bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2732: Short inverted repeats are hot spots for genetic instability in mammalian cells
Authors: Lu Steve , Wang Guliang , Vasquez Karen M. 
Published: June 2012

Abstract
Analyses of chromosomal aberrations in genetic disorders such as leukemia and lymphoma have provided compelling evidence that segments of the human genome are prone to breakage that lead to DNA rearrangements. Many of these hot spot areas contain sequences that have the potential to form non-B DNA such as Z-DNA, H-DNA or cruciforms. Although research has shown that large palindromes are mutagenic in mammalian cells, the instability of short inverted repeat sequences (30 bp), which are mapped near breakpoints and quite abundant in the eukaryotic genome, has not been investigated. In order to study the effects of short cruciform-forming sequences on genetic instability, we subcloned short AT- and CG-rich inverted repeats into a lacZ’ mutation-reporter shuttle vector. The cruciform structures that formed at the palindromic sequences were probed using S1 nuclease to confirm the presence of the non-B DNA structure. Cruciform-induced mutagenesis was measured in mammalian COS-7 cells via transfection then blue-white screening in DH5α cells. Ligation-mediated PCR provided direct evidence that cruciform-forming sequences induced double-stranded breaks in mammalian cells. In vitro replication assays using SV40- HeLa cell-free extracts were employed to establish the connection between replication and cruciform-induced genetic instability. Results from our study demonstrate for the first time that cruciform structures that form at short inverted repeats are mutagenic in mammalian cells. The majority of the mutants induced by cruciforms were large-scale deletions that spanned the inverted repeat sequence. Analyses of junctions revealed that &gt;80% of the mutants contained microhomologies which are characteristic of error-prone nonhomologous end-joining repair. This suggests that cruciform structure is cleaved by replication-independent, structure-specific nucleases in mammalian cells that result in DNA double-stranded breaks at positions directly adjacent to the inverted repeat. These results indicate that cruciform-forming sequences may play a role in genetic instability and contribute to human diseases associated with gene translocations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2732. doi:10.1158/1538-7445.AM2011-2732
Abstract 2751: Fanconi anemia pathway and DNA repair-based prognostic signatures in ovarian cancer
Authors: Kang Josephine , D'Andrea Alan , Kozono David 
Published: June 2012

Abstract
Introduction: Of the 21,000 patients diagnosed annually in the United States with epithelial ovarian cancer, approximately 75% present with Stage III-IV disease. The vast majority of these patients are treated with cytotoxic chemotherapy regimens, where clinical response may be associated with activity of DNA repair pathways in tumors. Characterizing these repair pathways should help predict clinical response to specific chemotherapeutic agents.
Methods: We devised a set of 150 DNA repair genes with documented functional importance in key DNA repair pathways including base excision repair (BER), Fanconi Anemia (FA), homologous recombination (HR), mismatch repair (MMR), non-homologous end joining (NHEJ), nucleotide excision repair (NER) and translesion synthesis (TLS). We extracted microarray expression data for these genes for 511 tumors and 8 normal specimens using data from Agilent Custom 244K Gene Expression and Affymetrix Human Genome U133A arrays. We performed Significance Analysis of Microarrays (SAM) to determine which of the 150 DNA repair genes were significantly more expressed in tumor vs. normal specimens. We then generated Kaplan-Meier survival curves using overall survival data.
Results: Using the Affymetrix data, we identified 57 genes that were significantly up-regulated with a median fold change of 3.15 (range, 2.03-6.07) and 6 genes that were significantly down-regulated with a median fold change of 2.67 (range, 2.11-4.74) among tumor vs. normal tissue samples by SAM (delta 1.013, false discovery rate 0%). SAM using the Agilent data showed similar results; a total of 46 genes were significant hits in both datasets. A DNA repair signature consisting of genes significant in both platforms was defined and revealed a correlation between high expression values and decreased survival (median overall survival 4.5 vs. 5.2 years, log-rank p = 0.0086). DNA repair signatures specific to individual repair pathways were defined and demonstrated that high FA pathway (BRCA2, FAAP24, FANCA, FANCE, FANCG, FANCI and PALB2) expression in particular was inversely correlated with survival (median overall survival 4.1 vs. 5.2 years, log-rank p = 0.029 and 0.019 for the Affymetrix and Agilent datasets, respectively).
Conclusion: Evidence from literature supports the critical role of the Fanconi Anemia (FA) pathway in repairing DNA damage caused by platinum-based agents such as cisplatin and carboplatin, commonly utilized to treat ovarian cancer patients. We show that a DNA repair signature specific to FA can be utilized to identify patients with high FA expression, whom we hypothesize may be more resistant to traditional platinum-based therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2751. doi:10.1158/1538-7445.AM2011-2751
Abstract 2757: Characterization of the glucuronidation of the major nicotine metabolite, 3’-hydroxycotinine: Potential role for knock-out polymorphisms in UGTs 2B17 and 2B10
Authors: Chen Gang , Giambrone Nino E. , Muscat Joshua E. , Lazarus Philip 
Published: June 2012

