bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 998: KLF4 interacts with β-catenin/TCF4 and blocks p300/CBP recruitment by β-catenin
Authors: Chen Xi , Evans Paul M. , Zhang Wen , Liu Chunming 
Published: February 2011

Abstract
Wnt signaling is crucial in the organization and maintenance of the human intestinal epithelium, and somatic mutations that result in deregulated Wnt signaling are an early event in the development of colorectal cancer. The Wnt ligand ultimately results in the stabilization of cytoplasmic β-catenin, which is then free to enter the nucleus and activate transcription through its interaction with the transcription factor TCF4. Our laboratory recently found that KLF4, a transcription factor highly expressed in the adult intestine and critical for intestinal differentiation, interacts with β-catenin and inhibits Wnt signaling. In this study, we characterize the molecular mechanisms of KLF4-mediated inhibition of Wnt/β-catenin signaling. We find that the KLF4 directly interacts with the C-terminal transactivation domain of β-catenin and inhibits p300/CBP recruitment by β-catenin. KLF4 inhibits p300/CBP-mediated β-catenin acetylation as well as histone acetylation on Wnt target genes. In addition, we observe that KLF4 directly interacts with TCF4 independently of β-catenin, and that KLF4 and TCF4 are expressed in similar patterns within the large intestine, with greatest staining near the epithelial surface. These results provide a deeper understanding of the regulation of β-catenin in the intestine, and will have important implications in cancer and stem cell research.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 998.
Abstract LB-100: Optimal modulation of DNA repair in CLL therapy
Authors: Amrein Lilian , Davidson David , Shawi May , Petruccelli Luca , Miller Wilson , Aloyz Raquel , Panasci Lawrence 
Published: February 2011

Abstract
Resistance to chlorambucil (CLB) in chronic lymphocytic leukemia (CLL) can occur as a consequence of increased DNA repair including c-abl stimulated Rad-51 related homologous recombinational repair (HRR) and DNA-PK related nonhomologous endjoining (NHEJ).
Recent reports suggest that the nonreceptor tyrosine kinase c-abl plays an important role in CLL. In particular, we have previously demonstrated that imatinib inhibition of c-abl or NU7026 inhibition of DNA-PK in CLL lymphocytes results in sensitization to CLB in most samples. Here we report that nilotinib, a superpotent (20-30 fold greater than niltinib) inhibitor of c-abl is more efficacious than imatinib in sensitizing CLL lymphocytes to CLB in the majority of the CLL lymphocyte samples associated with a greater nilotinib related inhibition of c-abl autophosporylation, increased apoptosis and decreased repair of CLB-induced DNA damage (increased activated H2AX).
Furthermore, in CLL samples in which c-abl was inhibited by either inhibitor, there was an increased activation of DNA-PK. Utilizing NU7026, a specific inhibitor of DNA-PK, with nilotinib or imatinib resulted in further sensitization to CLB but there was a greater sensitization to CLB with nilotinib than imatinib. These results suggest: (1) a more potent inhibition of c-abl is more efficacious in sensitizing CLL lymphocytes to CLB, (2) inhibition of c-abl results in a compensatory increase in DNA-PK and (3) inhibiting both DNA repair systems optimally sensitizes CLL lymphocytes to CLB, an effect which is most pronounced with the more potent c-abl inhibitor, nilotinib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-100.
Abstract LB-105: Single nucleotide polymorphisms (SNPs) in the CYP19A1 gene are strongly associated with CYP1A2 expression: First evidence for epistasis in the CYP superfamily
Authors: Zhang Xuemei , Kadlubar Susan , Mercer Kelly , Yu Xinfeng , Dhakal Ishwori , Beggs Marjorie , Caldwell David , Edavana Vineetha Koroth , Williams Suzanne , Kadlubar Fred F. 
Published: February 2011

