bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A38: In vitro and in vivo interaction of Cdk6 and Eya2 indicate potential crosstalk
Authors: Kohrt Dawn , Hinds Philip , Ford Heide , Grossel Martha 
Published: May 2016

Abstract
We have identified a novel association of the developmentally significant protein, Eya2, with cyclin dependent kinase (cdk) 6. Eya2 is part of the conserved retinal determination network that has been shown to function in fly eye development (Rebay, 2005). In mammals, the EYA gene product has been implicated in gonadogenesis, myogenesis, neurognenesis, limb formation, thymus, and kidney development, in part through its ability to regulate cell proliferation (Zhang 2005). Eya2 is overexpressed in several types of cancers including epithelial ovarian (Zhang et al, 2005), cervical (Bierkens et al, 2013), lung adenocarcinoma (Guo et al, 2009), breast and hematopoietic (Patrick, 2013, Wang, 2011). Cdk6 knockout mice display defects in hematopoiesis, including decreased cellularity of the thymus, red blood cells and lymphocytes (Malumbres, 2004). Cdk6 kinase activity is required for thymocyte development (Hu et al, 2011) and this role is partially mediated by modulating Notch target gene expression.
The interaction of these two proteins, each important in both development and cancer, and both involved in regulation of cell proliferation and transcription, was first identified in a yeast two-hybrid analysis of a human fetal brain library. Subsequent results from our labs confirm the association of cdk6 and Eya2 in GST binding assays and co-immunoprecipitations. GST binding assays demonstrated that Six4, a cofactor of Eya2, competes with cdk6 for Eya2 binding. Co-immunoprecipitation of transfected cell lysates and native immunoprecipitations also demonstrate binding. Finally, co-expression of cdk6 with Eya2 reduces the half-life of the Eya2 protein in cell lysates. We propose that cdk6 and Eya2 interact to affect the function of cell proliferation and differentiation that is crucial to both the biology of cancer and development. This interaction could provide a mechanism to allow the expansion of the progenitor cell population prior to differentiation.
References:
Rebay I, Silver SJ, Tootle TL (2005) Trends Genet 21: 163-171.
Zhang L, et al. (2005). Cancer Research 65: 925-932.
Bierkens M, et al. (2013). Genes, Chromosomes & Cancer 52: 56-68.
Guo JT et al. (2009) Chinese journal of oncology 31: 528-531.
Patrick AN, et al. (2013) Nature Structural & Molecular Biology 20: 447-453.
Wang QF, et al. (2011) Blood 117: 6895-6905.
Malumbres et al. (2004). Cell 118: 493-504.
Hu MG, et al. (2011) Blood 117: 6120-6131.
Citation Format: Dawn Kohrt, Philip Hinds, Heide Ford, Martha Grossel. In vitro and in vivo interaction of Cdk6 and Eya2 indicate potential crosstalk. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A38.
Abstract B07: Tead and AP1 coordinate transcription and motility in cancer cells
Authors: Liu Xiangfan , Li Huapeng , Rajurkar Mihir , Cotton Jennifer , Mercurio Arthur , Davis Roger , Mao Junhao 
Published: May 2016

Abstract
The Tead family transcription factors are the major mediators of the Hippo-Yap pathway. Although misregulation of Hippo signaling has been implicated in many human cancers, Tead dependent downstream transcriptional programs in cancer cells remain poorly understood. Here we characterize Tead4-mediated transcriptional networks in diverse cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 factors to coordinate target gene transcription. We find that the interaction of AP1 and Tead4 is JNK independent, but engages the SRC coactivators to promote downstream transcription. Furthermore we show that Tead and AP1 drive the expression of a unique core set of target genes to direct cell motility and invasion. Together, our data unveil a critical regulatory mechanism coordinating AP1 and Tead -controlled transcriptional and functional output in cancer cells.
Citation Format: Xiangfan Liu, Huapeng Li, Mihir Rajurkar, Jennifer Cotton, Arthur Mercurio, Roger Davis, Junhao Mao. Tead and AP1 coordinate transcription and motility in cancer cells. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B07.
Abstract B28: The stem cell gene ABCB5 mediates colorectal cancer resistance to apoptosis
Authors: Guo Qin , Berg Gretchen , Wilson Brian J. , Gonzalez Gabriel , Ma Jie , Gold Jason S. , Nandi Bisweswar , Huang Qin , Zhan Qian , Murphy George F. , Waaga-Gasser Ana Maria , Lian Christine G. , Frank Markus H. , Gasser Martin , Frank Natasha 
Published: May 2016

