bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytogenetic and cDNA Microarray Expression Analysis of MCF10 Human Breast Cancer Progression Cell Lines
Authors: Marella Narasimharao V. , Malyavantham Kishore S. , Wang Jianmin , Matsui Sei-ichi , Liang Ping , Berezney Ronald 
Published: July 2009

Abstract
We used a combination of spectral karyotyping, array comparative genomic hybridization, and cDNA microarrays to gain insights into the structural and functional changes of the genome in the MCF10 human breast cancer progression model cell lines. Spectral karyotyping data showed several chromosomal aberrations and array comparative genomic hybridization analysis identified numerous genomic gains and losses that might be involved in the progression toward cancer. Analysis of the expression levels of genes located within these genomic regions revealed a lack of correlation between chromosomal gains and losses and corresponding up-regulation or down-regulation for the majority of the ∼1,000 genes analyzed in this study. We conclude that other mechanisms of gene regulation that are not directly related to chromosomal gains and losses play a major role in breast cancer progression. [Cancer Res 2009;69(14):5946–53]
Epstein-Barr Virus Latent Membrane Protein-1 Effects on Junctional Plakoglobin and Induction of a Cadherin Switch
Authors: Shair Kathy H.Y , Schnegg Caroline I. , Raab-Traub Nancy 
Published: July 2009

Abstract
Latent membrane protein-1 (LMP1) is considered the major oncoprotein of Epstein-Barr virus and is frequently expressed in nasopharyngeal carcinoma (NPC). LMP1 promotes growth and migration of epithelial cells, and the loss of plakoglobin has been identified as a contributing factor to LMP1-induced migration. Plakoglobin is a junctional protein that can also serve as a transcription factor in Tcf/Lef signaling. To determine the effects of LMP1 on the molecular and functional properties of plakoglobin, LMP1 was overexpressed in the NPC cell line C666-1. LMP1 did not affect plakoglobin stability but did decrease plakoglobin transcription. The resultant decreased levels of nuclear plakoglobin did not affect Tcf/Lef activity or the amount of plakoglobin bound to Tcf4. Although LMP1 induced and stabilized β-catenin, a protein with common binding partners to plakoglobin, the loss of plakoglobin did not affect its association with Tcf4. However, LMP1 did induce a cadherin switch from E- to N-cadherin, a process involved in cancer progression, and enhanced the association of junctional β-catenin with N-cadherin. LMP1 decreased overall levels of junctional plakoglobin but the remaining junctional plakoglobin was found associated with the induced N-cadherin. This increased association of junctional plakoglobin with N-cadherin was a distinguishing feature of LMP1-expressing cells that have reduced migration due to restoration of plakoglobin. Low levels of plakoglobin were also detected in human NPC tissues. These findings reveal that the effects of LMP1 on junctional plakoglobin and the initiation of a cadherin switch likely contribute to metastasis of NPC. [Cancer Res 2009;69(14):5734–42]
Tumor Necrosis Factor-α and Interleukin-1 Antagonists Alleviate Inflammatory Skin Changes Associated with Epidermal Growth Factor Receptor Antibody Therapy in Mice
Authors: Surguladze David , Deevi Dhanvanthri , Claros Nidia , Corcoran Erik , Wang Su , Plym Mary Jane , Wu Yan , Doody Jacqueline , Mauro David J. , Witte Larry , Busam Klaus J. , Pytowski Bronek , Rodeck Ulrich , Tonra James R. 
Published: July 2009

Abstract
Cancer patients receiving epidermal growth factor receptor (EGFR) antibody therapy often experience an acneiform rash of uncertain etiology in skin regions rich in pilosebaceous units. Currently, this condition is treated symptomatically with very limited, often anecdotal success. Here, we show that a monoclonal antibody targeting murine EGFR, ME1, caused a neutrophil-rich hair follicle inflammation in mice, similar to that reported in patients. This effect was preceded by the appearance of lipid-filled hair follicle distensions adjacent to enlarged sebaceous glands. The cytokine tumor necrosis factor-α (TNFα), localized immunohistochemically to this affected region of the pilosebaceous unit, was specifically up-regulated by ME1 in skin but not in other tissues examined. Moreover, skin inflammation was reduced by cotreatment with the TNFα signaling inhibitor, etanercept, indicating the involvement of TNFα in this inflammatory process. Interleukin-1, a cytokine that frequently acts in concert with TNFα, is also involved in this process given the efficacy of the interleukin-1 antagonist Kineret. Our results provide a mechanistic framework to develop evidence-based trials for EGFR antibody–induced skin rash in patients with cancer. [Cancer Res 2009;69(14):5643–7]
MicroRNA Classifiers for Predicting Prognosis of Squamous Cell Lung Cancer
Authors: Raponi Mitch , Dossey Lesley , Jatkoe Tim , Wu Xiaoying , Chen Guoan , Fan Hongtao , Beer David G. 
Published: July 2009

