bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-348: Identifying novel oncogenes in ovarian cancer using integrative genomics and gene-knock downs
Authors: Ramakrishna Manasa , Williams Louise H. , Bearfoot Jennifer L. , Boyle Samantha E. , Sridhar Anita , Davis Sally , Gorringe Kylie L. , Campbell Ian G. 
Published: February 2011

Abstract
Ovarian cancer is a disease characterised by complex genomic rearrangements but the majority of the genes that are the target of these alterations remain unidentified. Cataloguing these target genes will provide useful insights into the disease etiology and may provide an opportunity to develop novel diagnostic and therapeutic interventions. To expedite identification of ovarian oncogenes we have integrated matching gene copy number and gene expression data from a cohort of 68 primary epithelial ovarian cancers to identify genes in regions of most frequent amplification with the strongest correlation with expression and copy number. Chromosomes 3, 7, 8, and 20 were most frequently increased in copy number (&gt;40% of samples). Within these regions, 703/1370 (51%) unique gene expression probesets were differentially expressed when samples with gain were compared to samples without gain. 41% of these differentially expressed probesets also showed a strong positive correlation (r≥0.6) between expression and copy number. We also identified 21 regions of high amplitude copy number gain, in which 43 known protein coding genes showed a strong positive correlation between expression and copy number. We have verified previously known ovarian oncogenes such as ERBB2 and also identified novel potential oncogenic drivers such as PUF60 (SIAHBP1) and TPX2. Functional characterisation and mutation analysis of these novel oncogene candidates will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-348.
Abstract LB-350: MicroRNA-301a, elevated in pancreatic cancer, targets tumor suppressor CDKN1A/p21 blocking cellular senescence and promoting invasion of pancreatic epithelial cells
Authors: Wang Jin , Katayama Hiroshi , Leblanc Aimee B. , Frazier Marsha L. , Killary Ann M. , Sen Subrata 
Published: February 2011

Abstract
MicroRNAs (miR) are negative regulators of gene expression and have been implicated to play important roles in the carcinogenic processes. Expression of miR-301a is elevated in multiple solid tumors including pancreatic cancer, small cell lung cancer, breast and liver cancer. However, the targets and function of miR-301a remain unknown. Here, we report that miR-301a targets CDKN1A/p21 tumor suppressor gene transcript leading to down regulation of the protein. Luciferase reporter assay of p21 3′UTR construct revealed that p21 is a direct target of miR-301a. Over expression of miR-301a in immortalized non-tumorigenic pancreatic epithelial cells (HPNE and HPDE) by transient transfection of precursor miR-301a resulted in down-regulation of p21 protein level with accompanying accelerated cell proliferation and increase in invasive potential detected in matrigel assays. Conversely, knockdown of miR-301a by antigomir301a resulted in elevated levels of p21 protein in pancreatic ductal adenocarcinoma cells (Panc-1 and Aspc-1). These cells displayed accumulation in G1 cell cycle phase and induction of cellular senescence. The results suggest that the use of synthetic antigomir301a may be a promising approach to pancreatic cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-350.
Abstract LB-351: miR-221&222 regulate cell motility in glioma cell lines targeting the protein phosphates PTPμ
Authors: Quintavalle Cristina , Garofalo Michela , Romano Giulia , Iaboni Margherita , Zanca Ciro , Brenca Monica , Nuovo Gerald , Croce Carlo Maria , Condorelli Gerolama 
Published: February 2011

