bluuebunny/crossref_metadata_2025_split huggingface dataset:
Macrophage Depletion Combined with Anticoagulant Therapy Increases Therapeutic Window of Systemic Treatment with Oncolytic Adenovirus
Authors: Shashkova Elena V. , Doronin Konstantin , Senac Julien S. , Barry Michael A. 
Published: July 2008

Abstract
Liver tropism of systemically delivered adenoviruses (Ad) represents a considerable challenge for their use as anticancer therapeutics. More than 90% of i.v. injected Ad is rapidly taken up by the liver leading to hepatotoxicity, reduced virus uptake by target tumor tissue, and diminished therapeutic efficacy. The lack of clinical activity of systemically given oncolytic Ad demands for better understanding and improvement of virus pharmacokinetics. We studied the effects of Ad “detargeting” from liver macrophages (Kupffer cells) and hepatocytes on toxicity and anticancer efficacy using a nonattenuated oncolytic Ad expressing enhanced green fluorescent protein-firefly luciferase fusion protein (Ad-EGFPLuc). Kupffer cell depletion before i.v. injection of Ad-EGFPLuc increased transgene expression in the liver 40.7-fold on day 3 after the injection indicating compensatory enhancement of hepatocyte transduction due to increased bioavailability of the virus. Pretreatment of mice with the anticoagulant drug warfarin to block blood factor–dependent binding of the virus to hepatocytes markedly reduced luciferase expression in the liver and mediated the corresponding decrease of hepatotoxicity in mice with intact and depleted liver macrophages. Combined depletion of Kupffer cells and pretreatment with warfarin before a single i.v. injection of Ad-EGFPLuc significantly reduced tumor growth and prolonged survival of nude mice bearing subcutaneous xenografts of aggressive human hepatocellular carcinoma. The improved antitumor activity correlated with enhanced transgene expression and virus spread in the tumors. These data suggest that detargeting oncolytic Ad from liver macrophages and hepatocytes is an effective strategy to increase the therapeutic window for therapy against disseminated tumor sites. [Cancer Res 2008;68(14):5896–904]
Monitoring Serial Changes in Circulating Human Breast Cancer Cells in Murine Xenograft Models
Authors: Eliane Jean-Pierre , Repollet Madeline , Luker Kathryn E. , Brown Martha , Rae James M. , Dontu Gabriela , Schott Anne F. , Wicha Max , Doyle Gerald V. , Hayes Daniel F. , Luker Gary D. 
Published: July 2008

Abstract
Circulating tumor cells (CTC) are emerging as a powerful prognostic and predictive biomarker in several types of cancer, including breast, colon, and prostate. Studies of CTC in metastasis and further development of CTC as a biomarker in cancer have been limited by the inability to repetitively monitor CTC in mouse models of cancer. We have validated a method to enumerate CTC in blood samples obtained from living mice using a modified version of an in vitro diagnostic system for quantifying CTC in patients. Different routes of blood collection were tested to identify a method to reproducibly recover CTC from tumor-bearing mice without interference from contaminating normal murine epithelial cells. CTC are present in blood samples from mice bearing orthotopic xenografts of several different breast cancer cell lines and primary breast cancer cells from patient biopsies. We also show that this technology can be used for serial monitoring of CTC in mouse xenograft models of human breast cancer. These results establish a new method for studying CTC in mouse models of epithelial cancer, providing the foundation for studies of molecular regulation of CTC in cancer and CTC as biomarker for therapeutic efficacy. [Cancer Res 2008;68(14):5529–32]
Defining a Chromatin Pattern that Characterizes DNA-Hypermethylated Genes in Colon Cancer Cells
Authors: McGarvey Kelly M. , Van Neste Leander , Cope Leslie , Ohm Joyce E. , Herman James G. , Van Criekinge Wim , Schuebel Kornel E. , Baylin Stephen B. 
Published: July 2008

