bluuebunny/crossref_metadata_2025_split huggingface dataset:
2-[11C]Thymidine Positron Emission Tomography Reproducibility in Humans
Authors: Wells Paula , Gunn Roger N. , Steel Colin , Ranicar Alex S. , Brady Frank , Osman Safiye , Jones Terry , Price Pat 
Published: September 2005

Abstract
Purpose: To evaluate the reproducibility of 2-[11C]thymidine positron emission tomography (PET) scanning in patients with advanced intra-abdominal malignancies.
Patients and Methods: The reproducibility of 2-[11C]thymidine PET was studied by comparing interpatient and intrapatient variability (coefficient of variability, COV) of both blood and tissue data. Arterial plasma metabolite levels were measured using on-line sampling and high-pressure liquid chromatography. 2-[11C]Thymidine retention in tissue was measured as the standardized uptake value at the end of the scan (SUVend), the area under the time-activity curve (AUC0-1 hour), and the fractional retention of thymidine (FRT). A group of seven patients were scanned 1 week apart with no intervening anticancer therapy.
Results: There was interpatient variability in the levels of 2-[11C]thymidine and its main metabolite, 11CO2, in plasma. Variability in 2-[11C]thymidine PET data was greater between (COV: SUVend = 38%, AUC0-1 hour = 32%, FRT = 47%) than within (COV: SUVend = 8%, AUC0-1 hour = 2%, FRT = 9%) patients. There was a borderline significant difference between the paired tumor data for SUVend (P = 0.041), but not for AUC0-1 hour (P = 0.81) or FRT (P = 0.90). There was a good correlation between paired data for SUVend (r = 0.98), AUC0-1 hour (r = 0.99), and FRT (r = 0.95).
Conclusions: This is the first report showing that 2-[11C]thymidine PET scanning is reproducible in humans. Repeat scanning of tumor proliferation using 2-[11C]thymidine PET is feasible to perform in human intra-abdominal malignancies and should aid the future rapid assessment of antiproliferative tumor agents.
Formation and Antitumor Activity of PNU-159682, A Major Metabolite of Nemorubicin in Human Liver Microsomes
Authors: Quintieri Luigi , Geroni Cristina , Fantin Marianna , Battaglia Rosangela , Rosato Antonio , Speed William , Zanovello Paola , Floreani Maura 
Published: September 2005

Abstract
Purpose: Nemorubicin (3′-deamino-3′-[2″(S)-methoxy-4″-morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3′-deamino-3″,4′-anhydro-[2″(S)-methoxy-3″(R)-oxy-4″-morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPH-supplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682.
Experimental Design: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively.
Results: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts.
Conclusions: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.
Somatic Mutations of Epidermal Growth Factor Receptor in Colorectal Carcinoma
Authors: Nagahara Hisashi , Mimori Koshi , Ohta Mitsuhiko , Utsunomiya Tohru , Inoue Hiroshi , Barnard Graham F. , Ohira Masaichi , Hirakawa Kosei , Mori Masaki 
Published: September 2005

Abstract
Purpose: Somatic mutations of the epidermal growth factor receptor (EGFR) gene may predict the sensitivity of non–small cell lung carcinoma to gefitinib. However, no mutations have been reported for colorectal carcinoma. We therefore analyzed EGFR mutations in colorectal adenocarcinomas by the combined use of laser microdissection and sequencing of genomic DNA.
Experimental Design: We examined 11 representative colorectal adenocarcinoma cell lines and 33 clinical samples of colorectal carcinoma. In the clinical cases, we carefully dissected only carcinoma cells from frozen sections by laser microdissection. After DNA extraction and PCR, we examined EGFR mutations by sequencing genomic DNA.
Results: None of 11 colorectal carcinoma cell lines exhibited somatic mutations, but 4 of 33 clinical tumors (12%) exhibited mutations in the EGFR kinase domain. This may be the first report of somatic mutations in colorectal adenocarcinoma.
Conclusions: Our findings suggest that a distinct minority of colorectal adenocarcinomas exhibit somatic mutations of EGFR, and these tumors may be susceptible to gefitinib treatment.
The p53 Codon 72 Proline Allele Is Associated with p53 Gene Mutations in Non–Small Cell Lung Cancer
Authors: Hu Yingchuan , McDermott Michael P. , Ahrendt Steven A. 
Published: September 2005