Abstract
Glioblastoma multiforme (GBM) is the most frequent brain tumor in adults and is the most lethal form of human cancer. Despite the improvements in treatments, patients's survival remains poor. Different evidences indicate that microRNAs might play a fundamental role in tumorigenesis, cell proliferation, migration and apoptosis. Through a microarray analysis we identified different microRNAs upregulated in the tumorigenic glioma cell lines U87 compared with the non tumorigenic cell lines T98G. Among different microRNAs we focused our attention on miR221&222. By bioinformatic analysis we identified a binding site for these two miRs in the 3′UTR of the protein phosphatase PTPμ. Luciferase assay confirmed that miR-221 and 222 bind to the 3′UTR of PTPμ and impairs its mRNA translation. Previous studies indicated that PTPμ suppresses cell migration/invasion and is downregulated in glioma. Significantly, we found that miR 221&222 overexpression induced a downregulation of PTPμ as analyzed by both western blot and RT-PCR. Furthermore, miR222&221 induced an increase in cell migration/invasion in glioma cells. Accordingly, we found an inverse correlation between miR221&222 and PTPμ in glioma cancer samples, as analyzed by immunohistochemistry and in situ hybridization on a tissue array representing 46 glioma and normal brain tissues. In conclusion, our results suggest that microRNA 221&222 might regulate glioma tumorigenesis through the control of cell migration process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-351.
Abstract LB-36: Antibody mediated neutralization of sema4D reduces tumor angiogenesis and growth In Vivo.
Authors: Jonason Alan , Fisher Terrance , Torno Sebold , Bussler Holm , Li Ji , Winter Laurie , Kirk Renee , Howell Alan , Caplan Jeff , Kenney Patrick , Reilly Christine , Scrivens Maria , Evans Elizabeth , Paris Mark , Watkins Raymond , Zauderer Maurice , Leonard John E. , Smith Ernest S. 
Published: February 2011

Abstract
It has been demonstrated that semaphorin 4D (SEMA4D; CD100) is a potent pro-angiogenic molecule. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells transactivates c-MET and promotes formation of new blood vessels and tumor growth in vivo. SEMA4D is over-expressed in a wide array of tumor types, and is also produced by inflammatory cells present in the tumor microenvironment. It has recently been demonstrated that in an environment lacking SEMA4D, the ability of mouse breast cancer cells to originate tumor masses and metastases is severely impaired, and that SEMA4D produced by tumor associated macrophages is required for tumor angiogenesis and growth.
In addition to its effects on endothelial cells, SEMA4D binding to PLXNB1 on tumor cells results in MET transactivation and migration of tumor cells. It has been further reported that overexpression of PLXNB1 and MET in breast and ovarian cancers is a negative prognostic factor. Tumors co-expressing PLXNB1 and MET were characterized as having a higher grade and an increased frequency of metastases.
Collectively, these results suggest that expression of SEMA4D, either by tumor cells or by tumor associated macrophages, may represent a mechanism of tumor neovascularization, and that expression of the SEMA4D receptor in tumors may further induce tumor invasion, thereby enhancing their growth, survival, and metastatic potential.
Antibody neutralization of SEMA4D thus may represent a new therapeutic strategy for cancer treatment. We selected a high affinity human IgG4 antibody that is specific for both mouse and human SEMA4D, and utilized several in vitro functional assays to demonstrate that this antibody blocks SEMA4D - PLXNB 1 interactions. Using both transplanted and orthotopic tumor models we demonstrated that antibody mediated SEMA4D neutralization in vivo inhibits tumor growth and tumor angiogenesis. This human antibody is currently in IND-enabling toxicology testing and we anticipate the initiation of human clinical trials in 2H 2010.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-36.
Abstract LB-370: A placental growth factor variant unable to recognize VEGFR-1 inhibits VEGF-dependent tumor angiogenesis via heterodimerization
Authors: De Falco Sandro , Tarallo Valeria , Capasso Onofrio , Vesci Loredana , Esposito Maria Teresa , Pastore Lucio , Orlandi Augusto , Pisano Claudio 
Published: February 2011

