bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-408: An integrative genomic approach uncovers oncogenic roles of YY1-signaling in hepatocellular carcinoma with stem cell-like traits
Authors: Zhao Xuelian , Roessler Stephanie , Budhu Anuradha , Yu Zhipeng , Jia Huliang , Ye Qinghai , Qin Lunxiu , Tang Zhaoyou , Wang Xin Wei
Published: August 2012

Hepatocellular carcinoma (HCC) is an aggressive solid tumor with vast heterogeneity in its clinical presentation and tumor biology. Genomic and transcriptomic analyses have revealed numerous HCC subtypes that are associated with patient outcome. Recently, we have identified a subset of aggressive HCC with stem cell-like traits and elevated levels of EpCAM and AFP (EpCAMhigh/AFPhigh). To identify key pathways contributing to this subset of HCCs, we used an integrated genomic strategy by comparing gene expression profiles of a well-defined HCC cohort consisting of 38 EpCAMhigh/AFPhigh and 40 EpCAM−/AFP− HCC cases using Affymetrix U133A array analyses. We identified a robust gene expression signature that can classify these two subgroups and is predictive of HCC prognosis. We validated this signature as an independent predictor of patient survival in two additional independent cohorts of HCC samples with mixed etiologies and ethnicity. Gene Set Enrichment Analysis revealed that genes containing YY1 transcriptional factor binding sites are most significantly enriched in the signature, suggesting that the YY1 signaling pathway may be functionally critical in regulating stem cell-like HCC. Genomic analysis using the Agilent 105A human arrayCGH platform revealed that the YY1 co-activator gene YY1AP1, but not YY1, is highly amplified in a majority of EpCAMhigh/AFPhigh HCCs (85%). YY1AP1 expression in HCC was significantly correlated with its genomic amplification and was also associated with patient prognosis. Using a lentiviral construct expressing YY1AP1 shRNA either constitutively or inducibly via tetracycline, we found that silencing of YY1AP1 completely blocked the growth of EpCAMhigh/AFPhigh HCC cell lines that contain YY1AP1 gene amplification. Furthermore, we found that YY1 transcriptionally activated YY1AP1-dependent EpCAM expression. In parallel, silencing of EpCAM via RNA interference also inhibited HCC cell growth. Our results suggest that YY1-YY1AP1 signaling is an oncogenic driver critical to the development of stem cell-like HCC through activation of EpCAM. Our results also demonstrate the feasibility and power of our strategy to utilize well-defined patient samples to uncover critical pathways linked to HCC subtypes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-408. doi:1538-7445.AM2012-LB-408
Abstract LB-419: Multi-scalar approaches to interrogate the IκBα:NF-κB negative feedback loop: Quantitative dynamics in single cells, cell populations, and live animals in vivo
Authors: Moss Britney , Elhammali Adnan , Fowlkes Tiffanie , Gross Shimon , Vinjamoori Anant , Contag Christopher H. , Piwnica-Worms David
Published: August 2012

Cells have evolved complex molecular networks to sense environmental signals, transmit this information through the cell, and elicit appropriate biological responses. In particular, negative feedback loops represent a widely-utilized network motif capable of eliciting transient responses. To truly understand the biological significance of negative feedback processes, it is critical to study them at multiple scales: in single cells, in cell populations, and in animals. The IκBα:NF-κB negative feedback loop, a pivotal regulatory node of innate immunity and inflammation active in both immune cells and non-immune tissues, represents a model system for the use of multi-scalar reporter systems. To this end, we have utilized the κB5→IκBα-FLuc bioluminescent reporter to study dynamics of this transcriptionally-coupled negative feedback loop in response to diverse modes of stimulation which may be particularly relevant during cellular responses to inflammatory cytokines, such as TNFα. The κB5→IκBα-FLuc reporter enabled rigorous evaluation of the stimulus-specific dynamics of βκγα degradation and the downstream consequences of NF-κΔ nuclear translocation (i.e., NF-κΔ transcriptional activity) in single cells, cell populations and live animals in vivo. In response to modulation of TNFα concentration and pulse duration, complex, differential patterns in βκγα degradation and re-synthesis were discovered in both cell populations and single cells. Furthermore, IκBα dynamics observed in live animals in vivo upon modulation of TNFα dose strongly resembled those observed in single cells and cell populations upon modulating TNFα pulse duration, suggesting that increased doses of circulating TNFα were perceived by hepatocytes in vivo as pulses of increasing duration. Thus, a single bioluminescent reporter strategy enabled correlative quantitation of dynamic NF-κα:βκβα negative feedback loop responses in live single cells, cell populations, and tissues in vivo with a variety of rapid, low-cost, high-throughput approaches.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-419. doi:1538-7445.AM2012-LB-419
Abstract LB-42: Susan G. Komen for the Cure- Puerto Rico- fighting breast cAncer through awareness, alliances and community grants
Authors: Segarra-Vasquez Barbara
Published: August 2012