Abstract
The p53 gene plays a critical role in cell cycle control, the initiation of apoptosis, and in DNA repair. An Arg/Pro polymorphism at codon 72 of the p53 gene alters the ability of the p53 protein to induce apoptosis, influences the behavior of mutant p53, decreases DNA repair capacity, and may be linked with an increased risk of lung cancer. To further define the role of the p53 codon 72 polymorphism on DNA repair, lung cancer risk, and mutant p53 function, we examined the effect of this polymorphism on mutation of the p53 gene and patient survival in non–small cell lung cancer (NSCLC). Tumor and nonneoplastic (lung or lymphocyte) samples were collected from 182 patients with NSCLC. p53 mutations were detected by direct sequencing and/or the Gene Chip p53 assay in 93 of 182 (51%) tumors. p53 codon 72 polymorphisms were identified by PCR/RFLP analysis. p53 mutations were significantly (P = 0.01) associated with the number of codon 72 Pro alleles: Pro/Pro homozygotes, 17 of 26 (65%); Arg/Pro heterozygotes, 45 of 79 (57%); and Arg/Arg homozygotes, 31 of 77 (40%). The number of codon 72 Pro alleles was independently associated with p53 mutations (odds ratio, 1.97; 95% confidence interval, 1.14-3.40; P = 0.01) in a multiple logistic regression model. The codon 72 polymorphism did not influence patient survival in either the entire patient group or among patients with p53 mutant tumors. In summary, the p53 Pro allele is associated with an increased frequency of p53 mutations in NSCLC.
DDEF1 Is Located in an Amplified Region of Chromosome 8q and Is Overexpressed in Uveal Melanoma
Authors: Ehlers Justis P. , Worley Lori , Onken Michael D. , Harbour J. William 
Published: September 2005

Abstract
Purpose: The molecular pathogenesis of uveal melanoma is poorly understood but is usually accompanied by amplification of chromosome 8q, suggesting the activation of one or more oncogenes. We recently identified a gene expression profile that distinguishes low-grade from high-grade melanomas. In this profile, a cluster of genes at chromosome 8q was overexpressed in high-grade tumors, providing an opportunity to search for potential oncogenes in this region.
Experimental Design: Gene expression microarray analysis was done on 25 primary uveal melanomas. Microarray comparative genomic hybridization (CGH), quantitative PCR, and immunohistochemistry were done on a subset of these tumors. Cell motility was measured using a wound-healing assay.
Results: In melanomas analyzed for microarray gene expression and CGH, gain of chromosome 8q correlated most strongly with expression of DDEF1, a gene located at 8q24. In contrast, the nearby MYC oncogene exhibited no significant change in expression. Confirming the microarray findings, DDEF1 mRNA levels and protein expression were significantly higher in high-grade melanomas. Furthermore, ectopic expression of DDEF1 in low-grade melanoma cells resulted in a significant increase in cell motility, a feature of high-grade metastasizing cells.
Conclusions: These findings suggest that DDEF1 overexpression may be a pathogenetically relevant consequence of chromosome 8q amplification, which commonly occurs in high-grade uveal melanomas. We conclude that DDEF1 may act as an oncogene in this cancer, and it may be a useful diagnostic marker and therapeutic target.
In vitroCanine Distemper Virus Infection of Canine Lymphoid Cells: A Prelude to Oncolytic Therapy for Lymphoma
Authors: Suter Steven E. , Chein May B. , von Messling Veronika , Yip Becky , Cattaneo Roberto , Vernau William , Madewell Bruce R. , London Cheryl A. 
Published: September 2005