AbstractEpigenetic gene regulation is a key determinant of heritable gene expression patterns and is critical for normal cellular function. Dysregulation of epigenetic transcriptional control is a fundamental feature of cancer, particularly manifesting as increased promoter DNA methylation with associated aberrant gene silencing, which plays a significant role in tumor progression. We now globally map key chromatin parameters for genes with promoter CpG island DNA hypermethylation in colon cancer cells by combining microarray gene expression analyses with chromatin immunoprecipitation-on-chip technology. We first show that the silent state of such genes universally correlates with a broad distribution of a low but distinct level of the PcG-mediated histone modification, methylation of lysine 27 of histone 3 (H3K27me), and a very low level of the active mark H3K4me2. This chromatin pattern, and particularly H3K4me2 levels, crisply separates DNA-hypermethylated genes from those where histone deacetylation is responsible for transcriptional silencing. Moreover, the chromatin pattern can markedly enhance identification of truly silent and DNA-hypermethylated genes. We additionally find that when DNA-hypermethylated genes are demethylated and reexpressed, they adopt a bivalent chromatin pattern, which is associated with the poised gene expression state of a large group of embryonic stem cell genes and is characterized by an increase in levels of both the H3K27me3 and H3K4me2 marks. Our data have great relevance for the increasing interest in reexpression of DNA-hypermethylated genes for the treatment of cancer. [Cancer Res 2008;68(14):5753–9]
Class I PI3 Kinase Inhibition by the Pyridinylfuranopyrimidine Inhibitor PI-103 Enhances Tumor Radiosensitivity
Authors: Prevo Remko , Deutsch Eric , Sampson Oliver , Diplexcito Julie , Cengel Keith , Harper Jane , O'Neill Peter , McKenna W. Gillies , Patel Sonal , Bernhard Eric J. 
Published: July 2008

Abstract
Cell signaling initiated at the epidermal growth factor receptor (EGFR), RAS oncoproteins, or PI3K contributes to a common pathway that promotes tumor survival after radiation-induced DNA damage. Inhibition of signaling at the level of EGFR, RAS, and PI3K has been tested, but clinical applicability has been shown only at the level of the EGFR or by inhibiting RAS indirectly with prenyltransferase inhibitors. Inhibition of PI3K with LY294002 or wortmannin lacks specificity and has shown unacceptable toxicity in preclinical studies. We previously showed that inhibiting class I PI3K expression with siRNA resulted in enhanced radiation killing of tumor cells. Here, we tested the possibility of achieving specific tumor cell radiosensitization with a pharmacologic inhibitor of class I PI3K, the pyridinylfuranopyrimidine inhibitor PI-103. Our results show that inhibiting PI3K activity reduces phosphorylation of AKT at serine 473. Reduced survival is seen in cells with AKT activation and seems preferential for tumor cells over cells in which AKT activity is not elevated. Reduced survival is accompanied by persistence of DNA damage as evidenced by persistence of γH2AX and Rad 51 foci after irradiation in the presence of the inhibitor. Reduced survival does not result from cell cycle redistribution during the PI-103 treatment intervals tested, although combining PI-103 treatment with radiation enhances the G2-M delay observed after irradiation. These results indicate that pharmacologic inhibitors with enhanced specificity for class I PI3K may be of benefit when combined with radiotherapy. [Cancer Res 2008;68(14):5915–23]
Genomic Alterations Indicate Tumor Origin and Varied Metastatic Potential of Disseminated Cells from Prostate Cancer Patients
Authors: Holcomb Ilona N. , Grove Douglas I. , Kinnunen Martin , Friedman Cynthia L. , Gallaher Ian S. , Morgan Todd M. , Sather Cassandra L. , Delrow Jeffrey J. , Nelson Peter S. , Lange Paul H. , Ellis William J. , True Lawrence D. , Young Janet M. , Hsu Li , Trask Barbara J. , Vessella Robert L. 
Published: July 2008

Abstract
Disseminated epithelial cells can be isolated from the bone marrow of a far greater fraction of prostate-cancer patients than the fraction of patients who progress to metastatic disease. To provide a better understanding of these cells, we have characterized their genomic alterations. We first present an array comparative genomic hybridization method capable of detecting genomic changes in the small number of disseminated cells (10–20) that can typically be obtained from bone marrow aspirates of prostate-cancer patients. We show multiple regions of copy-number change, including alterations common in prostate cancer, such as 8p loss, 8q gain, and gain encompassing the androgen-receptor gene on Xq, in the disseminated cell pools from 11 metastatic patients. We found fewer and less striking genomic alterations in the 48 pools of disseminated cells from patients with organ-confined disease. However, we identify changes shared by these samples with their corresponding primary tumors and prostate-cancer alterations reported in the literature, evidence that these cells, like those in advanced disease, are disseminated tumor cells (DTC). We also show that DTCs from patients with advanced and localized disease share several abnormalities, including losses containing cell-adhesion genes and alterations reported to associate with progressive disease. These shared alterations might confer the capability to disseminate or establish secondary disease. Overall, the spectrum of genomic deviations is evidence for metastatic capacity in advanced-disease DTCs and for variation in that capacity in DTCs from localized disease. Our analysis lays the foundation for elucidation of the relationship between DTC genomic alterations and progressive prostate cancer. [Cancer Res 2008;68(14):5599–608]
New Insights into Tumor Microstructure Using Temporal Diffusion Spectroscopy
Authors: Colvin Daniel C. , Yankeelov Thomas E. , Does Mark D. , Yue Zoe , Quarles Chad , Gore John C. 
Published: July 2008