Abstract
Non–small cell lung cancer (NSCLC), which is comprised mainly of adenocarcinoma and squamous cell carcinoma (SCC), is the cause of 80% of all lung cancer deaths in the United States. NSCLC is also associated with a high rate of relapse after clinical treatment and, therefore, requires robust prognostic markers to better manage therapy options. The aim of this study was to identify microRNA (miRNA) expression profiles in SCC of the lung that would better predict prognosis. Total RNA from 61 SCC samples and 10 matched normal lung samples was processed for small RNA species and profiled on MirVana miRNA Bioarrays (version 2, Ambion). We identified 15 miRNAs that were differentially expressed between normal lung and SCC, including members of the miR-17-92 cluster and its paralogues. We also identified miRNAs, including miR-155 and let-7, which had previously been shown to have prognostic value in adenocarcinoma. Based on cross-fold validation analyses, miR-146b alone was found to have the strongest prediction accuracy for stratifying prognostic groups at ∼78%. The miRNA signatures were superior in predicting overall survival than a previously described 50-gene prognostic signature. Whereas there was no overlap between the mRNAs targeted by the prognostic miRNAs and the 50-gene expression signature, there was a significant overlap in the corresponding biological pathways, including fibroblast growth factor and interleukin-6 signaling. Our data indicate that miRNAs may have greater clinical utility in predicting the prognosis of patients with squamous cell lung carcinomas than mRNA-based signatures. [Cancer Res 2009;69(14):5776–83]
Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers
Authors: Rebbeck Timothy R. , Mitra Nandita , Domchek Susan M. , Wan Fei , Chuai Shannon , Friebel Tara M. , Panossian Saarene , Spurdle Amanda , Chenevix-Trench Georgia ,   kConFab, Singer Christian F. , Pfeiler Georg , Neuhausen Susan L. , Lynch Henry T. , Garber Judy E. , Weitzel Jeffrey N. , Isaacs Claudine , Couch Fergus , Narod Steven A. , Rubinstein Wendy S. , Tomlinson Gail E. , Ganz Patricia A. , Olopade Olufunmilayo I. , Tung Nadine , Blum Joanne L. , Greenberg Roger , Nathanson Katherine L. , Daly Mary B. 
Published: July 2009

Abstract
Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]
Down-regulation of Epidermal Growth Factor Receptor by Selective Expansion of a 5′-End Regulatory Dinucleotide Repeat in Colon Cancer with Microsatellite Instability
Authors: Baranovskaya Svetlana , Martin Yolanda , Alonso Sergio , Pisarchuk Ksenia L. , Falchetti Mario , Dai Yuichi , Khaldoyanidi Sophia , Krajewski Stan , Novikova Inna , Sidorenko Yuri S. , Perucho Manuel , Malkhosyan Sergei R. 
Published: July 2009