Abstract
Cancer stem cells (CSC) responsible for disease progression and therapeutic resistance have been identified in several human malignancies, including colorectal cancer (CRC). However, the molecular mechanisms through which CSC drive tumor growth are incompletely understood. ABCB5, a member of the ATP-binding cassette superfamily of active transporters, serves as a CSC-specific multidrug resistance mechanism in diverse human malignancies. Additionally, ABCB5 has recently been demonstrated to function as an anti-apoptotic gene in tissue-specific non-malignant stem cells. Here we demonstrate that ABCB5 also serves an anti-apoptotic role required for CSC maintenance in human cancer. Targeted inhibition of ABCB5, previously shown to be preferentially expressed on CD133-positive CRC stem cells, induced tumor cell apoptosis in vitro and in vivo and inhibited human CRC growth in NSG recipient mice. Mechanistically, ABCB5-positive tumor cell ablation through monoclonal antibody-mediated blockade or shRNA-mediated gene knockdown resulted in diminished production of the receptor tyrosine kinase AXL, a pro-tumorigenic molecule identified herein to be preferentially produced by CRC stem cells. Restoration of AXL expression through gene transfection in ABCB5 knockdown tumors partially restored tumor growth, demonstrating that ABCB5-positive CRC stem cells drive tumorigenicity at least in part through production of AXL. Our results establish a novel anti-apoptotic function of ABCB5 in human cancer and indicate that targeted blockade of ABCB5 represents a novel strategy for CSC eradication, independent of its previously established function as a multidrug resistance mediator.
Citation Format: Qin Guo, Gretchen Berg, Brian J. Wilson, Gabriel Gonzalez, Jie Ma, Jason S. Gold, Bisweswar Nandi, Qin Huang, Qian Zhan, George F. Murphy, Ana Maria Waaga-Gasser, Christine G. Lian, Markus H. Frank, Martin Gasser, Natasha Frank. The stem cell gene ABCB5 mediates colorectal cancer resistance to apoptosis. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B28.
Abstract B38: Quiescence as a marker of treatment resistance and malignancy in GBM
Authors: Atkins Ryan J. , Stylli Stanley S. , Luwor Rodney B. , Ware Thomas MB , Kaye Andrew H. , Hovens Christopher M. 
Published: May 2016