AbstractMagnetic resonance images (MRI) that depict rates of water diffusion in tissues can be used to characterize the cellularity of tumors and are valuable in assessing their early response to treatment. Water diffusion rates are sensitive to the cellular and molecular content of tissues and are affected by local microstructural changes associated with tumor development. However, conventional maps of water diffusion reflect the integrated effects of restrictions to free diffusion at multiple scales up to a specific limiting spatial dimension, typically several micrometers. Such measurements cannot distinguish effects caused by structural variations at a smaller scale. Variations in diffusion rates then largely reflect variations in the density of cells, and no information is available about changes on a subcellular scale. We report here our experiences using a new approach based on Oscillating Gradient Spin-Echo (OGSE) MRI methods that can differentiate the influence on water diffusion of structural changes on scales much smaller than the diameter of a single cell. MRIs of glioblastomas in rat brain in vivo show an increased contrast and spatial heterogeneity when diffusion measurements are selectively sensitized to shorter distance scales. These results show the benefit of OGSE methods for revealing microscopic variations in tumors in vivo and confirm that diffusion measurements depend on factors other than cellularity. [Cancer Res 2008;68(14):5941–7]
Myricetin Suppresses UVB-Induced Skin Cancer by Targeting Fyn
Authors: Jung Sung Keun , Lee Ki Won , Byun Sanguine , Kang Nam Joo , Lim Sung Hwan , Heo Yong-Seok , Bode Ann M. , Bowden G. Tim , Lee Hyong Joo , Dong Zigang 
Published: July 2008

Abstract
Skin cancer is currently the most common type of human cancer in Americans. Myricetin, a naturally occurring phytochemical, has potent anticancer-promoting activity and contributes to the chemopreventive potential of several foods, including red wine. Here, we show that myricetin suppresses UVB-induced cyclooxygenase-2 (COX-2) expression in mouse skin epidermal JB6 P+ cells. The activation of activator protein-1 and nuclear factor-κB induced by UVB was dose-dependently inhibited by myricetin treatment. Western blot and kinase assay data revealed that myricetin inhibited Fyn kinase activity and subsequently attenuated UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays revealed that myricetin competitively bound with ATP to suppress Fyn kinase activity. Importantly, myricetin exerted similar inhibitory effects compared with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a well-known pharmacologic inhibitor of Fyn. In vivo mouse skin data also revealed that myricetin inhibited Fyn kinase activity directly and subsequently attenuated UVB-induced COX-2 expression. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Docking data suggest that myricetin is easily docked to the ATP-binding site of Fyn, which is located between the N and C lobes of the kinase domain. Overall, these results indicated that myricetin exerts potent chemopreventive activity mainly by targeting Fyn in skin carcinogenesis. [Cancer Res 2008;68(14):6021–9]
Hepatitis B Virus–Associated Multistep Hepatocarcinogenesis: A Stepwise Increase in Allelic Alterations
Authors: Lee Joyce Man-Fong , Wong Chun-Ming , Ng Irene Oi-Lin 
Published: July 2008

