bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4781: A comprehensive screen for protein kinases involved in histone phosphorylation using a biochemical in-vitro approach
Authors: Mueller Daniel , Totzke Frank , Ketterer Constance , Beisenherz-Huss Christian , Krämer Diane , Weber Thomas , Heidemann-Dinger Carolin , Kubbutat Michael H.G. 
Published: August 2015

Abstract
Gene expression is regulated by multiple mechanisms. The structure of the chromatin has been identified as one major regulator of gene expression. Histone proteins constitute the core of the nucleosomal particles, which are essential for structuring the DNA into chromatin. Various post-translational modifications of histones mainly in the N-terminal region of these proteins will compact or loosen the chromatin which in turn changes the accessibility of the DNA.
Such histone modifications like methylation, acetylation and phosphorylation can therefore result either in activation or in repression of the transcription of the respective genes, depending on the specific amino acid residues modified. While histone-acetylases and histone-methyl-transferases as well as their corresponding counterparts, histone-deacetylases and histone-demethylases, are currently in the focus of epigenetic research, it is also well documented that histones are extensively modified and regulated by phosphorylation.
In order to identify protein kinases able to phosphorylate histones we have generated a series of N-terminal peptides of human histone proteins H1, H2A, H2B, H3 and H4 as well as recombinant histone proteins. In a biochemical in-vitro activity assay (“KinaseFinder”) we tested these peptides and proteins as potential substrates against a panel of 339 recombinant human serine-threonine- and tyrosine-kinases. The results of the screens will be presented showing different protein kinases able to phosphorylate various histones in vitro. Additional data of approaches to verify and to characterize hit kinases, e.g. with respect to the specific target amino acid sequences, will be shown.
Citation Format: Daniel Mueller, Frank Totzke, Constance Ketterer, Christian Beisenherz-Huss, Diane Krämer, Thomas Weber, Carolin Heidemann-Dinger, Michael H.G. Kubbutat. A comprehensive screen for protein kinases involved in histone phosphorylation using a biochemical in-vitro approach. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4781. doi:10.1158/1538-7445.AM2015-4781
Abstract 4782: Genome-wide chromatin profiling in bladder and prostate cancers
Authors: Kim Sohyoung , Varticovski Lyuba , Lao Qizong , Baek Songjoon , Sung Myong-Hee , Grøntved Lars , Nickerson Michael L. , Thompson Bethtrice , Theodorescu Dan , Dean Michael , Hager Gordon H. 
Published: August 2015

Abstract
Mutations in a few driver genes can cause cancer, and a main goal of cancer genome analysis has been the identification of these cancer genes. Recent findings, however, indicate that deregulation of enhancers can play a major role in carcinogenesis. In this study, we aim to understand how enhancer networks evolve during cancer initiation and progression and to identify epigenetic states that are predictive of cancer stage and drug response. We surveyed 15 bladder cell lines, including the T24 lineage (T24, T24T, FL, and SL) and the UMUC3 lineage (UMUC3 and LUL2), and 10 prostate cancer cell lines including BPH1, DU145 and LNCap. These cell lines display different tumorigenic and metastatic potentials, and thus present a model for cancer progression and development of castration-resistance. DNase-seq was performed to map genome-wide regulatory profiles in these cells. The enhancers detected as DNase I hypersensitivity sites (DHSs) showed large-scale changes in the chromatin accessibility landscape during the acquisition of tumorigenic and metastatic phenotypes. Selective sets of gained or lost DHSs were identified. Among the changes during the T24 to T24T transition, the loss of DHSs was remarkable. Some of these DHSs were found near genes that are in the downstream response to HDACs. Induction of expression by the HDAC inhibitor, Na butyrate, was correlated with DNase-seq signal for these genes. Gene Ontology (GO) enrichment analysis also indentified a set of genes neighboring lost DHSs that belong to the focal adhesion class in GO category. This study identified a set of DHSs that were associated with cancer progression in bladder and prostate cancer, and the potential clinical application of the identified DHSs will be discussed.
Citation Format: Sohyoung Kim, Lyuba Varticovski, Qizong Lao, Songjoon Baek, Myong-Hee Sung, Lars Grøntved, Michael L. Nickerson, Bethtrice Thompson, Dan Theodorescu, Michael Dean, Gordon H. Hager. Genome-wide chromatin profiling in bladder and prostate cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4782. doi:10.1158/1538-7445.AM2015-4782
Abstract 4784: Effect of epigenetic drugs on chromatin remodeling complexes disrupted in cancer
Authors: Pérez-Salvia Montserrat , Simó-Riudalbas Laia , Esteller Manel 
Published: August 2015