Abstract
Angiogenesis is one of the crucial events for cancer development and growth. Two members of vascular endothelial growth factor (VEGF) family, VEGF-A and placental growth factor (PlGF), which are able to heterodimerize if co-expressed in the same cell, are both required for pathological angiogenesis. We generated a PlGF1 variant, named PlGF1-DE in which the residues Asp72 and Glu73 were substituted with Ala. PlGF1-DE is unable to bind and activate VEGFR-1 but can heterodimerize with VEGF (J. Biol. Chem., 279: 43929-43939, 2004).
Here we demonstrate that overexpression of PlGF1-DE variant in tumor cells by adenoviral delivery or stable transfection significantly reduced the production of VEGF homodimer via heterodimerization, leading to a strong inhibition of xenograft tumor growth and neoangiogenesis, as well as significant reduction of vessel size, vessel stabilization by smooth muscle cells and monocyte-macrophage infiltration. PlGF1-DE/VEGF heterodimer, differently from wild type heterodimer able to induce VEGFR-1 dimerization as well as VEGFR-1/R-2 heterodimerization and activation, failed to induce receptors phosphorylation demonstrating that co-expression of PlGF1-DE variant in VEGF-producing cells effectively sequestered active VEGF, biasing toward the generation of a non-functional heterodimer.
Conversely, overexpression of PlGF1wt, while reducing VEGF homodimer production comparably to PlGF1-DE variant through the generation of VEGF/PlGF heterodimer, did not inhibit tumor growth and vessel density compared to controls, but induced an increase of vessel size, vessel stabilization and monocyte-macrophage infiltration.
The ability of PlGF and VEGF-A to heterodimerize represents a successful strategy to inhibit VEGF-dependent angiogenesis. The PlGF1-DE variant, and not PlGF1wt as previously reported, acts as a ‘dominant negative’ of VEGF molecule and is a new candidate for anti-angiogenic gene therapy in cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-370.
Abstract LB-38: Evaluation of a PSA cleavable doxorubicin prodrug in the in vitro and in vivo LNCaP LN model
Authors: Elsadek Bakheet , Esser Norbert , Graeser Ralph , Warnecke André , Unger Clemens , Saleem Tahia , Kratz Felix 
Published: February 2011

Abstract
The goal of this work was to investigate the biological activity of a doxorubicin prodrug that is efficiently cleaved by prostate specific antigen (PSA) rapidly liberating doxorubicin as the final cleavage product. For this purpose we have developed an albumin-binding prodrug of doxorubicin, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Leu-PABC-DOXO [EMC: ε-maleimidocaproyl; PABC: p-aminobenzyloxycarbonyl; DOXO: doxorubicin]. The incorporation of the PABC self-eliminating linker between the peptide sequence and doxorubicin enhanced the enzymatic cleavage rate and improved the cleavage profile. PSA cleavage produced the metabolite H-Ser-Leu-PABC-DOXO which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. In the cell culture experiments, our prodrug exhibited antiproliferative activity in the low micromolar range with an IC50 value of ∼1 μM against a PSA-expressing prostate cancer cell line with a stably integrated Luciferase-Neomycin (LN) resistance fusion gene cassette (LNCaP LN). Moreover, H-Ser-Leu-PABC-DOXO showed comparable in vitro activity to doxorubicin (∼0.2 μM). Orientating toxicity studies in mice showed that the maximum tolerated dose of our novel prodrug was twice that of conventional doxorubicin. Consequently, the in vivo efficacy of the prodrug (6 mg/kg doxorubicin equivalents) is currently being compared to free doxorubicin (3 mg/kg) in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-38.
Abstract LB-380: Apo2L/TRAIL reduces interstitial fluid pressure and enhances gemicitabine uptake in patient pancreatic tumor xenografts
Authors: Hylander Bonnie L. , Sen Arindam , Beachy Sarah , Gibbs John , Pitoniak Rose , Prey Joshua , Fetterly Gerald , Repasky Elizabeth A. 
Published: February 2011