Abstract
Purpose: The epidermal growth factor receptor (EGFR) is overexpressed in several tumor types, and its expression is influenced by the length of a 5′-end microsatellite repeat (CA)n: the longer the repeat, the lower the expression. Dinucleotide repeats accumulate insertion/deletion types of mutations in tumors with microsatellite instability. We designed this study to estimate the occurrence of these mutations in EGFR(CA)n and their relevance in carcinogenesis of microsatellite instability–positive colon and gastric tumors.
Experimental Design: We analyzed the frequency of EGFR(CA)n mutations in vivo in 55 colorectal and 14 gastric microsatellite instability–positive cancers, and in vitro in single-cell clone cultures of microsatellite instability–positive colon tumor cell line LS174. Single-cell clone cultures with different repeat lengths were analyzed by fluorescent-activated cell sorter for EGFR cell-surface expression. A correlation analysis was done between EGFR(CA)n mutations and mutations in KRAS, BRAF, and p53.
Results: Unlike single-cell clone cultures, which exhibited higher rate of deletions compared with insertions, most of EGFR(CA)n mutations in colon and gastric tumors were insertions. Longer EGFR(CA)n correlated with lower EGFR cell-surface expression in single-cell clone cultures. In colon cancers, the elongation of the repeat was associated negatively with mutations in KRAS and BRAF, but not in p53.
Conclusions: The EGFR(CA)n elongation observed in tumors cannot be explained by an intrinsic property of this repeat favoring insertions versus deletions. Instead, a selection for repeat elongation occurs in microsatellite instability–positive tumors, leading to EGFR down-regulation. These findings suggest that in microsatellite instability–positive tumors current therapies targeting EGFR overexpression may have either no effect or an opposite to the expected effect.
The Influence of Prostate Volume on Prostate-Specific Antigen Performance: Implications for the Prostate Cancer Prevention Trial Outcomes
Authors: Elliott Christopher S. , Shinghal Rajesh , Presti Joseph C. 
Published: July 2009

Abstract
Purpose: Although showing a 25% reduction in the biopsy prevalence of cancer compared with placebo in the Prostate Cancer Prevention Trial, finasteride was associated with a higher prevalence of high-grade disease. This observation was driven by “for-cause” biopsies. We sought to understand how volume-dependent changes in prostate-specific antigen test performance characteristics may have contributed.
Experimental Design: A retrospective review was done on 1,304 men referred for initial biopsy with a prostate-specific antigen between 4 and 10 ng/mL or an abnormal digital rectal examination. Receiver-operator curves and positive predictive values were ascertained for prostate-specific antigen stratified by diagnosis and prostate volume.
Results: The performance of prostate-specific antigen changed for any and high-grade (Gleason, ≥3 + 4) cancer in a volume-specific manner. For any cancer, the area under the curve (AUC) decreased from 0.758 to 0.629 to 0.520 as prostate volume increased (&lt;30, 30-50, &gt;50 cm3, respectively). For high-grade cancer, a similar trend was shown (AUC, 0.712, 0.639, and 0.497, respectively). The positive predictive value of a prostate-specific antigen of ≥4 ng/mL was also affected by prostate volume. Trends for Gleason ≤ 6 decreased as prostate volume increased (positive predictive value for &lt;30 cm3, 25.0%; positive predictive value for 30-50 cm3, 23.8%; and positive predictive value for &gt;50 cm3, 17.3%). A more significant trend was seen for high-grade cancer (positive predictive value for &lt;30 cm3, 39.0%; positive predictive value for 30-50 cm3, 22.3%; and positive predictive value for &gt;50 cm3, 10.7%).
Conclusion: Decreases in prostate volume over time and the resultant change in prostate-specific antigen performance characteristics may have contributed a bias toward the detection of high-grade disease in the finasteride arm of the Prostate Cancer Prevention Trial.
15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Gastric Cancer
Authors: Thiel Alexandra , Ganesan Aparna , Mrena Johanna , Junnila Siina , Nykänen Antti , Hemmes Annabrita , Tai Hsin-Hsiung , Monni Outi , Kokkola Arto , Haglund Caj , Petrova Tatiana V. , Ristimäki Ari 
Published: July 2009