AbstractPurpose: Measles virus (MV) causes the regression of human lymphoma xenografts. The purpose of this study was to determine if canine lymphoid cells could be infected in vitro with MV or canine distemper virus (CDV, the canine Morbillivirus equivalent of MV) and determine if in vitro viral infection leads to apoptotic cell death.Experimental Design: Reverse transcriptase-PCR was used to examine the expression of both signal lymphocyte activation molecule (CD150) and membrane cofactor molecule (CD46) mRNA. An attenuated CDV expressing enhanced green fluorescent protein was used to infect canine cells in vitro. Both flow cytometry and reverse transcriptase-PCR was used to document CDV infection. Cell death was examined using a propidium iodide staining assay and Annexin V binding.Results: Canine lymphoid cell lines and neoplastic B and T lymphocytes collected from dogs with spontaneous lymphoma expressed the Morbillivirus receptor CD150 mRNA. In contrast, only neoplastic lymphocytes expressed detectable levels of CD46 mRNA. Although MV did not infect canine cells, CDV efficiently infected between 40% and 70% of all three canine lymphoid lines tested. More importantly, CDV infected 50% to 90% of neoplastic lymphocytes isolated from dogs with both B and T cell lymphoma. Apoptosis of CDV-infected cell lines was documented.Conclusions: Attenuated CDV may be a useful treatment for canine lymphoma. As such, dogs with lymphoma may represent a biologically relevant large animal model to investigate the feasibility, safety, and efficacy of Morbillivirus therapy in a clinical setting with findings that may have direct applicability in the treatment of human non-Hodgkin's lymphoma.
Functional Expression of the Angiotensin II Type1 Receptor in Human Ovarian Carcinoma Cells and Its Blockade Therapy Resulting in Suppression of Tumor Invasion, Angiogenesis, and Peritoneal Dissemination
Authors: Suganuma Takayasu , Ino Kazuhiko , Shibata Kiyosumi , Kajiyama Hiroaki , Nagasaka Tetsuro , Mizutani Shigehiko , Kikkawa Fumitaka 
Published: September 2005

Abstract
Purpose: Angiotensin II is a bioactive peptide of the renin-angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type 1 receptors (AT1R). The present study examined AT1R expression in human ovarian carcinoma and attempted to determine whether AT1R blocker could suppress the tumor progression.
Experimental Design: Expression of AT1R, vascular endothelial growth factor (VEGF), and CD34 was immunohistochemically analyzed in ovarian tumor tissues (n = 99). Effects of AT1R blocker on invasive potential and VEGF secretion in ovarian cancer cells were examined in vitro. Effects of AT1R blocker in vivo were evaluated in a mouse model of peritoneal carcinomatosis.
Results: AT1R was expressed in 57 of 67 (85%) invasive ovarian adenocarcinomas and 12 of 18 (66%) borderline malignant tumors but in only 2 of 14 (14%) benign cystadenomas. In invasive carcinomas, VEGF expression intensity and intratumor microvessel density were significantly higher in cases that were strongly positive for AT1R (n = 37) compared with those in cases weakly positive (n = 20) or negative (n = 10) for AT1R. Angiotensin II significantly enhanced the invasive potential and VEGF secretion in AT1R-positive SKOV-3 ovarian cancer cells, both of which were completely inhibited by the AT1R blocker candesartan. Administration of candesartan into SKOV-3-transplanted athymic mice resulted in the reduction of peritoneal dissemination, decreased ascitic VEGF concentration, and suppression of tumor angiogenesis.
Conclusions: AT1R is functionally expressed in ovarian carcinoma and involved in tumor progression and angiogenesis. AT1R blockade therapy may become a novel and promising strategy for ovarian cancer treatment.
Vitamin D3 Metabolism in Human Glioblastoma Multiforme: Functionality of CYP27B1 Splice Variants, Metabolism of Calcidiol, and Effect of Calcitriol
Authors: Diesel Britta , Radermacher Jens , Bureik Matthias , Bernhardt Rita , Seifert Markus , Reichrath Jörg , Fischer Ulrike , Meese Eckart 
Published: September 2005