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) has promising anti-tumor therapeutic potential and is in clinical trials. It is known that microenvironmental factors such as elevated interstitial fluid pressure limits uptake and greatly inhibits anti-tumor efficacy of many therapeutics. We are investigating the role of interstitial fluid pressure in the anti-tumor effect of Apo2L/TRAIL alone and in combination with gemcitabine.
We first carried out a histological analysis of Colo205 tumors treated with a single 1000 g dose of Apo2L/TRAIL. Apoptosis (ck18+ cells) and infiltration of macrophages (F4/80+ cells) peaks by 8 hrs; by 24 and 48 hours, apoptotic debris has been cleared and the lumen of tumor vessels is clearly apparent. This is in sharp contrast to untreated tumors in which cells are densely packed and vessels with an open lumen are seldom seen. Correspondingly, measurements of tumor interstitial fluid pressure (IFP) taken 48 hrs after a single treatment of Apo2L/TRAIL revealed a significant reduction in IFP compared to tumors in the untreated mice (n=5; 0.3 cm H2O vs. 3.4 cm H2O, P= 0.002).
We have characterized the Apo2L/TRAIL sensitivity of a panel of patient pancreatic tumor xenografts and found a range of responses to Apo2L/TRAIL from actual regression (tumor growth inhibition, TGI, of 108%) to complete resistance (TGI of 0%). Histological analysis of a sensitive tumor showed that Apo2L/TRAIL induced both the physical changes seen in Colo205 as well as a similarly significant reduction in IFP (n=7; P= 0.003). Importantly, in these patient xenografts, combination therapy with Apo2L/TRAIL and chemotherapy has been shown to enhance the antitumor effect of gemcitabine. Therefore, we investigated the effect of Apo2L/TRAIL induced lowering of IFP on gemcitabine uptake. In these studies, a single dose of gemcitabine was administered 48 hrs after Apo2L/TRAIL administration. Pharmacological analysis reveals a 33% increase in gemcitabine uptake in tumors in the 6 hours following Apo2L/TRAIL administration; no such increase was observed in normal liver.
These results support the idea that pretreatment of a tumor with Apo2L/TRAIL leads to “decompression” of the tumor and will selectively improve tumor uptake of chemotherapeutics. We are currently investigating different schedules of administration in order to maximize the uptake of gemcitabine and optimize the anti-tumor efficacy of this combination therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-380.
Abstract LB-408: NAT2 polymorphisms, tobacco smoking, and breast cancer risk in the Breast and Prostate Cancer Cohort Consortium (BPC3)
Authors: Cox David G. , Dostal Lucie , Hunter David J. , Ziegler Regina G. , LeMarchand Loïc , Thun Michael J. 
Published: February 2011

Abstract
Aromatic and heterocyclic amines are carcinogens in tobacco smoke that cause mammary tumors in rodents. N-acetyltransferase 2 (NAT2) can detoxy aromatic amines and polymorphisms in the NAT2 gene result in slow, intermediate and rapid acetylation phenotypes. Slow NAT2 acetylation has been hypothesized to potentiate the risk of smoking for both breast and bladder cancer. Whereas this hypothesis is reasonably well-established for bladder cancer, the data for breast cancer are still being evaluated, most recently in a meta-analysis of up to 13 studies. In a subset of these studies including 4,264 cases, a ∼1.4 fold increase in risk of breast cancer was observed among women exposed to more than 20 pack-years of cigarette smoking. This increase in risk was confined to slow acetylators, and no statistically significant increase in risk was observed among rapid acetylators. We sought to replicate this finding in a consortium of six large prospective cohorts in the United States and Europe. We genotyped the three most common polymorphisms that define NAT2 acetylation phenotype in populations of European origin among approximately 7,750 breast cancer cases and 9,900 matched controls with prospectively collected information on tobacco smoking and established risk factors for breast cancer. Nested case-control analyses showed no association between NAT2 acetylation phenotype (rapid, intermediate, slow) and breast cancer risk. Furthermore, no interaction was observed between smoking status (specifically never, former or current) and NAT2 acetylation phenotype on breast cancer risk (likelihood ratio test p-interaction 0.58). Ongoing analyses are examining more detailed measures of cigarette smoking such as duration, intensity, pack years, and smoking during the potentially critical period between menarche and first full term pregnancy, as well as subsets of patients defined by menopausal or steroid hormone receptor status. These data contribute substantially to resolving the longstanding debate over whether smoking affects breast cancer risk particularly in women with limited capacity to acetylate tobacco carcinogens.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-408.
Abstract LB-412: Urinary polyphenols, GST copy number variation, and breast cancer risk: Results from the Shanghai Women's Health Study (SWHS)
Authors: Luo Jianfeng , Gao Yu-Tang , Chow Wong-Ho , Shu Xiao-ou , Li Honglan , Yang Gong , Cai Qiuyin , Li Guoliang , Rothman Nathaniel , Cai Hui , Shrubsole Martha J. , Franke Adrian A. , Zheng Wei , Dai Qi 
Published: February 2011