Abstract
Purpose: We have investigated the expression and regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in gastric cancer.
Experimental Design: Clinical gastric adenocarcinoma samples were analyzed by immunohistochemistry and quantitative real-time PCR for protein and mRNA expression of 15-PGDH and for methylation status of 15-PGDH promoter. The effects of interleukin-1β (IL-1β) and epigenetic mechanisms on 15-PGDH regulation were assessed in gastric cancer cell lines.
Results: In a gastric cancer cell line with a very low 15-PGDH expression (TMK-1), the 15-PGDH promoter was methylated and treatment with a demethylating agent 5-aza-2′-deoxycytidine restored 15-PGDH expression. In a cell line with a relatively high basal level of 15-PGDH (MKN-28), IL-1β repressed expression of 15-PGDH mRNA and protein. This effect of IL-1β was at least in part attributed to inhibition of 15-PGDH promoter activity. SiRNA-mediated knockdown of 15-PGDH resulted in strong increase of prostaglandin E2 production in MKN-28 cells and increased cell growth of these cells by 31% in anchorage-independent conditions. In clinical gastric adenocarcinoma specimens, 15-PGDH mRNA levels were 5-fold lower in gastric cancer samples when compared with paired nonneoplastic tissues (n = 26) and 15-PGDH protein was lost in 65% of gastric adenocarcinomas (n = 210).
Conclusions: 15-PGDH is down-regulated in gastric cancer, which could potentially lead to accelerated tumor progression. Importantly, our data indicate that a proinflammatory cytokine linked to gastric carcinogenesis, IL-1β, suppresses 15-PGDH expression at least partially by inhibiting promoter activity of the 15-PGDH gene.
Imaging Biomarkers Predict Response to Anti-HER2 (ErbB2) Therapy in Preclinical Models of Breast Cancer
Authors: Shah Chirayu , Miller Todd W. , Wyatt Shelby K. , McKinley Eliot T. , Olivares Maria Graciela , Sanchez Violeta , Nolting Donald D. , Buck Jason R. , Zhao Ping , Ansari M. Sib , Baldwin Ronald M. , Gore John C. , Schiff Rachel , Arteaga Carlos L. , Manning H. Charles 
Published: July 2009

Abstract
Purpose: To evaluate noninvasive imaging methods as predictive biomarkers of response to trastuzumab in mouse models of HER2-overexpressing breast cancer. The correlation between tumor regression and molecular imaging of apoptosis, glucose metabolism, and cellular proliferation was evaluated longitudinally in responding and nonresponding tumor-bearing cohorts.
Experimental Design: Mammary tumors from MMTV/HER2 transgenic female mice were transplanted into syngeneic female mice. BT474 human breast carcinoma cell line xenografts were grown in athymic nude mice. Tumor cell apoptosis (NIR700-Annexin V accumulation), glucose metabolism [2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography ([18F]FDG-PET)], and proliferation [3′-[18F]fluoro-3′-deoxythymidine-PET ([18F]FLT-PET)] were evaluated throughout a biweekly trastuzumab regimen. Imaging metrics were validated by direct measurement of tumor size and immunohistochemical analysis of cleaved caspase-3, phosphorylated AKT, and Ki67.
Results: NIR700-Annexin V accumulated significantly in trastuzumab-treated MMTV/HER2 and BT474 tumors that ultimately regressed but not in nonresponding or vehicle-treated tumors. Uptake of [18F]FDG was not affected by trastuzumab treatment in MMTV/HER2 or BT474 tumors. [18F]FLT-PET imaging predicted trastuzumab response in BT474 tumors but not in MMTV/HER2 tumors, which exhibited modest uptake of [18F]FLT. Close agreement was observed between imaging metrics and immunohistochemical analysis.
Conclusions: Molecular imaging of apoptosis accurately predicts trastuzumab-induced regression of HER2+ tumors and may warrant clinical exploration to predict early response to neoadjuvant trastuzumab. Trastuzumab does not seem to alter glucose metabolism substantially enough to afford [18F]FDG-PET significant predictive value in this setting. Although promising in one preclinical model, further studies are required to determine the overall value of [18F]FLT-PET as a biomarker of response to trastuzumab in HER2+ breast cancer.
A Phase I Clinical Trial of Darinaparsin in Patients with Refractory Solid Tumors
Authors: Tsimberidou Apostolia Maria , Camacho Luis H. , Verstovsek Srdan , Ng Chaan , Hong David S. , Uehara Cynthia K. , Gutierrez Catalina , Daring Shawn , Stevens Jan , Komarnitsky Philip B. , Schwartz Brian , Kurzrock Razelle 
Published: July 2009