Abstract
Purpose: A better understanding of the vitamin D3 metabolism is required to evaluate its potential therapeutic value for cancers. Here, we set out to contribute to the understanding of vitamin D3 metabolism in glioblastoma multiforme.
Experimental Design: We did nested touchdown reverse transcription-PCR (RT-PCR) to identify CYP27B1 splice variants and real-time RT-PCR to quantify the expression of CYP27B1. A cell line was treated with calcitriol to determine the effect on the expression of CYP27B1, 1α,25-dihydroxyvitamin D3-24-hydroxylase (CYP24), and vitamin D3 receptor (VDR). We generated three antibodies for the specific detection of CYP27B1 and splice variants. High-performance TLC was done to determine the endogenous CYP27B1 activity and the functionality of CYP27B1 splice variants. Using WST-1 assay, we determined the effect of vitamin D3 metabolites on proliferation.
Results: We report a total of 16 splice variants of CYP27B1 in glioblastoma multiforme and a different expression of CYP27B1 and variants between glioblastoma multiforme and normal tissues. We found preliminary evidence for enzymatic activity of endogenous CYP27B1 in glioblastoma multiforme cell cultures but not for the functionality of the splice variants. By adding calcitriol, we found a proliferative effect for some cell lines depending on the dose of calcitriol. The administration of calcitriol led to an elevated expression of CYP27B1 and CYP24 but left the expression of the VDR unaltered.
Conclusions: Our findings show that glioblastoma multiforme cell lines metabolize calcidiol. In addition, we show various effects mediated by calcitriol. We found a special vitamin D3 metabolism and mode of action in glioblastoma multiforme that has to be taken into account in future vitamin D3–related therapies.
Elevated Serum Cytokines Correlated with Altered Behavior, Serum Cortisol Rhythm, and Dampened 24-Hour Rest-Activity Patterns in Patients with Metastatic Colorectal Cancer
Authors: Rich Tyvin , Innominato Pasquale F. , Boerner Julie , Mormont M. Christine , Iacobelli Stefano , Baron Benoit , Jasmin Claude , Lévi Francis 
Published: September 2005

Abstract
Purpose: Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated.
Experimental Design: Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-α, tumor necrosis factor-α, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated.
Results: Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-α (TGF-α) and IL-6 were significantly increased in the patients with WHO performance status &gt;1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-α only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome.
Conclusions: Significant correlations were found between serum levels of TGF-α and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine signaling pathways, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and efferent pathways of the suprachiasmatic nucleus that control circadian physiology, opens the way to new rational interventions for symptom management in cancer patients.
Microarray Analysis of Endometrial Carcinomas and Mixed Mullerian Tumors Reveals Distinct Gene Expression Profiles Associated with Different Histologic Types of Uterine Cancer
Authors: Maxwell G. Larry , Chandramouli G.V.R. , Dainty Lou , Litzi Tracy J. , Berchuck Andrew , Barrett J. Carl , Risinger John I. 
Published: September 2005

Abstract
Previous studies using cDNA microarray have indicated that distinct gene expression profiles characterize endometrioid and papillary serous carcinomas of the endometrium. Molecular studies have observed that mixed mullerian tumors, characterized by both carcinomatous and sarcomatous components, share features that are characteristic of endometrial carcinomas. The objective of this analysis was to more precisely define gene expression patterns that distinguish endometrioid and papillary serous histologies of endometrial carcinoma and mixed mullerian tumors of the uterus. One hundred nineteen pathologically confirmed uterine cancer samples were studied (66 endometrioid, 24 papillary serous, and 29 mixed mullerian tumors). Gene expressions were analyzed using the Affymetrix Human Genome Arrays U133A and U133B Genechip set. Unsupervised analysis revealed distinct global gene expression patterns of endometrioid, papillary serous, mixed mullerian tumors, and normal tissues as grossly separated clusters. Two-sample t tests comparing endometrioid and papillary serous, endometrioid and mixed mullerian tumor, and papillary serous and mixed mullerian tumor pairs identified 1,055, 5,212, and 1,208 differentially expressed genes at P &lt; 0.001, respectively. These data revealed that distinct patterns of gene expression characterize various histologic types of uterine cancer. Gene expression profiles for select genes were confirmed using quantitative PCR. An understanding of the molecular heterogeneity of various histologic types of endometrial cancer has the potential to lead to better individualization of treatment in the future.
O6-Methylguanine-DNA Methyltransferase, O6-Benzylguanine, and Resistance to Clinical Alkylators in Pediatric Primary Brain Tumor Cell Lines
Authors: Bobola Michael S. , Silber John R. , Ellenbogen Richard G. , Geyer J. Russell , Blank A. , Goff Ryan D. 
Published: September 2005