Puerto Rico (PR) is a Caribbean island with a population of 3.7 million. Currently, PR has 16% unemployment rate, which affects the health care of approximately 42% of the population and their access to quality health services. Cancer represents the second cause of death among Puerto Ricans. Breast cancer is the most diagnosed cancer among women representing 33% of the yearly cancer cases. Susan G. Komen for the Cure (SGK) is the global leader of breast cancer awareness. The SGK Puerto Rico affiliate was established in 2003 and currently has a Board of Directors of 11 members, three full-time employees and a group of passionate volunteers. With awareness ans service initiatives, SKG Puerto Rico has positively impacted 1.8 million people 15 years and older during 2011. The affiliate's 2011 community profile defined three major objectives: continue educational efforts for breast cancer awareness provide access to early detection programs and create a breast cancer patient profile. Grants are giver to community outreach organizations through a structured process. The affiliate's signature program is Banders through which alliances with companies, organizations, hospitals, schools and other entities are formed. With Banderas, large amount of individuals are educated, volunteers are recruits, sponsors are engaged and the network of breast cancer advocates increases.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-42. doi:1538-7445.AM2012-LB-42
Abstract LB-420: Long circulating 18F-labeled liposomes for PET imaging
Authors: Xu Biying , Basuli F , Wu H , Salima A. , Opina A , Lane K , Griffiths G. L. , Jagoda E. , Green M , Seidel J. , Choyke P.
Published: August 2012

Liposomes are lipid nanoparticles comprised of phospholipid bilayers with an aqueous interior. They have emerged as promising multi-modality imaging agents and engender significant interest as drug delivery vehicles, e.g. doxorubicin liposomes. Although a number of methods for radiolabeling liposomes with various radionuclides have been developed, 18F is the most useful for PET imaging. In this study, preformed maleimide-PEG functionalized liposomes with a mean diameter of 70 nm were obtained by sonication of a lipid mixture consisting of DPPC, cholesterol, and DSPE-PEG2000-Mal (61:30:9) in acetate buffer (pH 6.5) followed by extrusion. 18F labeled 2-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)ethanethiol was prepared, followed by conjugation with the maleimide-PEG functionalized liposome in 0.1M acetate buffer (0.1% EDTA), pH 6.5-8.0. Liposome sizes did not differ significantly before and after the 18F labeling. The overall radiochemical yield of the reaction was 10-25% (n= 12, uncorrected) in a 180 minute radiolabeling time. Micro PET imaging of rats was done at various times, up to 4 hrs, following IV injection of the 18F liposomes and their bio-distribution was also investigated. Our imaging studies with 18F liposomes appear comparable to images from previously described labeling methods with 18F liposomes remaining in the blood pool at 4 hrs. Our results indicate that this will allow the ready availability of 18F liposomes for vascular imaging and also potentially for cancer imaging. Research Support: This study was funded by the intramural program of the National Institutes of Health.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-420. doi:1538-7445.AM2012-LB-420
Abstract LB-80: Role of ER calcium in Bcl-2 resistance to dosage and duration-related cytotoxic efficacy of Taxol
Authors: Pan Zhi , Gollahon Lauren
Published: August 2012

Background and Objectives: Calcium is one of the key regulators in apoptosis. Among various calcium sources, our previous study shows that the endoplasmic reticulum (ER), the main intracellular calcium storage site, provides a specific target for the chemotherapy agent Taxol and thus contributes to apoptosis. Although the expression of the anti-apoptotic protein Bcl-2 has been shown to confer resistance to Taxol, the exact mechanism of how it inhibits apoptosis and the role of ER calcium in this process remains unclear. This study investigated whether ER-associated calcium changes were generated and related to resistance by Bcl-2 to Taxol-induced apoptosis. Materials and methods: Fluo4-AM and Cameleon D1ER was used to monitor cytosolic and ER calcium dynamics by advanced time-lapsed imaging. Annexin V-FITC and propidium iodide were used to detect various phases of apoptosis induced by Taxol at different dosages from 10−12 to 10−5 M and at different durations from 5 min to 12 hours. Breast cancer cell lines MDA-MB-M468 and MDA-MB-231 were used and Bcl-2 transfectant cell lines were constructed by stable transfection. Results and Significance: Our previous data shows that Taxol (above 10−6 M) induces a rapid ER calcium release (peaking at 5 minutes) that promotes apoptosis. In this study, upon the expression of Bcl-2, basal ER calcium levels are decreased and Taxol-induced ER calcium release is inhibited, playing a major role in Bcl-2 resistance to Taxol. Depending upon dose and exposure time, long-term (hours) Taxol treatment partially overcame the Bcl-2 inhibition of ER calcium release by continually stimulating the ER calcium release, ultimately inducing significant, although smaller apoptosis in the presence of Bcl-2 expression. In addition to the effect on ER calcium, our data shows that the extracellular calcium pool is involved in Bcl-2 resistance through increased capacitative calcium entry to refill the ER calcium store, preventing ER calcium depletion. Taxol does not have a significant effect on the enhanced calcium influx from the extracellular medium. Taken together, out results indicate that the ER calcium store is the focus of the Taxol attack and plays a key role in Bcl-2 resistance to cytotoxic efficacy of Taxol in breast cancer cells. This finding provides insight to better understand the complex relationship between Bcl-2, calcium and Taxol towards improving breast cancer chemotherapies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-80. doi:1538-7445.AM2012-LB-80
Abstract LB-91: Transcriptome analysis of esophageal squamous cell carcinoma by SAGE identifies a new biomarker, NRD1
Authors: Uraoka Naohiro , Sakamoto Naoya , Oue Naohide , Sentani Kazuhiro , Anami Katsuhiro , Noguchi Tsuyoshi , Yoshida Kazuhiro , Yasui Wataru
Published: August 2012