Abstract
Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer.
Experimental Design: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m2) escalated to 109, 153, 214, 300, 420, and 588 mg/m2. A conventional “3 + 3” design was used.
Results: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of &lt;420 mg/m2. At 588 mg/m2, two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m2, one developed similar toxicities. De-escalating the dose to 420 mg/m2 (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m2 (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for ≥4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer.
Conclusions: The recommended dose for phase II trials is 300 mg/m2 i.v. given daily for 5 days every 4 weeks.
EGFR/KRAS/BRAF Mutations in Primary Lung Adenocarcinomas and Corresponding Locoregional Lymph Node Metastases
Authors: Schmid Katharina , Oehl Natalie , Wrba Fritz , Pirker Robert , Pirker Christine , Filipits Martin 
Published: July 2009

Abstract
Purpose: The epidermal growth factor receptor (EGFR) and its downstream factors KRAS and BRAF are mutated with different frequencies in non–small cell lung cancer and mutations predict clinical response to EGFR inhibitors. The present study compared the mutational status of EGFR, KRAS, and BRAF in primary tumors with the one in corresponding lymph node metastases.
Experimental Design: Direct bidirectional sequencing of EGFR gene exons 18 to 21, KRAS gene codons 12/13 and 61 to 68, and BRAF exon 15 was done on 96 paired samples of primary lung adenocarcinomas and corresponding locoregional lymph node metastases. In addition, comparative genomic hybridization analyses in two pairs of corresponding primary and metastatic tumor samples with discordant EGFR mutation status were done.
Results: Mutations in EGFR, KRAS, and BRAF were observed in 7 (7%), 36 (38%), and 2 (2%) patients, respectively. Interestingly, KRAS mutations were observed in two patients with an EGFR mutation. Mutations in primary tumors and lymph node metastases were identical in 1 of 7 (14%) patients in case of EGFR and 11 of 36 (31%) patients in case of KRAS. One patient harbored different KRAS mutations in primary and corresponding metastatic tumors. Comparative genomic hybridization analysis revealed similar patterns of chromosomal changes, strongly supporting a common clonal origin of primary tumors and metastases.
Conclusions: The possibility of differences in the mutational status of EGFR, KRAS, BRAF between primary tumors and corresponding lymph node metastases should be considered whenever these mutations are used for the selection of patients for EGFR-directed tyrosine kinase inhibitor therapy.
Antiangiogenesis Targeting Tumor Microenvironment Synergizes Glucuronide Prodrug Antitumor Activity
Authors: Juan Ting-Yi , Roffler Steve R. , Hou Hsien-San , Huang Shih-Ming , Chen Kai-Chuan , Leu Yu-Lin , Prijovich Zeljko M. , Yu Cheng-Ping , Wu Chang-Chieh , Sun Guang-Huan , Cha Tai-Lung 
Published: July 2009

Abstract
Purpose: This study is aimed at investigating the in vivo antitumor activity of a novel cell-impermeable glucuronide prodrug, 9-aminocamptothecin glucuronide (9ACG), and elucidating the synergistically antitumor effects of antiangiogenesis therapy by targeting the tumor microenvironment.
Experimental Design: We analyzed the antitumor effects of 9ACG alone or combined with antiangiogenic monoclonal antibody DC101 on human tumor xenografts by measuring tumor growth and mouse survival in BALB/c nu/nu nude and NOD/SCID mice. The drug delivery, immune response, and angiogenesis status in treated tumors were assessed by high performance liquid chromatography, immunohistochemistry, and immunofluorescence assays.
Results: We developed a nontoxic and cell-impermeable glucuronide prodrug, 9ACG, which can only be activated by extracellular β-glucuronidase to become severely toxic. 9ACG possesses potent antitumor activity against human tumor xenografts in BALB/c nu/nu nude mice but not for tumors implanted in NOD/SCID mice deficient in macrophages and neutrophils, suggesting that these cells play an important role in activating 9ACG in the tumor microenvironment. Most importantly, antiangiogenic monoclonal antibody DC101 potentiated single-dose 9ACG antitumor activity and prolonged survival of mice bearing resistant human colon tumor xenografts by providing strong β-glucuronidase activity and prodrug delivery through enhancing inflammatory cell infiltration and normalizing tumor vessels in the tumor microenvironment. We also show that inflammatory cells (neutrophils) were highly infiltrated in advanced human colon cancer tissues compared with normal counterparts.
Conclusions: Our study provides in vivo evidence that 9ACG has potential for prodrug monotherapy or in combination with antiangiognesis treatment for tumors with infiltration of macrophage or neutrophil inflammatory cells.