Abstract
Background: In vitro studies found that the flavanol epigallocatechin (EGC) and flavonols, but not the flavanol epicatechin (EC), activated glutathione s-transferases (GST), a family of phase II enzymes which detoxify reactive oxygen species, such as catechol estrogen metabolites. Objective: To investigate whether urinary excretion of tea polyphenols interacted with GST polymorphism in relation to breast cancer risk.
Design: We conducted a study of 353 incident breast cancer cases and 701 individually-matched controls nested within the Shanghai Women's Health Study cohort of women aged 40-70 years at baseline. Liquid chromatography tandem mass spectrometry was used to measure urinary excretion of flavanols and flavonols. Real-time multiplex PCR were used to quantify the copy number variation for the GSTM1 and GSTT1 genes.
Results: Urinary excretion of flavonols and flavanols, particularly, EGC(p=0.02), were significantly higher among those null for GSTM1 than those positive for GSTM1. Furthermore, urinary excretion of flavanol EGC significantly interacted with GSTM1 polymorphism (p=0.04), while flavonols, particularly kaempferol, may interact with both GSTM1 and GSTT1 genotype in relation to breast cancer. As a result, flavanols (primarily EGC) and flavonols significantly interacted with the joint genotypes of GSTM1 and GSTT1 in relation to breast cancer risk. Flavonols and flavanols (EGC in particular) were associated with a reduced risk of breast cancer among those null for GSTM1 and GSTT1, whereas flavonols, particularly kaempferol, were significantly associated with an increased risk of breast cancer for those possessing both GSTM1 and GSTT1.
Conclusion: These results, if confirmed, may provide a new avenue for the personalized prevention of breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-412.
Abstract LB-413: A multi-stage association study in breast cancer identifies a protective allele at NCOA7
Authors: Poland Kathryn S. , Breyer Joan P. , Bradley Kevin M. , Schuyler Peggy A. , Plummer W. Dale , Freudenthal Marcia G. , Trentham-Dietz Amy , Newcomb Polly A. , Titus-Ernstoff Linda T. , Garcia-Closas Montserrat , Sanders Melinda E. , Page David L. , Egan Kathleen M. , Dupont William D. , Smith Jeffrey R. 
Published: February 2011

Abstract
Estrogen metabolism and growth factor signaling pathway genes play a potential role in breast cancer predisposition. We evaluated pathway genes in a nested case-control investigation of women within the Nashville Breast Cohort, using germline DNA obtained from archival benign breast biopsies (formalin-fixed paraffin embedded). We applied methods enabling large-scale candidate gene investigation in the archival DNA (2 to 6 decades old). The study included 447 women who progressed to breast cancer (cases), and 838 women who did not (controls, matched on age and year of biopsy to cases in a ∼ 2:1 ratio). Single allele- and haplotype-based tests of association were explored among 115 tagged pathway genes, and results were compared to those of the CGEMS GWAS (1,145 cases, 1,142 controls). Findings across the two study populations were concordant in 8 genes. Further replication of results was sought in the Collaborative Breast Cancer Study (1,552 cases, 1,185 controls). FGFR2 and NCOA7 associations were concordant across all three studies. FGFR2 carries known susceptibility variants confirmed in prior GWAS, whereas the association at NCOA7 on 6q22.32 is novel. NCOA7 encodes a nuclear receptor co-activator that directly interacts with estrogen receptor to modulate its activity. A haplotype of NCOA7 had a significant inverse association with breast cancer in each of the three studies (odds ratios of 0.67, 0.77, and 0.78 (respectively) for haplotype carriers relative to non-carriers), with a combined odds ratio of 0.77 (95% CI 0.65-0.89), P = 5.1 × 10-4. These observations provide credible evidence that this NCOA7 variant has a protective effect on breast cancer risk.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-413.