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Because most ESCC is diagnosed at advanced stages, the overall 5-year survival rate of ESCC still remains low in spite of the use of various treatment modalities. Therefore, identification of new diagnostic markers and therapeutic targets for ESCC is important. Serial Analysis of Gene Expression (SAGE) is one of the common comprehensive methods to analyze transcript expression levels, and enables the quantitative and simultaneous analysis of a large number of transcripts. To identify potential diagnostic markers and therapeutic targets for ESCC, the SAGE library was generated from one ESCC sample. A total of 14,430 tags were generated, including 5,765 that were unique. By comparing SAGE tags from the ESCC sample with those from normal human squamous esophagus, several genes that is upregulated in ESCC compared with normal squamous esophagus in ESCC were identified. Among these, we focused on the nardilysin (N-arginine dibasic convertase, NRD1) gene. NRD1 has been reported to be associated with ectodomein shedding of TNF-α through activation of ADAM proteases. There is only one report in the literature mentioning the association of NRD1 with cancer (breast cancer), however, there is no report that links expression of NRD1 and ESCC. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis showed a high level of NRD1 expression in three of five esophageal cancer cell lines and seven of 14 ESCC samples, but not in 14 normal systemic tissues. Western blot analysis also showed upregulation of NRD1 protein in total five esophageal cancer cell lines. Immunohistochemical analysis revealed expression of NRD1 in cytoplasm of 43 out of 109 ESCC cases (39%), as well as heart, skeletal muscle, and testis in agreement with previous reports. In clinicopathological analysis, expression of NRD1 correlated with the advanced T grade, N grade and tumor stage, and was an independent predictor of survival in patients with ESCC. Knockdown of NRD1 in TE5 cells inhibited cell invasion ability. Furthermore, qRT-PCR analysis showed a reduction of matrix metalloproteinase-2 (MMP-2) expression in NRD1 knocked down cells. In conclusion, NRD1 is an independent predictor of survival, and contribute to cell invasion through regulation of MMP-2 in ESCC. NRD1 could be a novel diagnostic and therapeutic target for ESCC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-91. doi:1538-7445.AM2012-LB-91
Abstract LB-99: EGF receptor tyrosine kinase defines critical prognostic genes of stage IA lung adenocarcinoma
Authors: Nakata Asuka , Yamauchi Mai , Yamaguchi Rui , Kohno Takashi , Nagasaki Masao , Shimamura Teppei , Imoto Seiya , Saito Ayumu , Ueno Kazuko , Hatanaka Yousuke , Yoshida Ryo , Higuchi Tomoyuki , Nomura Masaharu , Beer David G. , Yokota Jun , Miyano Satoru , Gotoh Noriko
Published: August 2012

Non-small cell lung cancer (NSCLC) is the commonest and the most fatal histological subtype of lung cancer. About 10-30% of patients diagnosed as stage IA (the earliest stage of a lung tumor, smaller than three centimeters in diameter with no evidence of regional lymph node and/or regional metastasis) and submitted to surgery die due to recurrence. Therefore, the identification of prognostic biomarkers for stage IA lung adenocarcinoma with poor prognosis is of great importance to select patients who will be benefited by adjuvant therapy. To the best of our knowledge, there is not a set of genes that identifies these patients. It is known that epidermal growth factor (EGF) signaling pathway is closely related to aggressive phenotypes of lung and other cancers. EGFR tyrosine kinase-specific inhibitor, namely gefitinib is expected to alter the gene expression patterns caused by EGFR tyrosine kinase activity. We performed microarray assays in order to obtain the entire gene expression time course profile of human primary lung epithelial cells that were stimulated with EGF in both the presence and absence of gefitinib. The time courses are composed of 19 time points along 48 hours. The data were subjected to a mathematical analysis, namely the State Space Model (SSM) in order to select genes with gene expressions altered by gefitinib. One hundred thirty nine genes were identified. These genes were used as expression signatures to train a risk scoring model that classifies patients in high- or low-risk (risk of dying in five years). This model was trained by using a data set composed of 253 North American patients with lung adenocarcinomas. Then, the predictive ability of the risk scoring model was examined in two independent cohorts composed of North American and Japanese patients. The model enabled the statistically significant identification of high-risk stage IA lung adenocarcinoma in both cohorts, with hazard ratios (HRs) for death of 7.16 (P=0.029) for North American and 10.98 (P=0.008) for Japanese. The set of 139 genes altered by gefitinib includes several ones that are involved in biological aspects of cancer phenotypes but are yet unknown to be involved in EGF signaling. This result strongly re-emphasizes that EGF signaling status underlies aggressive phenotype of cancer cells, and also suggests the first set of genes that are useful for the identification of stage IA lung adenocarcinoma patients with poor prognosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-99. doi:1538-7445.AM2012-LB-99
Abstract PL02-03: Genomic mapping of cancer origins
Authors: Gilbertson Richard J.
Published: August 2012

