to perform functional analysis of 1,992 publications reporting p53 alterations. This analysis was done using a statistical approach similar to that of clinical meta-analyses.
Results: This analysis reveals that some reports of infrequent mutations are associated with almost normal activities of p53 proteins. These particular mutations are frequently found in studies reporting multiple mutations in one tumor, silent mutations, or lacking mutation hotspots. These reports are often associated with particular methodologies, such as nested PCR, for which key controls are not satisfactory.
Conclusions: We show the importance of accurate functional analysis before inferring any genetic variation. The quality of the p53 databases is essential in order to prevent erroneous analysis and/or conclusions. The availability of functional data from our new p53 web site (http://p53.free.fr and http://www.umd.be:2072/) will allow functional prescreening to identify potential artifactual data.