Abstract
Glioblastoma multiforme (GBM) is a World Health Organization grade IV astrocytic tumor, and is the most common primary brain malignancy. GBM is characterized as being highly malignant and rapidly progressive with a high mitotic index, diffuse invasion, microvascular proliferation and pseudopalisading necrosis. Current best treatment for GBM involves maximal safe surgical resection, with radiotherapy (XRT) and temozolomide (TMZ), but even with this regime patients survive for an average of only ~15 months. GBM’s position within the brain and diffuse progression profile prevents a surgical cure, and the cells left behind following surgery contain a quiescent, treatment-resistant subpopulation of cells with a stem-like capacity for self-renewal which survive chemoradiotherapy and cause relapse. These resistant cells have been referred to as cancer stem cells, but while stem cell markers have been useful in enriching stem populations in some cancers, a marker that reliably defines the glioma stem cell has remained elusive. The critical feature that allows these resistant cells to survive treatment is their slow division rate, which helps them to avoid chemoradiotherapy-induced cell death by virtue of their condensed chromatin and reduced requirement for DNA replication. In the present study we use a pulse-chase assay to ubiquitously label glioma cell lines with the fluorescent dye Oregon Green and observe the label dilution as an indicator of cell division. Based on their slower division rates, quiescent cells retain the dye longer than rapidly-dividing cells and are easily identified by fluorescence imaging and FACS analysis. Once such a population is isolated it can then be compared to a rapidly-dividing (Oregon Green-diluting) subpopulation of cells to analyze differences in treatment resistance, migration, invasion, and gene expression between the two populations. It is hoped that by elucidating the molecular mechanisms that drive treatment resistance and migration/invasion we will be able to inform novel GBM treatments that improve patient outcomes.
We have shown that quiescent cells are innately resistant to the current gold standard GBM treatments and display more malignant features in vitro than rapidly dividing cells. We have developed a platform for quick, easy, and reliable isolation of this quiescent fraction of cells to facilitate its interrogation. This method has the potential to identify future treatment targets, and could, in principle, be extended to other malignancies.
Citation Format: Ryan J. Atkins, Stanley S. Stylli, Rodney B. Luwor, Thomas MB Ware, Andrew H. Kaye, Christopher M. Hovens. Quiescence as a marker of treatment resistance and malignancy in GBM. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr B38.
Abstract IA12: Lgr5 stem cell-based organoids in human disease
Authors: Clevers Hans 
Published: May 2016

Abstract
The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We originally defined Lgr5 as a Wnt target gene, transcribed in colon cancer cells. Two knock-in alleles revealed exclusive expression of Lgr5 in cycling, columnar cells at the crypt base. Using lineage tracing experiments in adult mice, we found that these Lgr5+ve crypt base columnar cells (CBC) generated all epithelial lineages throughout life, implying that they represent the stem cell of the small intestine and colon. Lgr5 was subsequently found to represent an exquisitely specific and almost ‘generic’ marker for stem cells, including in hair follicles, kidney, liver, mammary gland, inner ear tongue and stomach epithelium.
Single sorted Lgr5+ve stem cells can initiate ever-expanding crypt-villus organoids, or so called ‘mini-guts’ in 3D culture. The technology is based on the observation that Lgr5 is the receptor for a potent stem cell growth factor, R-spondin. Similar 3D cultures systems have been developed for the Lgr5+ve stem cells of human stomach, liver, pancreas, prostate and kidney. Using CRISPR/Cas9 technology, genes can be efficiently modified in organoids of various origins.
Citation Format: Hans Clevers. Lgr5 stem cell-based organoids in human disease. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA12.
Abstract IA15: The unique genomic and epigenomic landscape of pediatric high-grade glioma
Authors: Larson Jon D. , Silveira Andre B. , Kasper Lawryn H. , Diaz Alexander K. , Zhu Xiaoyan , Baker Suzanne J. 
Published: May 2016

Abstract
Diffuse high-grade gliomas (HGGs) of childhood are a spectrum of disease with devastatingly poor outcome. Despite similar histological features, pediatric HGGs arise from a broader distribution of anatomical locations when compared to adults, with approximately 50% arising in the brainstem as diffuse intrinsic pontine glioma (DIPG), a disease found almost exclusively in children. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation as well as developmental signaling pathways. The striking association between frequencies of specific mutations with spatiotemporal pattern of HGG formation in children further highlights context-dependent connections between developmental states and oncogenic drivers. Activating mutations in the BMP receptor ACVR1 are found exclusively in the youngest subgroup of DIPG patients, and not identified in HGGs outside the brainstem. Recurrent mutations in histone H3 establish a critical role for epigenetic regulation in disease pathogenesis of childhood HGG. H3K27M mutations occur in nearly 80% of DIPGs and more than half of HGGs arising in midline structures outside the brainstem such as the thalamus. In contrast, approximately 15% of HGGs arising in the cerebral cortex have an alternative H3 mutation, G34R/V, and are predominantly found in older adolescents and young adults. To study these mutations in the developing mammalian brain, we generated conditionally activated, epitope tagged H3f3a knock-in mice to express K27M, G34R or non-mutated H3.3 proteins from the endogenous H3f3a locus. We will present early analyses of these new oncohistone mouse models.
Citation Format: Jon D. Larson, Andre B. Silveira, Lawryn H. Kasper, Alexander K. Diaz, Xiaoyan Zhu, Suzanne J. Baker. The unique genomic and epigenomic landscape of pediatric high-grade glioma. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA15.
Abstract IA28: Epigenetic heterogeneity in breast cancer
Authors: Polyak Kornelia 
Published: May 2016