Cancer comprises a bewildering assortment of diseases that kill 7.5 million people each year. Poor understanding of cancer's diversity currently thwarts our goal of a cure for every patient, but recent integration of genomic and stem cell technologies promises a route through this impasse. In particular these studies have provided new insight into the origin of cancer subgroups currently regarded and treated as single diseases. The improved understanding of tumor biology and accurate preclinical models derived from these studies hold promise to advance cures for all patients with cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr PL02-03. doi:1538-7445.AM2012-PL02-03
Abstract SY02-01: Targeting the histone methyltransferase DOT1L in MLL-rearranged leukemia
Authors: Richon Victoria M.
Published: August 2012

Protein methyltransferases (PMTs) are enzymes that catalyze the addition of methyl groups to the lysine and arginine residues of proteins, including histones. Recent evidence shows that PMTs are misregulated in a variety of cancers and thus may serve as therapeutic targets. A subset of acute leukemias have reciprocal translocations at 11q23 involving the PMT gene mixed lineage leukemia (MLL). MLL translocations occur in approximately 5% of adult acute lymphocytic leukemias (ALL) and 5 to 10% of adult acute myeloid leukemias (AML) including therapy-related leukemias. Multiple studies have demonstrated that patients with leukemias bearing the MLL translocation have a poor prognosis and are in need of new therapies. Translocations of the MLL gene result in the loss of the catalytic domain of the protein. The most common translocation partners, AF4, AF9 and ENL, recruit another PMT, DOT1L that methylates histone H3K79. Recruitment of DOT1L to the MLL fusion protein results in increased H3K79 methylation at MLL fusion protein target genes and elevated expression of the MLL target genes resulting in leukemogenesis. Mistargeted DOT1L enzymatic activity has therefore been proposed to be required for the development and maintenance of leukemias bearing the MLL translocation. To evaluate the potential of DOT1L as a therapeutic target in MLL- rearranged leukemia, we designed and characterized the DOT1L inhibitor EPZ004777, a small molecule with sub-nanomolar affinity for this enzyme and >1000 fold selectivity against other PMTs. EPZ004777 selectively inhibits intracellular histone H3K79 methylation in a concentration and time dependent manner. Significant changes in genes expression were observed in MLL-rearranged cell lines following the decrease in histone H3K79 methylation. Gene set enrichment analysis (GSEA) of genes downregulated following EPZ004777 treatment demonstrated strong enrichment for genes overexpressed in MLL-rearranged human acute leukemias as compared with MLL-germline acute leukemias. Phenotypically, EPZ004777 inhibits proliferation and induces apoptosis in human MLL-rearranged leukemia cell lines, with little effect on non-MLL-translocated cells. In vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These studies provide compelling validation for the development of DOT1L inhibitors as targeted therapeutics for MLL-rearranged leukemia.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY02-01. doi:1538-7445.AM2012-SY02-01
Abstract SY05-02: Novel roles for microRNAs in metastatic progression
Authors: Tavazoie Sohail
Published: August 2012

Metastasis is the major cause of death for cancer patients. This fact highlights the importance of committing significant research efforts to the elucidation of the molecular mechanisms underlying metastatic progression. We had previously investigated the mechanisms by which post-transcriptional mechanisms regulate metastatic gene expression. By using an in vivo selection mouse system that recapitulates human breast cancer metastasis in conjunction with a systematic and functional approach, we previously identified the first set of metastasis suppressor microRNAs (miR-335, miR-126, and miR-206), which strongly suppress human breast cancer metastasis to bone and lung of mice. These small non-coding RNAs are silenced in metastatic cell lines and in human metastatic primary breast cancer cell populations; they are also prognostic biomarkers in that their silencing in primary tumors of patients correlates with the likelihood of metastatic free survival in patients. Since our findings, a number of investigators have implicated these miRNAs in suppression of cancer progression in additional cancer types as well as silencing of these miRNAs in additional cancers. Also, many other microRNAs have been identified by the research community with metastasis suppressive capacities. Our group has focused our efforts on characterizing both the mechanisms by which miR-335, miR-126, and miR-206 mediate metastasis suppression as well as the mechanisms by which the expression of these molecules are silenced in highly metastatic cells. By applying an integrative experimental approach, we have begun delineating the molecular mechanisms by which these miRNAs suppress metastatic progression. While miR-335 acts cell-autonomously to suppress metastatic invasion and migration, miR-126 acts non-cell autonomously to modulate the recruitment of endothelial cells to breast cancer cells. We find that highly metastatic cells recruit mature endothelial cells with higher efficiency than poorly metastatic cells. MiR-126 suppresses endothelial recruitment by cancer cells through targeting of a novel set of pro-metastatic and pro-angiogenic genes that correlate in expression with human metastatic relapse. Mir-126 targets two distinct signaling pathways that promote cancer-mediated endothelial recruitment resulting in enhanced metastatic colonization. Our findings reveal the mechanisms by which a set of non-coding RNAs mediate metastasis suppression and reveal a novel set of miRNA targets with potential for therapeutic targeting in human breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY05-02. doi:1538-7445.AM2012-SY05-02
Abstract SY06-02: The nontraditional peptide therapeutics
Authors: Suga Hiroaki
Published: August 2012