Abstract
Hepatocarcinogenesis is a multistep process, but systematic analysis using a genetic or molecular approach to accurately delineate the different stages of hepatocellular carcinoma (HCC) development is scarce. In this study, we used genome-wide allelotyping to systematically evaluate the allelic alterations in the multisteps of hepatitis B virus–associated hepatocarcinogenesis. The overall fractional allelic loss (FAL) indices of cirrhosis, dysplastic nodules (DN), and HCC were significantly different, with a clear stepwise increase (P &lt; 0.001). Loss of heterozygosity (LOH) was uncommon in cirrhotic livers (n = 24; mean FAL index ± SD, 0.09 ± 0.09; median, 0.07). In contrast, LOH was common in our 74 HCC nodules, which were predominantly hepatitis B virus–associated (mean FAL index ± SD, 0.40 ± 0.23; median, 0.38). The 18 DNs had FAL index (mean ± SD, 0.27 ± 0.19; median, 0.20) in between that of cirrhosis and HCC. Importantly, high-grade DNs had FAL index significantly higher than that of low-grade DNs (P = 0.031) and close to that of HCC, indicating that high-grade DNs were genetically closer to HCC. However, there was no significant difference in FAL indices between primary HCCs and their corresponding intrahepatic metastases, but this absence of major allelic losses in this transformation to a metastatic phenotype does not exclude small-scale chromosomal losses or gene deletions. To conclude, hepatitis B virus–associated hepatocarcinogenesis is a multistep process accompanied by stepwise increase in allelic losses from cirrhosis and low- and high-grade DN to HCC. Such allelic losses contribute to promote tumor development and progression. [Cancer Res 2008;68(14):5988–96]
Refractoriness to Antivascular Endothelial Growth Factor Treatment: Role of Myeloid Cells
Authors: Shojaei Farbod , Ferrara Napoleone 
Published: July 2008

Abstract
CD11b+Gr1+ cells, which include neutrophils, macrophages, and myeloid-derived suppressor cells, have been shown to contribute to tumor angiogenesis. Recently, we found that accumulation of CD11b+Gr1+ in tumors renders them refractory to angiogenic blockade by vascular endothelial growth factor (VEGF) antibodies. This effect was traced to a pathway of CD11b+Gr1+–mediated angiogenesis that is, at least in part, driven by the secreted protein Bv8, which is up-regulated by the important myeloid growth factor granulocyte colony-stimulating factor (G-CSF). Thus, G-CSF may promote tumor angiogenesis through a Bv8-dependent pathway that bypasses VEGF and renders tumors refractory to anti-VEGF therapy. [Cancer Res 2008;68(14):5501–4]
Regulation of the Adenomatous Polyposis Coli Gene by the miR-135 Family in Colorectal Cancer
Authors: Nagel Remco , le Sage Carlos , Diosdado Begoña , van der Waal Maike , Oude Vrielink Joachim A.F. , Bolijn Anne , Meijer Gerrit A. , Agami Reuven 
Published: July 2008

Abstract
Inactivation of the adenomatous polyposis coli (APC) gene is a major initiating event in colorectal tumorigenesis. Most of the mutations in APC generate premature stop codons leading to truncated proteins that have lost β-catenin binding sites. APC-free β-catenin stimulates the Wnt signaling pathway, leading to active transcription of target genes. In the current study, we describe a novel mechanism for APC regulation. We show that miR-135a&b target the 3′ untranslated region of APC, suppress its expression, and induce downstream Wnt pathway activity. Interestingly, we find a considerable up-regulation of miR-135a&b in colorectal adenomas and carcinomas, which significantly correlated with low APC mRNA levels. This genetic interaction is also preserved in full-blown cancer cell lines expressing miR-135a&b, regardless of the mutational status of APC. Thus, our results uncover a miRNA-mediated mechanism for the control of APC expression and Wnt pathway activity, and suggest its contribution to colorectal cancer pathogenesis. [Cancer Res 2008;68(14):5795–802]
CTCFL/BORIS Is a Methylation-Independent DNA-Binding Protein That Preferentially Binds to the Paternal H19 Differentially Methylated Region
Authors: Nguyen Phuongmai , Cui Hengmi , Bisht Kheem S. , Sun Lunching , Patel Krish , Lee Richard S. , Kugoh Hiroyuki , Oshimura Mitsuo , Feinberg Andrew P. , Gius David 
Published: July 2008