Abstract
3’-Hydroxycotinine (3HC) and its glucuronide (3HC-Gluc) conjugate are major nicotine metabolites excreted in the urine of smokers and other tobacco or nicotine users. Previous studies have demonstrated that human liver microsomes (HLM) were active in catalyzing the formation of both 3HC-O-Gluc and 3HC-N-Gluc. While not all human UDP-glucuronosyltransferases (UGTs) were previously screened, UGTs 2B7, 1A9, 2B4 and 2B15 were shown to be active in the formation of 3HC-O-Gluc and UGT1A4 active in 3HC-N-Gluc formation. In the present study, all known human UGTs except for UGT2B28 were screened for glucuronidation activity against 3HC. Homogenates from cell lines over-expressing UGTs 2B17 and 2B10 exhibited the highest O- and N-glucuronidation activities, respectively for the UGTs tested. Kinetic analysis for the formation of 3HC-O-Gluc demonstrated that the KM for UGT2B17 is 3.7- and 4.2-fold lower than that observed for UGTs 1A9 (p&lt;0.005) and 2B7 (p&lt;0.005); the KM of 3HC-N-Gluc formation was 4.4-fold lower (p&lt;0.05) for UGT2B10 than that observed for UGT1A4. Kinetic analysis demonstrated that HLM from subjects exhibiting the homozygous null UGT2B17 deletion [UGT2B17 (*2/*2)] exhibited a KM for 3HC-O-Gluc formation that was 3.1-fold higher (p&lt;0.001) than that observed in HLM from subjects exhibiting the wild-type UGT2B17(*1/*1) genotype. The KM of 15.6 μM for 3HC-O-Gluc formation in UGT2B17 (*2/*2) HLM was close to that observed for UGT2B17 (8.3 μM). 3HC-N-Gluc formation activity was decreased by 91% (p&lt;0.001) in HLM from subjects with the UGT2B10(*2/*2) knock-out genotype and 39% (p&lt;0.001) in HLM from subjects with the UGT2B10(*1/*2) genotype as compared to that observed for UGT2B10(*1/*1) HLMs. The KM of 13 μM for 3HC-N-Gluc formation in UGT2B10 (*1/*1) HLM (n=6) was close to that observed for UGT2B10 (13 μM). These results demonstrate that UGTs 2B17 and 2B10 play key roles in the hepatic glucuronidation of 3HC and that functional polymorphisms in UGT2B17 and UGT2B10 are associated with significantly reduced glucuronidation activities against 3HC in HLM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2757. doi:10.1158/1538-7445.AM2011-2757
Abstract 2785: Modulating the interaction between cdk2 and cyclin A: Screening, synthesis and characterization of a quinoline-based inhibitor
Authors: Windsor William T. , Deng Yongqi , Shipps Gerald W. , Zhao Lianyun , Siddiqui Arshad , Popovici-Muller Janeta , Curran Patrick , Fischmann Thierry , Duca Jose S. , Hruza Alan , Zhang Rumin , McNemar Charles , Mayhood Todd , Syto Rosalinda , Parry David A. , Lees Emma , Kirschmeier Paul 
Published: June 2012

Abstract
Cyclin dependent kinase 2 (CDK2) is aberrantly regulated in a wide range of cancers and small molecule inhibitors should be beneficial in the treatment of cancer. Preclinical and clinical CDK2 inhibitors are ATP competitive and bind at the ATP site in a canonical mode. A novel binding mode for a new class of quinoline-based inhibitors of CDK2 has been discovered using the affinity-based Automated Ligand Identification System (ALIS) technology. While the inhibitors do bind to the ATP site the key mechanism of action for inhibition is the induction of a novel protein conformational change that enables the compound to bind into the core of the kinase domain. Global changes to CDK2 upon compound binding result in a conformation that can no longer bind to its activating protein cyclin A. Therefore, these inhibitors are both ATP competitive and are protein-protein interaction disrupters. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the unphosphorylated monomer CDK2 in ALIS and to perform secondary binding and enzyme mechanism of action assays that identified quinoline-based compounds that only bound to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Ki) of the original hit improved from 0.9 μM to 0.005 μM. The screening strategy utilized and the discovery of this new kinase inhibitor binding mode may be applicable to other kinase programs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2785. doi:10.1158/1538-7445.AM2011-2785
Abstract 2795: An onco-protein axis linking polycomb repressive complex 2 and polycomb repressive complex 1 through miRNAs in cancer
Authors: Cao Qi , Mani Ram , Ateeq Bushra , Dhanasekaren Saravana M. , Asangani Irfan , Yu Jindan , Prensner John , Kim Jung J. , Brenner J. Chad , Cao Xuhong , Jing Xiaojun , Wang Rui , Li Yong , Dahiya Arun , Wang Lei , Lonigro Robert , Tomlins Scott , Palanisamy Nallasivam , Maher Christopher , Varambally Sooryanarayana , Chinnaiyan Arul M. 
Published: June 2012