Despite the fact that some peptides had strong affinity or inhibitory activity to certain proteins, because of their poor in-vivo stability there are only a limited number of drugs based on the peptide scaffold to date. However, non-standard peptides, represented by cyclosporine A that is originally isolated as a natural product and developed as an oral available immunosuppressive agent, have remarkable in-vivo stability and membrane permeability, unlike ordinary peptides. To uncover and develop more cyclosporine A-like peptide drugs, it is critical to build a non-traditional strategy involving a system that enables us to discover non-standard peptides quickly and less expensively against a wide variety of intra- and extra-cellular targets. In this talk, I shall introduce a new technology, involving genetic code reprogramming coupled with an in-vitro display, referred to as referred to as RaPID (Random non-standard Peptide Integrated Discovery) system. By means of the RaPID system, we are able to ribosomally express natural product-like peptides containing the features of macrocyclic and N-methylated backbone, and rapidly select highly active sequences against various targets. In this seminar, I shall discuss our recent advance in the discovery of macrocyclic non-standard peptides against EpCAM, Sirt2, E6AP, and JMJD2a, as examples.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY06-02. doi:1538-7445.AM2012-SY06-02
Abstract SY08-01: Large-scale screens for cancer genes in the mouse
Authors: van der Weyden Louise , Rust Alistair , Perez-Mancera Pedro , Tuveson David , Jonkers Jos , Mullighan Charles , Winton Doug , Adams David
Published: August 2012

As efforts to sequence thousands of human cancer genomes gain momentum, the challenge of distinguishing driver cancer genes from passengers, and determining how these genes contribute to tumorigenesis remains a major challenge. Many key cancer pathways have been identified from large-scale screens in model organisms due to the fact that most cancer genes are highly conserved, and play roles in a range of critical biological processes. We have been using mouse models of bowel, breast, pancreatic cancer and leukemia, to identify novel candidate cancer genes using approaches including transposon-mediated mutagenesis coupled with high-throughput insertion site sequencing, and next-generation sequencing of mouse tumours. Using these approaches we have not only recovered known cancer genes but also a large number of new candidates, many of which appear to be disrupted in human tumours and represent potential diagnostic and therapeutic targets. I will discuss the results of the screens we have performed and give specific examples of some of the novel cancer genes discovered from this work.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY08-01. doi:1538-7445.AM2012-SY08-01
Abstract SY35-01: Clonal evolution of pre-leukemic hematopoietic stem cells precedes human acute myeloid leukemia
Authors: Jan Max , Snyder Thomas , Corces-Zimmerman M. Ryan , Quake Stephen , Weissman Irving , Majeti Ravindra
Published: August 2012

Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic progenitors with poor clinical outcomes. Despite the power of next-generation genome sequencing to describe AML genomes and to identify recurrent mutations, our fundamental understanding of both the genomics of leukemogenesis and the genetic heterogeneity within the precursor cells is incomplete. Founding mutations in the majority of AML cases are largely unknown because pre-leukemic cells are clinically silent and are outcompeted by their malignant descendants. Our limited knowledge of founding mutations comes from infrequent cases of AML arising secondary to antecedent clonal bone marrow disorders or rare instances of inherited syndromes, but this does not include the large majority of de novo AML cases. Recently, advances in AML stem cell biology have enabled the prospective separation of residual hematopoietic stem cells (HSC) from AML cells. We previously showed that residual HSC contain clonal antecedents of AML in patients in long-term remission post-therapy, and have proposed a model in which serial acquisition of mutations occurs in self-renewing HSC. Here, we investigated this model and the nature of founder mutations through the genomic analysis of de novo AML and patient-matched residual HSC. Using exome sequencing, we defined mutations present in individual AML genomes from cases harboring the FLT3-ITD mutation, and screened for these mutations in the residual HSC. We identified several mutations present in residual HSC retaining normal multilineage differentiation in vivo, including mutations in NPM1, TET2, and SMC1A, a newly identified recurrently mutated gene in AML. Finally, through single cell analysis, we determined that as we hypothesized, a clonal progression of multiple mutations occurs in HSC. These pre-leukemic HSC reveal the clonal evolution of AML genomes from founder mutations, suggest a potential mechanism contributing to relapse, and constitute a cellular reservoir that may need to be targeted for more durable remissions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY35-01. doi:1538-7445.AM2012-SY35-01
Abstract SY38-02: Molecular oncogenesis of human T-cell lymphoma: Common features with myeloid malignancies
Authors: Bernard Olivier A.
Published: August 2012

T-cell lymphomas are a heterogeneous group of diseases associated with poor outcome whose molecular bases are ill characterized. Prompted by the effect of Tet2 inactivation in lymphoid differentiation and the co occurrence of lymphoma in patients with myeloid neoplasm with TET2 mutations, we uncovered TET2 mutations in 2% of B-cell lymphoma and 11% of T-cell lymphoma samples. The highest frequency of TET2 mutation in T-cell lymphoma was observed in the ImmunoAngioblastic (AITL) (10/30: 30%) and the Peripheral T-cell lymphoma, Not otherwise specified (PTCL, NOS) (6/30:20%) subtypes. Cellular analyses showed that TET2 mutations in AITL patients may also be observed in CD34+ hematopoietic progenitors able to differentiate along the myeloid lineages, indicating that TET2 mutations may have occurred in an immature progenitor able to differentiate along both lymphoid and myeloid lineages.