Abstract
The CTCF paralog BORIS (brother of the regulator of imprinted sites) is an insulator DNA-binding protein thought to play a role in chromatin organization and gene expression. Under normal physiologic conditions, BORIS is predominantly expressed during embryonic male germ cell development; however, it is also expressed in tumors and tumor cell lines and, as such, has been classified as a cancer-germline or cancer-testis gene. It has been suggested that BORIS may be a pro-proliferative factor, whereas CTCF favors antiproliferation. BORIS and CTCF share similar zinc finger DNA-binding domains and seem to bind to identical target sequences. Thus, one critical question is the mechanism governing the DNA-binding specificity of these two proteins when both are present in tumor cells. Chromatin immunoprecipitation (ChIP) in HCT116 cells and their hypermethylated variant showed that BORIS binds to methylated DNA sequences, whereas CTCF binds to unmethylated DNA. Electromobility shift assays, using both whole-cell extracts and in vitro translated CTCF and BORIS protein, and methylation-specific ChIP PCR showed that BORIS is a methylation-independent DNA-binding protein. Finally, experiments in murine hybrid cells containing either the maternal or paternal human chromosome 11 showed that BORIS preferentially binds to the methylated paternal H19 differentially methylated region, suggesting a mechanism in which the affinity of CTCF for the unmethylated maternal allele directs the DNA binding of BORIS toward the paternal allele. [Cancer Res 2008;68(14):5546–51]
Presence of a TA Haplotype in the APC Gene Containing the Common 1822 Polymorphism and Colorectal Adenoma
Authors: Egan Jan B. , Jacobs Elizabeth T. , Martínez María Elena , Gerner Eugene W. , Jurutka Peter W. , Thompson Patricia A. 
Published: July 2008

Abstract
Acquired or inherited mutations in the adenomatous polyposis coli (APC) tumor suppressor gene are causally linked to colorectal cancer. Given the significance of APC in colorectal cancer, we investigated the association between common single-nucleotide polymorphisms (SNP) in the APC gene and the odds of developing metachronous colorectal adenomas as a surrogate measure of colorectal cancer risk. Coding SNPs at codons 486, 1678, 1822, 1960, and 2502 were analyzed in a total of 1,399 subjects who participated in two randomized clinical trials for the prevention of colorectal adenomas. No association was found for any single SNP and the odds of metachronous adenoma. In contrast, a TA haplotype (codons 486 and 1822) was associated with a statistically significant 27% and 26% reduction in the odds of any and nonadvanced metachronous adenoma after adjustment for baseline adenoma characteristics [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.59–0.91 and OR, 0.74; 95% CI, 0.57–0.94], respectively. No significant reduction in odds was observed for advanced metachronous lesions. Diplotype analysis revealed a strong gene dose effect with carriers of two alleles containing TT-AA (codons 486 and 1822, respectively) having an 89% lower odds for advanced metachronous adenomas (OR, 0.11; 95% CI, 0.01–0.80) when compared with the common CC-AA diplotype (codons 486 and 1822, respectively). Our findings support an important role for germ-line allele sequence in the APC gene and individual risk of metachronous adenomatous polyps. [Cancer Res 2008;68(14):6006–13]
PTEN Expression in Endometrial Biopsies as a Marker of Progression to Endometrial Carcinoma
Authors: Lacey James V. , Mutter George L. , Ronnett Brigitte M. , Ioffe Olga B. , Duggan Máire A. , Rush Brenda B. , Glass Andrew G. , Richesson Douglas A. , Chatterjee Nilanjan , Langholz Bryan , Sherman Mark E. 
Published: July 2008

Abstract
Inactivation of PTEN tumor suppressor gene is common in endometrial carcinoma and its precursor, atypical endometrial hyperplasia (EH). We compared PTEN expression via immunohistochemistry in endometrial biopsies diagnosed as EH in 138 cases, who were diagnosed with EH and then endometrial carcinoma at least 1 year later (median, 6 years), and 241 individually matched controls, who were diagnosed with EH but did not progress to carcinoma during equivalent follow-up. We assessed PTEN status (normal versus null) in index biopsies containing EH to estimate the relative risk (RR) of developing endometrial carcinoma up to 25 years later. Analysis of 115 cases and 193 controls with satisfactory assays revealed PTEN-null glands in index biopsies of 44% of cases and 49% of controls [P = 0.85; RR, 1.51; 95% confidence interval (CI), 0.73–3.13]. For predicting progression to carcinoma, PTEN-null status had low sensitivity (44%; 95% CI, 45–54%) and specificity (51%; 95% CI, 44–58%). Among 105 cases with PTEN results for both index biopsy and carcinoma, 16% had a PTEN-null index biopsy, 23% had PTEN-null carcinoma, and 26% had both a PTEN-null index biopsy and carcinoma. Loss of PTEN expression in endometrial biopsies was neither associated with nor a sensitive and specific marker of subsequent progression to endometrial carcinoma. [Cancer Res 2008;68(14):6014–20]