Abstract
CYP1A2 is a member of the cytochromes P450 enzymes responsible for the oxidative metabolism of a wide array of endo- and xenobiotics, and has been demonstrated to be the major isoform responsible for oxidation of estrone and estradiol. To date, SNPs identified in this gene do not adequately explain the 60-80-fold variation in activity observed in Caucasians. We hypothesized that CYP1A2 could be a target of epistatic regulation (i.e., gene-gene interactions where SNPs in one gene influence the expression of another). CYP1A2 and CYP19A1 both lie on chromosome 15, and since CYP19A1 (aromatase) is responsible for the production of estrogens, and CYP1A2 is the primary catabolic P450, we hypothesized that these genes could be coordinately regulated, and SNPs influencing levels of CYP19A1 could also be related to expression levels of CYP1A2. Two TagSNPs (rs749292 A&lt;G and rs727479 A&lt;C) in CYP19A1 were genotyped using Beckman Single Base Extension Kit and TaqMan MGB probe, respectively. Levels of CYP1A2 protein in human liver microsomes from 100 donors were assessed by Western blotting and correlations between CYP19A1 SNPs and CYP1A2 protein amounts were determined. CYP1A2 expression was significantly higher in specimens with CYP19A1 (rs727479) AA homozygous compared with CC genotype (P&lt;0.001), a SNP associated with increased CYP19A1 activity. CYP1A2 expression also is related CYP19A1 (rs749292) polymorphism and AA genotype carriers have higher CYP1A2 expression compared with GG genotype carriers. Moreover, in silico analyses shows the presence of over 300 putative estrogen-responsive elements upstream of the CYP1A2 transcription start sit. SNPs in CYP19A1 are significantly associated with CYP1A2 protein expression. This is the first evidence of epistasis in the P450 enzymes and suggests a role of estrogens in the regulation of CYP1A2.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-105.
Abstract LB-130: The NCI-Nature Pathway Interaction Database: A cell signaling resource
Authors: Schaefer Carl F. , Anthony Kira , Skinner Mhairi A. , Buchoff Jeffrey R. , Day Matthew , Buetow Kenneth H. 
Published: February 2011

Abstract
The NCI-Nature Pathway Interaction Database (PID, http://pid.nci.nih.gov) is a freely available collection of professionally curated and expert-reviewed signaling and regulatory pathways composed of human molecular interactions, signaling events and cellular processes extracted from primary literature. Pathways selected for curation are based on potential drug targets, suggestions made by our users and reviewers, and other prominent cell signaling molecules. As of February 2010, the database contains 106 pathways encompassing 6696 interactions, 3231 proteins, 142 small molecules, 2622 complexes and 4843 peer-reviewed publications, and includes recent additions to both the p53 and EGFR pathways. Created in a collaboration between the U.S. National Cancer Institute and Nature Publishing Group, the PID is aimed at researchers interested in cell signaling pathways, such as molecular cell biologists, and bioinformaticians. The database offers a range of tools to facilitate pathway exploration. Users can browse the pre-defined set of pathways and create network maps centered on a single molecule or biological process of interest. The Batch query tool allows users to upload molecule lists, such as those derived from microarray data, and visualize the resulting molecular connectivity map. In addition, users can download lists of proteins, references used to create the pathway and complete database content in extensible markup language (XML) or Biological Pathways Exchange (BioPAX) format. The database is updated every month and supplemented by a concise editorial section that provides synopses of recent noteworthy papers in cell signaling and specially commissioned articles on the practical uses of other relevant Bioinformatics tools. Users can sign up for email alerts or RSS feeds to receive database updates.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-130.
Abstract LB-138: In vivo imaging of DNA damage and repair
Authors: Wang Yanming , Liu Lili , Wu Chunying , Bulgar Alina , Zhu Wenxia , Somoza Eduardo , Gerson Stanton 
Published: February 2011

Abstract
Objectives: To directly quantify abasic sites induced by DNA-targeted chemotherapeutic agents for in vivo studies of base excision repair pathway.
Background: Current cancer treatments rely heavily on chemotherapeutic agents to induce cytotoxic DNA damages and programmed cell death in ancer cells. However, the efficacy of DNA-targeted agents such as temozolomide is often compromised by intrinsic cellular responses such as DNA base excision repair (BER). Previous studies have shown that BER pathway results in formation of abasic or apurinic/apyrimidinic (AP) sites and inhibition of AP sites leads to significant reduction of drug resistance and enhancement of drug sensitivity. Thus, AP-site formation has been identified as an important biomarker in DNA-targeted chemotherapies.
Methods: Design, synthesis, and evaluation of PET imaging agents that bind to AP sites with high affinity and specificity. We date, we have developed positron-emitting [11C]methoxyamine for positron emission tomography (PET) that allows for quantification of AP sites in vivo.
Results: [11C]methoxyamine has been synthesized with high radiochemical yield and purity. Following radiolabelling, microPET studies have been conducted to evaluate their pharmacokinetic profiles in melanoma and glioma xenograft tumor mouse models that are pre-treated with temozolomide to induce AP-site formation. Subsequent quantitative analysis showed that the radioactivity concentration were elevated in proportion to the AP sites induced in tumor regions pre-treated with temozolomide relative to tumor regions without any treatment. In vivo blocking studies based on microPET also showed that the agents bound to AP sites with high specificity.
Conclusion: our studies demonstrated that PET imaging can be used to monitor BER pathway and evaluate efficacy of DNA-targeted therapeutic treatments in cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-138.
Abstract LB-146: Identification of copy number alterations in small cell lung cancer
Authors: Dooley Alison L. , Winslow Monte M. , Chiang Derek , Banerji Shantanu , Whittaker Charles , Bronson Roderick , Crowley Denise , Meyerson Matthew , Jacks Tyler 
Published: February 2011