Current data indicate that TET2 participate to the control of DNA methylation, through the oxydation of methylcytosine, and therefore the epigenetic control of transcription. Further candidate gene sequencing showed DNMT3A mutations in 11% of T-cell lymphoma samples. In our series, DNMT3A mutations were significantly associated with the presence of TET2 mutations since 8 of the 11 DNMT3A mutated patients also carried a TET2 mutation. In some DNMT3A-mutated-patients, those mutations could be observed during an MDS phase, which had preceded the lymphoma phase. Our data point at transformation pathways common to T-cell lymphoma and myeloid neoplasms. They suggest deregulation of DNA methylation and and provide a further basis for the molecular classification of T-cell lymphomas.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY38-02. doi:1538-7445.AM2012-SY38-02
Abstract SY39-01: Harnessing cancer genome diversity for intervention target discovery and development
Authors: White Michael A.
Published: August 2012

The diverse assortment of somatic lesions associated with human cancer initiation and progression presents a formidable challenge against efforts to develop molecularly targeted therapeutic interventions. Here we are modeling genetic diversity within lung cancer using a panel of over 100 non small cell lung cancer derived cell lines. Broad-scale parallel testing of genetic and chemical perturbations, together with high-resolution genomic characterization, is being used to parse this panel into subtypes with shared target opportunities and molecular correlates that predict response to target intervention. In this way, we have begun to identify somatic allele combinations that drive sensitivity to selective gene depletions and to synthetic small molecules that target these genes and/or the biological processes they serve.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY39-01. doi:1538-7445.AM2012-SY39-01
GAB2—a Scaffolding Protein in Cancer
Authors: Adams Sarah J. , Aydin Iraz T. , Celebi Julide T.
Published: August 2012

Adaptor or scaffolding proteins mediate protein–protein interactions that drive the formation of protein complexes. Grb2-associated binding protein 2 (GAB2) scaffolding protein is an intermediary molecule that links plasma membrane receptor signaling including receptor tyrosine kinases with the downstream effectors, such as protein tyrosine phosphatase, nonreceptor type 11 (SHP2), p85 subunit of phosphoinositide-3 kinase (PI3-K), phospholipase C-gamma 1 (PLC-γ), v-crk sarcoma virus CT10 (CRK), Src homology 2 domain containing transforming protein 1 (SHC), and SH2 containing inositol phosphatase (SHIP). Although, well described in signal transduction, its role in cancer has recently been emerging especially in leukemia, breast and ovarian cancer, and melanoma. GAB2 is essential for two major signal transduction pathways in cancer, the PI3-K-AKT and extracellular signal-regulated kinase (ERK) signaling pathways, and thus regulates a number of key cellular processes. This review focuses on structure and function of GAB2, its regulatory proteins, emerging role in cancer, and potential as a therapeutic target. Mol Cancer Res; 10(10); 1265–70. ©2012 AACR.
Aromatase Gene Polymorphism Does Not Influence Clinical Phenotype and Response to Oral Contraceptive Pills in Polycystic Ovary Syndrome Women
Authors: Maier Polyana S. , Spritzer Poli Mara
Published: August 2012

Aims: To assess whether a single nucleotide polymorphism (SNP50) of the aromatase gene (CYP19) is associated with polycystic ovary syndrome (PCOS) phenotypes and to investigate the influence of this polymorphism on the response of PCOS to treatment with oral contraceptive pills (OCP). Methods: 162 hirsute women were stratified into a classic PCOS group (hyperandrogenism, ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS). 51 women completed a 6-month OCP trial (20 µg ethinyl estradiol + 75 µg gestodene, 21/28 days per cycle, plus 100 mg spironolactone in 32 women with moderate to severe hirsutism). We considered the presence of the polymorphic allele A (AG+AA) in comparison to the absence of the polymorphism (GG) to express results and to perform the comparisons regarding clinical variables. Results: Mean age was 23.3 ± 6.9 years. Hirsutism score was similar in c-PCOS and ov-PCOS (15 (11–20) vs. 13 (11–20)). The differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A. In the OCP trial subsample, no differences were observed between genotypes after 6 months’ treatment. Conclusion: The differences between c-PCOS and ov-PCOS cannot be explained by the genetic variation at SNP50 in the CYP19 gene.
Blood Loss during Flexible Bronchoscopy: A Prospective Observational Study
Authors: Carr Ighsaan M. , Koegelenberg Coenraad F.N. , von Groote-Bidlingmaier Florian , Mowlana Abdurasiet , Silos Kim , Haverman Thijs , Diacon Andreas H. , Bolliger Chris T.
Published: August 2012