Abstract
Heterogeneity of cancer cells between and within tumors is a major obstacle toward understanding and treatment of cancers. Variability of epigenetic states is one of the major contributor to both intertumor and intratumor heterogeneity. In breast cancer luminal and basal-like breast tumors have very different molecular and clinical profiles. However, even in individual tumors there is variability among cells for these features. The determinants of luminal cell phenotypes are fairly well understood and major transcriptional regulators have been identified. In contrast, transcriptional determinants of basal-like breast tumors are still poorly defined and high variability is observed among individual tumors. We have investigated molecular regulators of luminal and basal-like phenotypes by applying somatic cell genetics and cellular reprogramming approaches combined with comprehensive molecular profiling. We found that the basal-like state is predominantly dominant and it is defined mainly by epigenetic mechanisms. We have also identified candidate epigenetic and transcriptional regulators of basal-like cellular states. Modulation of epigenetic regulators may decrease intratumor heterogeneity and in combination with other agents could improve the efficacy of cancer therapies.
Citation Format: Kornelia Polyak. Epigenetic heterogeneity in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr IA28.
Abstract 22: Inferring regulatory element landscapes and transcription factor networks from cancer methylomes
Authors: Yao Lijing , Shen Hui , Laird Peter , Farnham Peggy , Benjamin Berman 
Published: May 2016

Abstract
Genome-wide DNA methylation studies have established that transcriptional enhancers can be detected from changes in methylation patterns. However, no systematic approach has been developed to infer the function of these elements within larger transcription factor networks. We developed ELMER (Enhancer Linking by Methylation/Expression Relationships), a computational tool that combines DNA methylation and gene expression data from tissue samples, along with annotations from epigenomic repositories, to infer multi-level cis-regulatory networks. ELMER uses DNA methylation to identify enhancers that differ between normal and disease tissues, and correlates these with gene expression to identify a target gene or genes (typically not the nearest gene). Transcription factor (TF) binding site analysis is then used in conjunction with TF expression patterns to infer the upstream regulators that drive enhancer changes. We applied ELMER to Infinium HM450k methylation and RNA-seq data for 2,000+ tumor samples and ten cancer types from The Cancer Genome Atlas (TCGA). Our multi-level analysis identified enhancer networks regulated by known cancer driver transcription factors, such as GATA3 and FOXA1 in breast cancer, FOXA2 and SOX17 in endometrial cancer, and NFE2L2, SOX2, and TP63 in squamous cell lung cancer. We also identified several novel networks with prognostic associations, including RUNX1 in kidney cancer, and putative target genes of these transcription factors in primary tumor.
Citation Format: Lijing Yao, Hui Shen, Peter Laird, Peggy Farnham, Berman Benjamin. Inferring regulatory element landscapes and transcription factor networks from cancer methylomes. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 22.
Changes in gene expression of neo‐squamous mucosa after endoscopic treatment for dysplastic Barrett’s esophagus and intramucosal adenocarcinoma
Authors: Levert‐Mignon Angelique , Bourke Michael J , Lord Sarah J , Taylor Andrew C , Wettstein Antony R , Edwards Melanie , Botelho Natalia K , Sonson Rebecca , Jayasekera Chatura , Fisher Oliver M , Thomas Melissa L , Macrae Finlay , Hussey Damian J , Watson David I , Lord Reginald V 
Published: May 2016