Abstract
Purpose: Primary brain tumors are the leading cause of cancer death in children. Our purpose is (a) to assess the contribution of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) to the resistance of pediatric brain tumor cell lines to clinical alkylating agents and (b) to evaluate variables for maximal potentiation of cell killing by the MGMT inhibitor O6-benzylguanine, currently in clinical trials. Few such data for pediatric glioma lines, particularly those from low-grade tumors, are currently available.
Experimental design: We used clonogenic assays of proliferative survival to quantitate cytoxicity of the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the methylating agent temozolomide in 11 glioma and five medulloblastoma lines. Twelve lines are newly established and characterized here, nine of them from low-grade gliomas including pilocytic astrocytomas.
Results: (a) MGMT is a major determinant of BCNU resistance and the predominant determinant of temozolomide resistance in both our glioma and medulloblastoma lines. On average, O6-benzylguanine reduced LD10 for BCNU and temozolomide, 2.6- and 26-fold, respectively, in 15 MGMT-expressing lines. (b) O6-Benzylguanine reduced DT (the threshold dose for killing) for BCNU and temozolomide, 3.3- and 138-fold, respectively. DT was decreased from levels higher than, to levels below, clinically achievable plasma doses for both alkylators. (c) Maximal potentiation by O6-benzylguanine required complete and prolonged suppression of MGMT.
Conclusions: Our results support the use of O6-benzylguanine to achieve full benefit of alkylating agents, particularly temozolomide, in the chemotherapy of pediatric brain tumors.
Resistance to the Tubulin-Binding Agents in Renal Cell Carcinoma: No Mutations in the Class I β-Tubulin Gene but Changes in Tubulin Isotype Protein Expression
Authors: Ferguson Roisean E. , Taylor Claire , Stanley Anthea , Butler Elizabeth , Joyce Adrian , Harnden Patricia , Patel Poulam M. , Selby Peter J. , Banks Rosamonde E. 
Published: September 2005

Abstract
Purpose: The primary purpose of this study was to determine whether mutations of the class I β-tubulin gene may be implicated in the inherent resistance to tubulin-binding agents (TBA) in renal cancer, with a small number of samples and cell lines also being examined for class I and III β-tubulin isotype protein expression.
Experimental Design: DNA was extracted from 90 renal tumors and the class I β-tubulin gene analyzed for mutations. For each sample, eight PCRs were used to cover the complete coding sequence with intronic primers ensuring highly homologous pseudogenes were not coamplified. Additionally, expression levels of class I and III β-tubulin isotypes in 17 matched normal and malignant renal samples and a panel of renal cell carcinoma cell lines with differing intrinsic resistance to the TBAs was examined by Western blotting.
Results: Four polymorphic sequence changes of the class I β-tubulin gene were identified with no mutations. Class I protein expression levels were higher in tumor tissue versus normal tissue, whereas class III expression showed no consistent change. In renal cancer cell lines, a significant correlation between class III isotype expression and vinblastine sensitivity was observed.
Conclusions: These results do not support a role for mutations in the class I β-tubulin gene in the intrinsic resistance of renal cancer to TBAs. Class III isotype expression may be implicated in resistance in vitro but in vivo, changes in class I isotype expression in renal cell carcinoma tissue may support a role in resistance to the TBAs and warrants further investigation.