Abstract
Small cell lung cancer (SCLC) comprises 20% of all lung cancer cases and is a particularly malignant disease. The identification of genomic alterations in small cell tumors and metastases and characterization of the genes within those regions will aid in our understanding of SCLC development and progression. DNA copy number gains and losses in human and mouse tumors frequently highlight genes of functional importance. Mouse tumors are often less genomically complex than their human counterparts and several recent studies have highlighted the power of comparative genomic studies of mouse models to identify genes relevant to human tumor progression. In a mouse model, inactivation of p53 and Rb following Cre-mediated recombination results in the development of lung tumors that resemble human SCLC histopathologically. Using this model of malignant SCLC, we have identified DNA copy number alterations in tumors and metastases using Illumina's Solexa massively parallel DNA sequencing technology. While the majority of the genome is unaltered, we observed several focal deletions and high-level amplifications. We detected an amplification of a region including the gene L-myc, a gene previously identified to be amplified in SCLC, and a region including Nuclear Factor 1/B (Nfib). Additionally, several cell lines derived from these lung tumors and metastases have high-level amplifications of Nfib. The DNA copy number data will be probed for conserved changes in tumors and metastases isolated from different animals and functionally validated using in vitro and in vivo assays.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-146.
Abstract LB-147: Characterization of a Kaiso overexpressing transgenic mouse model
Authors: Chaudhary Roopali , Nanan Kyster K. , Daniel Juliet M. 
Published: February 2011

Abstract
Introduction: The WNT signaling pathway plays critical roles during embryogenesis and maintaining homeostasis of adult tissues. However constitutive WNT signaling leads to tumorigenesis. Upon activation of the WNT pathway, the main downstream effector of the WNT pathway, ß-catenin, stabilizes and translocates to the nucleus where it activates transcription of WNT target genes. Recently, our lab along with others identified the novel transcription factor Kaiso as a negative regulator of WNT target genes in mammalian cell lines and Xenopus models. However a study using a Kaiso depleted mouse model implicated Kaiso as a positive regulator of WNT signaling. Kaiso is a member of the BTB/POZ (broad-complex, tramtrack and bric-à-brac/poxvirus and zinc finger) protein family. The goal of this study is to elucidate the role of Kaiso in WNT signaling using the ApcMin/+ mouse model of intestinal cancer.
Methodology: To assess the role of Kaiso in colon cancer in vivo, Kaiso overexpressing transgenic mice were created (KaisoTg). Targeted overexpression of Kaiso in KaisoTg mice was obtained by pronuclear injection of Kaiso cDNA under the control of the intestine-specific villin promoter. Reverse transcription PCR (RT-PCR) and Western Blot analyses were used to determine tissue specific Kaiso overexpression in KaisoTg mice. Immunohistochemisty (IHC) was performed on mouse intestinal tissues to examine the subcellular localization of Kaiso and assess developmental defects. KaisoTg mice were then mated with APCMin/+ mice models of intestinal cancer that develop polyps in the small intestine due to constitutively active -catenin. KaisoTg-APCMin/+ mice were examined for gross morphological phenotypes and IHC was performed on mouse intestinal tissues for Kaiso and other WNT target genes (e.g. cyclin D1) to elucidate the effects of Kaiso on the WNT pathway.
Results: Western Blot analysis revealed high, moderate and low levels of Kaiso overexpression in three founder lines of the KaisoTg mice. RT-PCR analysis showed Kaiso overexpression limited to villin positive tissues including kidney, small and large intestines. IHC analysis of KaisoTg tissues showed no gross morphological differences compared to non-transgenic mice. However KaisoTg-APCMin/+ displayed decreased body size and weight, and had decreased life span when compared to the parentals (i.e. KaisoTg and APCmin/+). IHC analysis of KaisoTg-APCMin/+ mouse intestines revealed increased polyp numbers with Kaiso staining concentrated near the basal surface of the polyps. These data support Kaiso's potential role as an oncogene in mouse intestinal tissues.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-147.
Abstract LB-158: A human xenograft model for developing personalized targeted therapy for pancreatic cancer
Authors: Walters Dustin M. , Adair Sara J. , Stokes Jayme B. , Borgman Cheryl , Lowrey Bryce , Adams Reid B. , Fox Jay W. , Papin Jason A. , Parsons J. Thomas , Bauer Todd W. 
Published: February 2011