Background: Haemorrhage remains a complication of flexible bronchoscopy. Objectives: We aimed to measure the actual blood loss in patients at low risk of bleeding and to assess its association with the underlying pulmonary pathology, superior vena cava (SVC) syndrome, procedure(s) performed and laboratory values. Methods: We screened all patients scheduled for flexible bronchoscopy and enrolled 234 subjects over 18 months. Subjects with a history of haemorrhagic tendency, platelets <20 × 103/µl, a history of anti-coagulation or anti-platelet therapy and a history or clinical evidence of liver failure were excluded. Blood loss during the procedure was measured from aspirated secretions with a haemoglobin detector and categorised into minimal (<5 ml), mild (5–20 ml), moderate (20–100 ml) and severe bleeding (>100 ml). Results: Overall, 210 subjects had minimal, 19 had mild and 5 had moderate bleeding. No subject experienced severe blood loss. Patients with SVC syndrome had the highest mean blood loss (6.0 ml) when compared to bronchogenic carcinoma without SVC syndrome (p = 0.033) and other diagnosis (p = 0.026). The blood loss with trans-bronchial needle aspiration (TBNA, mean 3.4 ml) was significantly less than with TBNA combined with endobronchial or transbronchial biopsy (mean 5.0 ml, p < 0.001). Anaemia, a platelet count of 25–155 × 103/µl and an international normalized ratio of >1.3 were not associated with an increased risk of bleeding. Conclusions: We found no severe bleeding in this cohort preselected to have a low clinical risk of bleeding. Moreover, our data suggest that clinical screening and a platelet count ≥20 × 103/µl alone may be sufficient to identify low-risk patients.
Effectiveness of Fissure Sealant Retention and Caries Prevention with and without Primer and Bond
Authors: Nazar Huda , Mascarenhas Ana Karina , Al-Mutwa Sabiha , Ariga Jitendra , Soparker Pramod
Published: August 2012

Objective: This study evaluated the effectiveness of sealant retention and caries prevention with and without primer and bond below the fissure sealant among Kuwaiti schoolchildren. Subjects and Methods: This clinical trial used fissure sealant that was applied to four sound first permanent molars on 78 children. All the teeth were cleaned with pumice and rubber cups, isolated with rubber dams, and etched for 20 s. In a split-mouth study design, for the test teeth (n = 156), primer and bond (3M Scotchbond Multi-Purpose Plus System primer and bond) were applied below the sealant, and for the control teeth (n = 156), only sealant (Delton Plus) was applied. The number of tooth surfaces included was 480. Due to loss to follow-up, only 60 children were evaluated at 5 years for sealant retention and caries. The evaluation criteria were: completely retained sealant, complete or partial sealant retention, and caries. Results: In teeth sealed with primer and bond, 47 (19.6%) tooth surfaces had completely retained sealant, 60 (9.2%) teeth had partially retained sealant, while in 51 (21.3%) caries was prevented and 120 (50%) tooth surfaces were carious or filled. In teeth sealed without primer and bond, 25% (60 tooth surfaces) had completely retained sealant, 6% (14 teeth surfaces) had partially retained sealant, 26% (54 teeth surfaces) showed caries prevention, and 49.6% (119 tooth surfaces) were carious or filled. There was no difference between teeth sealed with primer and bond (120 teeth) and teeth sealed without primer and bond (120 teeth) in completely retained sealant (p = 0.15), complete or partial sealant retention (p = 0.6), caries prevented (p = 0.37), and caries (p = 0.93). Conclusion: Caries prevention was not enhanced in teeth sealed with primer and bond sealant compared with those sealed with sealant alone.
Long-Term Outcome of Stents Versus Bypass Surgery in Diabetic and Nondiabetic Patients With Multivessel or Left Main Coronary Artery Disease
Authors: Park Duk-Woo , Kim Young-Hak , Song Hae Geun , Ahn Jung-Min , Kim Won-Jang , Lee Jong-Young , Kang Soo-Jin , Lee Seung-Whan , Lee Cheol Whan , Park Seong-Wook , Yun Sung-Cheol , Chung Sung-Ho , Choo Suk Jung , Chung Cheol Hyun , Lee Jae-Won , Park Seung-Jung
Published: August 2012

Background—

Coronary artery bypass grafting and percutaneous coronary intervention (PCI) are alternative treatments for complex multivessel or left main disease. However, the relative treatment effects in diabetic and nondiabetic patients remain uncertain.

Methods and Results—

We performed a pooled analysis of 5775 patients from 3 clinical studies comparing PCI and coronary artery bypass grafting for multivessel or left main disease and compared adverse outcomes (death; a composite outcome of death, Q-wave myocardial infarction, or stroke; and repeat revascularization) according to the diabetic status. Over a median follow-up of 5.5 years, risk-adjusted mortality after PCI relative to coronary artery bypass grafting was not different in diabetic (hazard ratio [HR], 1.15; 95% CI, 0.88–1.51) and nondiabetic (HR, 1.15; 95% CI, 0.88–1.50) patients. The adjusted risks of the composite outcome of death, Q-wave myocardial infarction, or stroke were also not different in diabetic (HR, 1.00; 95% CI, 0.79–1.26) and nondiabetic (HR, 0.99; 95% CI, 0.78–1.26) patients. However, PCI was significantly associated with higher risk of repeat revascularization both in diabetic (HR, 3.56; 95% CI, 2.62–4.83) and in nondiabetic (HR, 3.55; 95% CI, 2.61–4.83) patients. Significant interactions were absent between diabetic status and revascularization strategies for death (
P
=0.27), composite outcome of death, Q-wave myocardial infarction, or stroke (
P
=0.97), and repeat revascularization (
P
=0.08).