Abstract
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic histone methyltransferase subunit of the Polycomb Repressive Complex 2 (PRC2), that trimethylates histone H3 at lysine 27 (H3K27me3) resulting in the silencing of target genes. PRC2 plays a critical role in many basic cellular processes including cell proliferation, differentiation, early embryogenesis, and X chromosome inactivation. In cancer, EZH2 upregulation is implicated in metastasis and tumor aggressiveness of prostate and breast cancer and several other solid tumors. Recently our lab reported the genomic loss of miR-101 microRNA accompanying EZH2 overexpression in tumor cells. Here we identified several microRNAs that were downregulated by EZH2 and their levels were restored upon EZH2 depletion in cancer cell lines, and expression levels of these microRNAs were negatively correlated with EZH2 in human prostate tumors. Additionally, H3K27me3 modification was observed in the upstream regions of the miRNAs, suggesting a direct role for EZH2 in their regulation. Ectopic overexpression of the miRNAs suppressed cell proliferation, invasion, anchorage-independent growth, sphere formation and xenograft tumor growth of aggressive prostate and breast cancer cell lines. Finally, our investigations showed that the miRNAs also repress the expression of Polycomb Repressive Complex 1 (PRC1) members BMI1 and RING2, leading to a global decrease in the epigenetic marker, ubiquityl-H2A-K119 (uH2A) in cells, a key step in PRC1-mediated silencing. Our findings provide compelling argument for a regulatory axis joining PRC2 and PRC1 through miRNAs. This novel link between PRC2 and PRC1 indicates a coordinated mechanism by polycomb group proteins to promote an aggressive cancer phenotype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2795. doi:10.1158/1538-7445.AM2011-2795
Abstract 2805: Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma
Authors: Varela Ignacio , Tarpey Patrick , Raine Keiran , Huang Dachuan , Ong Choon Kiat , Stephens Philip , Davies Helen , Jones David , Lin Meng-Lay , Teague Jon , Bignell Graham , Butler Adam , Cho Juok , Dalgliesh Gillian L. , Galappaththige Danushka , Greenman Chris , Hardy Claire , Jia Mingming , Latimer Calli , Lau King Wai , Marshall John , McLaren Stuart , Menzies Andrew , Mudie Laura , Stebbings Lucy , Largaespada David A. , Wessels L.F.A. , Richard Stéphane , Kahnoski Richard J. , Anema John , Tuveson David , Perez-Mancera Pedro , Mustonen Ville , Fischer Andrej , Adams David J. , Rust Alistair , Chan-on Waraporn , Subimerb Chutima , Dykema Karl , Furge Kyle A. , Campbell Peter J. , Teh Bin Tean , Stratton Michael R. , Futreal P. Andrew 
Published: June 2012

Abstract
The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (KDM6A), JARID1C (KDM5C) and SETD2. These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodeling complex gene PBRM1 as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2805. doi:10.1158/1538-7445.AM2011-2805
Abstract 281: Prevalence of Human papilloma virus in oral squamous cell carcinoma using Liner Array HPV genotyping kit
Authors: Ohno Keisuke , Sugahara Keisuke , Katakura Akira , Kawachi Homare 
Published: June 2012

Abstract
Background. The major risk factors for oral squamous cell carcinoma (OSCC) are cigarette smoking, alcohol consumption, and betel quid chewing. In addition, human papillomavirus (HPV) infection has been associated with some OSCC. However, the relationships of HPVs to OSCCs remain unclear because of the difficulties in interpreting studies that demonstrate various prevalence rates of HPVs. We examined the prevalence of HPV in OSCCs. For HPV detection and genotyping, a sensitive and specific PCR-based method, the Roche Linear Array HPV genotyping kit test was used for these studies.
Materials and Methods. Forty-five Japanese patients with OSCC were included in the present study. Surgical resection of primary tumors and normal tissues from all patients was performed at the Hospital of Tokyo Dental College, between December 2007 and December 2010. We assessed HPV infection in OSCC patients using the Roche Liner Array HPV genotyping Test, which can detect 37 different HPV types.
Results. HPV was detected in 9 OSCC patients (20%). HPV subtype 39, 42 was the most prevalent type, but other types detected included 31, 33, 45 . . . high-risk types and 3, 6, 8 . . . low-risk types.
Conclusion. The Roche Liner Array HPV genotyping Test is currently used as a standardized diagnostic test for HPV detection in cervical carcinoma in Europe. Some studies have shown that the most prevalent HPV subtype was the high-risk type HPV-16, However we showed that HPV is detected multiple type involved low- and high-risk type in oral carcinoma. We suggested that multiple subtypes of HPV implicated OSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 281. doi:10.1158/1538-7445.AM2011-281
Abstract 2811: GPC1 promotes tumor growth and angiogenesis in a KrasG12D- Driven mouse model of pancreatic cancer
Authors: Whipple Chery A. , Korc Murray 
Published: June 2012