Abstract
Background: Effective treatment regimens for pancreatic ductal adenocarcinoma (PDAC) are currently lacking. Molecular-targeted therapies, while promising, have been ineffective likely due to the heterogeneity and redundancy of molecular signaling pathways. Identification of predictors of response to defined targeted therapies is critical for the development of effective and personalized therapies.
Methods: We have established a human PDAC tumor bank and have orthotopically implanted patient tumors into the pancreas of immunocompromised mice. Clinicopathologic data has been collected for each patient's tumor. Tumors successfully propagated in mice are routinely screened for six genetic mutations commonly found in pancreatic cancer. Gene expression profiling and phospho-receptor tyrosine kinase (pRTK) arrays, cytokine arrays, and reverse phase protein arrays (RPPAs) are used to profile the activated signaling pathways in individual tumors. A unique genetic and molecular profile is then constructed for each human tumor. Ingenuity pathway analysis software (Ingenuity Systems, Inc., Redwood, CA) is being implemented to map the unique signaling network for each tumor using the genetic and molecular data.
Results: To date 7 tumors have been analyzed, including 2 metastatic tumors and 5 primary adenocarcinomas. All tumors contained TP53 gene mutation, whereas 5 tumors exhibited mutated KRAS and 3 contained mutations in the SMAD4 gene. Analysis using pRTK arrays revealed universal activation of EGFR and variable activation of ErbB2/Her2, RON, Tie-2, FGF-R1 and 3, and Axl. The profile of pRTKs appeared stable upon tumor passage both in vivo and in culture. RPPAs revealed significant variation among tumors in activation for MAPK, AKT, SAPK, and p38. Additional cytokine/growth factor array analysis and gene expression profiling is currently underway.
Conclusion: The establishment of an orthotopic human pancreatic cancer xenograft model allows for the systematic analysis of genetic and molecular characteristics of human tumors propagated within a relevant tumor microenvironment. This model affords the ability to assess tumor growth responses to targeted therapies currently in use for multiple malignancies and to correlate tumor response with genetic perturbations, changes in gene expression and activation of cell signaling networks. This model will be a significant step toward developing personalized targeted therapy for pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-158.
Abstract LB-162: The onset of MYCN overexpression-induced neuroblastoma is accelerated by ALK mutation in zebrafish
Authors: Lee Jeong-Soo , Zhu Shizhen , Shin Jimann , Perez-Atayde Antonio R. , Feng Hui , Guo Feng , Helman Daniel , Wang Wenchao , Stewart Rodney A. , George Rani , Kanki John , Look A. Thomas 
Published: February 2011

Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in infancy and originates in the peripheral sympathetic nervous system (PSNS). High-risk NB is fatal in the majority of patients, despite intensive myeloablative chemotherapy. The MYCN oncogene is amplified in over 20% of NB, particularly in those with highest risk treatment failure. We have developed a zebrafish NB model by overexpressing human MYCN under the control of the dopamine-beta-hydroxylase (D) promoter specific for noradrenergic cells in the PSNS. Fish from this stable transgenic line developed tumors as early as 4 months of age with approximately 20% penetrance at 8 months of age. The tumors resemble human NB histologically, immunohistochemically, and ultrastructurally. The expression of MYCN suppressed the normal development of PSNS neurons and chromaffin cells in the head kidney during embryogenesis and in young adult fish. In some fish, tumor cells began to repopulate the interrenal gland of the head kidney by 2 months of age. Germline and somatic activating mutations have been identified in the ALK gene, which encodes a receptor tyrosine kinase, in human NB, including those with MYCN amplification. To assess cooperativity between amplified MYCN and mutant ALK genes in transformation, we generated a zebrafish stable transgenic line in which the activated mutant form of ALK (F1174L) was expressed under the control of the DßH promoter. These transgenic animals did not display an abnormal phenotype nor did they develop tumors during the first 6 months of life. In contrast, mutant ALK expression accelerated the onset of MYCN-induced neuroblastoma when the 2 genes were co-expressed in double transgenic fish, indicating that MYCN over-expression and activating ALK mutations can cooperate in tumorigenesis. Although co-expression of mutant ALK accelerated the onset of tumors, it did not rescue the MYCN-induced suppression of PSNS development, suggesting that an as-yet-unidentified tumor suppressor gene, possibly located on distal 1p in the human genome, may be lost to fulfill this role in NB tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-162.