BackgroundEndoscopic therapy, including by radiofrequency ablation (RFA) or endoscopic mucosal resection (EMR), is first line treatment for Barrett’s esophagus (BE) with high‐grade dysplasia (HGD) or intramucosal cancer (IMC) and may be appropriate for some patients with low‐grade dysplasia (LGD).ObjectiveThe purpose of this study was to investigate the molecular effects of endotherapy.MethodsmRNA expression of 16 genes significantly associated with different BE stages was measured in paired pre‐treatment BE tissues and post‐treatment neo‐squamous biopsies from 36 patients treated by RFA (19 patients, 3 IMC, 4 HGD, 12 LGD) or EMR (17 patients, 4 IMC, 13 HGD). EMR was performed prior to RFA in eight patients. Normal squamous esophageal tissues were from 20 control individuals.ResultsEndoscopic therapy resulted in significant change towards the normal squamous expression profile for all genes. The neo‐squamous expression profile was significantly different to the normal control profile for 11 of 16 genes.ConclusionEndotherapy results in marked changes in mRNA expression, with replacement of the disordered BE dysplasia or IMC profile with a more “normal” profile. The neo‐squamous mucosa was significantly different to the normal control squamous mucosa for most genes. The significance of this finding is uncertain but it may support continued endoscopic surveillance after successful endotherapy.
Multiradar observations of substorm‐driven ULF waves
Authors: James M. K. , Yeoman T. K. , Mager P. N. , Klimushkin D. Yu. 
Published: May 2016

AbstractA recent statistical study of ULF waves driven by substorm‐injected particles observed using Super Dual Auroral Radar Network (SuperDARN) found that the phase characteristics of these waves varied depending on where the wave was observed relative to the substorm. Typically, positive azimuthal wave numbers, m, were observed in waves generated to the east of the substorms and negative m to the west. The magnitude of m typically increased with the azimuthal separation between the wave observation and the substorm location. The energies estimated for the driving particles for these 83 wave events were found to be highest when the waves were observed closer to the substorm and lowest farther away. Each of the 83 events studied by James et al. (2013) involved just a single wave observation per substorm. Here a study of three individual substorm events are presented, with associated observations of multiple ULF waves using various different SuperDARN radars. We demonstrate that a single substorm is capable of driving a number of wave events characterized by different azimuthal scale lengths and wave periods, associated with different energies, W, in the driving particle population. We find that similar trends in m and W exist for multiple wave events with a single substorm as was seen in the single wave events of James et al. (2013). The variety of wave periods present on similar L shells in this study may also be evidence for the detection of both poloidal Alfvén and drift compressional mode waves driven by substorm‐injected particles.
Beyond the SCS‐CN method: A theoretical framework for spatially lumped rainfall‐runoff response
Authors: Bartlett M. S. , Parolari A. J. , McDonnell J. J. , Porporato A. 
Published: May 2016

AbstractSince its introduction in 1954, the Soil Conservation Service curve number (SCS‐CN) method has become the standard tool, in practice, for estimating an event‐based rainfall‐runoff response. However, because of its empirical origins, the SCS‐CN method is restricted to certain geographic regions and land use types. Moreover, it does not describe the spatial variability of runoff. To move beyond these limitations, we present a new theoretical framework for spatially lumped, event‐based rainfall‐runoff modeling. In this framework, we describe the spatially lumped runoff model as a point description of runoff that is upscaled to a watershed area based on probability distributions that are representative of watershed heterogeneities. The framework accommodates different runoff concepts and distributions of heterogeneities, and in doing so, it provides an implicit spatial description of runoff variability. Heterogeneity in storage capacity and soil moisture are the basis for upscaling a point runoff response and linking ecohydrological processes to runoff modeling. For the framework, we consider two different runoff responses for fractions of the watershed area: “prethreshold” and “threshold‐excess” runoff. These occur before and after infiltration exceeds a storage capacity threshold. Our application of the framework results in a new model (called SCS‐CNx) that extends the SCS‐CN method with the prethreshold and threshold‐excess runoff mechanisms and an implicit spatial description of runoff. We show proof of concept in four forested watersheds and further that the resulting model may better represent geographic regions and site types that previously have been beyond the scope of the traditional SCS‐CN method.