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy that is highly therapy-resistant and is the fourth leading cause of cancer-related deaths. The poor prognosis is due, in part, to late diagnosis in conjunction with a high frequency of activating Kras mutations, a loss of the tumor suppressor genes p16INK4A/p14ARF, as well as an over-abundance of heparin-binding growth factors (HBGFs) and their co-receptors. Glypican-1 (GPC1), a co-receptor required for efficient signaling by heparin-binding growth factors, is overexpressed in PDAC and plays a critical role in cell growth, metastasis, and angiogenesis of human and mouse cancer cells. While it is known that the loss of GPC1 results in decreased tumor growth and metastasis in orthotopic mouse models, GPC1's role in pancreatic tumor initiation, development, and progression is unknown. Accordingly, we generated a GPC1 null mouse that combines pancreas-specific Cre-mediated activation of oncogenic Kras (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. Loss of GPC1 resulted in attenuated pancreatic tumor growth and invasiveness, as well as decreased angiogenesis, cancer cell proliferation, and mitogen activated protein kinase (MAPK) activation. These differences were first observed in 30 day old mice and were still highly significant in 65 day old mice. Moreover, pancreatic cancer cells isolated from the tumors of GPC1 null mice were not as invasive in response to fibroblast growth factor 2 (FGF2) as cancer cells isolated from wild-type mice. These data demonstrate in a genetic mouse model of PDAC that GPC1 does not contribute to pancreatic cancer initiation, but that even in the presence of two highly prevalent molecular alterations (oncogenic Kras and loss of p16) endogenous GPC1 contributes to PDAC progression by facilitating tumor growth, angiogenesis, and invasion. Our findings support the concept that GPC1 may be a therapeutic target in PDAC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2811. doi:10.1158/1538-7445.AM2011-2811
Abstract 2819: Identification and characterization of a novel smoothened antagonist for the treatment of cancer with deregulated hedgehog signaling
Authors: Bender Mark H. , Hipskind Philip A. , Capen Andrew R. , Cockman Michael , Credille Kelly M. , Gao Hong , Bastian Jolie A. , Clay Julia M. , Lobb Karen L. , Sall Daniel J. , Thompson Michelle L. , Wilson Takako , Wishart Graham N. , Patel Bharvin K.R 
Published: June 2012

Abstract
The Hedgehog (Hh) pathway is a highly conserved signaling system that plays an important role in embryonic development and tissue homeostasis through regulation of cell differentiation and proliferation, and deregulated Hh signaling has been implicated in variety of cancers. Two distinct mechanisms are responsible for inappropriate and uncontrolled Hh pathway activation in human malignancies: ligand-dependent, due to over-expression of Hh ligand, and ligand-independent, resulting from genetic mutations in pathway components such as Patched (Ptch) and Smoothened (Smo). Smo, a member of the class F G-protein coupled receptor family, is a key regulator of Hh signaling pathway, and therefore is an attractive target for pathway modulation. We have identified a potent and selective small molecule antagonist of Smo. This novel molecule (LY2940680) binds to the Smo receptor and potently inhibits Hh signaling in Daoy, a human medulloblastoma tumor cell line, and C3H10T½, a mouse mesenchymal cell line. Importantly, LY2940680 binds to and inhibits the functional activity of resistant Smo mutant (D473H) produced by treatment with GDC-0449 (a Smo antagonist from Genentech). LY2940680 also has excellent pharmacokinetic properties in rodent and non-rodent species. Treatment of Ptch+/− p53−/− transgenic mice, which spontaneously develop medulloblastoma, with oral administration of LY2940680 produced remarkable efficacy and significantly improved their survival. Magnetic resonance imaging of these mice revealed rapid kinetics of anti-tumor activity. Immunohistochemistry analysis of medulloblastoma tumors showed that LY2940680 treatment induced Caspase-3 activity and reduced proliferation. LY2940680 inhibited Hh regulated gene expression in the subcutaneous xenograft tumor stroma and produced significant anti-tumor activity. In summary, we have characterized an orally bio-available small molecule Smo antagonist that may provide therapeutic benefit to cancer patients with deregulated Hh signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2819. doi:10.1158/1538-7445.AM2011-2819