Conclusions—

For multivessel or left main disease, the long-term risks of mortality and composite serious outcomes were not different between PCI and coronary artery bypass grafting in diabetic and nondiabetic patients, but PCI was associated with higher risk of repeat revascularization. These relative treatment effects were not modified by diabetic status. These results are hypothesis generating and should be addressed in a randomized trial.
Atrial Fibrillation and the Risk of Ischemic Stroke
Authors: Chao Tze-Fan , Liu Chia-Jen , Chen Su-Jung , Wang Kang-Ling , Lin Yenn-Jiang , Chang Shih-Lin , Lo Li-Wei , Hu Yu-Feng , Tuan Ta-Chuan , Wu Tsu-Juey , Chen Tzeng-Ji , Tsao Hsuan-Ming , Chen Shih-Ann
Published: August 2012

Background and Purpose—

Atrial fibrillation (AF) is an independent risk factor for stroke. Recent studies have demonstrated that the CHA
2
DS
2
-VASc scheme is useful for selecting patients who are truly at low risk. The goal of the present study was to compare the risk of ischemic stroke among AF patients with a CHA
2
DS
2
-VASc score of 0 (male) or 1 (female) with those without AF.

Methods—

The study enrolled 509 males (CHA
2
DS
2
-VASc score=0) and 320 females (CHA
2
DS
2
-VASc score=1) with AF who did not receive any antithrombotic therapy. Patients were selected from the National Health Insurance Research Database in Taiwan. For each study patient, 10 age-matched and sex-matched subjects without AF and without any comorbidity from the CHA
2
DS
2
-VASc scheme were selected as controls. The clinical end point was the occurrence of ischemic stroke.

Results—

During a follow-up of 57.4±35.7 months, 128 patients (1.4%) experienced ischemic stroke. The event rate did not differ between groups with and without AF for male patients (1.6% vs 1.6%;
P
=0.920). In contrast, AF was a significant risk factor for ischemic stroke among females (hazard ratio, 7.77), with event rates of 4.4% and 0.7% for female patients with and without AF (
P
<0.001).

Conclusions—

AF males with a CHA
2
DS
2
-VASc score of 0 were at true low risk for stroke, which was similar to that of non-AF patients. However, AF females with a score of 1 were still at higher risk for ischemic events than non-AF patients.
“Bridges Often Go”: Emily Dickinson's Bridge Poems
Authors: VanZanten Susan
Published: August 2012

Emily Dickinson's references to the nineteenth-century science of bridge building culminate in two major bridge poems that apply technical knowledge to transcendent concepts to produce powerful statements of faith. Transforming the technological sublime into the religious sublime, Dickinson captures the mystery of the transition from life to death.
Hail in Northeast Italy: A Neural Network Ensemble Forecast Using Sounding-Derived Indices
Authors: Manzato Agostino
Published: August 2012

In a previous work, the hailpad data collected over the plain of the Friuli Venezia Giulia region in northeast Italy during the April–September 1992–2009 period were studied through a bivariate analysis with 52 sounding-derived indices from the Udine–Campoformido station (WMO code 16044). The results showed statistically significant relations but, nevertheless, were not completely satisfactory from a practical point of view. In the current work, a prognostic multivariate analysis is performed, using linear and nonlinear approaches, finding the best results with an ensemble of neural networks. For the hail occurrence–classification problem, a novel method for combining binary classifiers (a variant of the Mojirsheibani major voting algorithm) is introduced. For the hail extension–regression problem the ensemble is built by choosing the members with a bagging algorithm, but combining them with a linear multiregression, in order to increase the forecast variability.
Higher Order Testlet Response Models for Hierarchical Latent Traits and Testlet-Based Items
Authors: Huang Hung-Yu , Wang Wen-Chung
Published: August 2012

Both testlet design and hierarchical latent traits are fairly common in educational and psychological measurements. This study aimed to develop a new class of higher order testlet response models that consider both local item dependence within testlets and a hierarchy of latent traits. Due to high dimensionality, the authors adopted the Bayesian approach implemented in the WinBUGS freeware for parameter estimation. A series of simulations were conducted to evaluate parameter recovery, consequences of model misspecification, and effectiveness of model–data fit statistics. Results show that the parameters of the new models can be recovered well. Ignoring the testlet effect led to a biased estimation of item parameters, underestimation of factor loadings, and overestimation of test reliability for the first-order latent traits. The Bayesian deviance information criterion and the posterior predictive model checking were helpful for model comparison and model–data fit assessment. Two empirical examples of ability tests and nonability tests are given.