Abstract
Chromatin remodeling complexes undergo dynamic assembly of chromatin to facilitate the access to DNA packed in nucleosomes during DNA-template cellular processes. They present genetic alterations in multiple of its components in a broad range of hematological and solid malignancies. The SWI/SNF ATP-dependent chromatin remodeling complex subunits BRG1 and ARID1A were reported to act as tumor suppressors and they are mutated in a variety of human cancers including breast cancer, prostate cancer, lung cancer and pancreatic cancer.
In contrast with the irreversible genomic mutations, epigenetic modifications can be reversed by therapeutic treatment. New generation of epigenetic drugs consists on specific inhibitors against chromatin associated proteins which present abnormal expression in tumors. Bromodomain and BET inhibitors block the assembly of a protein complex at a particular gene locus by impairing the interaction of the bromodomain with the acetylated lysine of a histone tail. To date, some BET inhibitors have been tested for the treatment of the rare NUT midline carcinoma disease, acute myeloid leukemia and multiple myeloma.
Our aim was to find new potential biomarkers for a personalized cancer treatment with new generation epigenetic drugs. Thus, we tested whether cell lines with a component of the SWI/SNF complex disrupted (BRG1 or ARID1A) present more sensitivity to bromodomain inhibitors.
Citation Format: Montserrat Pérez-Salvia, Laia Simó-Riudalbas, Manel Esteller. Effect of epigenetic drugs on chromatin remodeling complexes disrupted in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4784. doi:10.1158/1538-7445.AM2015-4784
Abstract 4787: Cyclin G2, a novel target of the SNF5/BAF47 tumor suppressor gene
Authors: Wei Darmood , Charboneau Aubri , Chung Ho-yoon , Sakellariou-Thompson Donastas , Davies Brian , Simpson Dennis A. , Kuwahara Yasumichi , Kaufmann William K. , Roberts Charles W. M. , Weissman Bernard E. 
Published: August 2015

Abstract
Malignant Rhabdoid Tumor (MRT) is a rare and aggressive pediatric cancer that most frequently appears in the kidney (RTK) and brain (AT/RT). They are generally characterized by the lack of SNF5 (SMARCB1/INI1) expression, a subunit of the SWI/SNF chromatin remodeling complex. Previous studies have shown that reintroducing SNF5 into MRT cell lines reconstitutes the SWI/SNF complex and results in an inhibition of growth through induction of p21WAF1/CIP1, p16INK4A and p57KIP2 expression. However, the mechanisms behind this growth arrest remain incompletely characterized. In this current report, we used a RT-PCR Cell Cycle SuperArray to identify six candidate genes that showed increased expression after SNF5 reexpression but not after expression of a constitutively active RB gene. One of these genes, Cyclin G2 (CCNG2), a member of the non-canonical Cyclin G family, is thought to act as a negative regulator of the cell cycle. Using a panel of RTK and AT/RT cell lines, we confirmed that SNF5 reexpression leads to induction of CCGN2 in additional MRT cell lines. To determine if CCNG2 is a direct target of SNF5, we used chromatin immunoprecipitation analyses (ChIP) to verify that SNF5 binds to the CCNG2 promoter with peak binding at the transcription start site (TSS) after its reexpression in a MRT cell line. Importantly, primary MRT samples display reduced CCNG2 expression when compared to normal brain tissue or other types of pediatric brain cancers. Therefore, CCNG2 represents a new SNF5 target gene whose downregulation may play a role during MRT development.
Citation Format: Darmood Wei, Aubri Charboneau, Ho-yoon Chung, Donastas Sakellariou-Thompson, Brian Davies, Dennis A. Simpson, Yasumichi Kuwahara, William K. Kaufmann, Charles W. M. Roberts, Bernard E. Weissman. Cyclin G2, a novel target of the SNF5/BAF47 tumor suppressor gene. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4787. doi:10.1158/1538-7445.AM2015-4787
Abstract 4799: Variation in mutational landscape among small colonic polyps with differential growth rates
Authors: Sievers Chelsie K. , Pickhardt Perry J. , Matkowskyj Kristina , Albrecht Dawn , Zou Luli , Kim David , Lubner Meghan , Reichelderfer Mark , Halberg Richard 
Published: August 2015

Abstract
Background: Benign adenomatous colonic polyps are transformed into cancers through the stepwise accumulation of mutations. However, not all polyps will progress. A significant number remain static in size, regress, or resolve completely. The mechanisms underlying these differential fates are unknown, and currently there are no biological characteristics that can reliably predict which polyps will grow or progress into invasive cancer. A multiancestral origin contributes to tumor heterogeneity and might provide additional growth promoting signals via increased genetic diversity.
Methods: Utilizing a unique cohort of patients with small (&lt;9mm) colorectal polyps in which growth was followed over a mean of 2.3 years by CT colonography, we performed next generation sequencing followed by micro-dissection and quantitative PCR to determine tumor origin.
Results: The mutational landscape of small polyps is highly heterogeneous. Polyps carried 0 - 5 pathogenic mutations, with the most commonly altered gene being APC, which is considered the gatekeeper of the intestine. Interestingly, the percentage of cells harboring mutations in APC within a single polyp ranged from 2.0% to 70.6% with an average of 22.1%. In contrast, the frequency of a common APC single nucleotide polymorphism was 0% for non-carriers (n = 3), 55.9% for heterozygotes (n = 6), and 97.9% for homozygotes (n = 10). In the presence of an APC mutation, the average frequency of a second pathogenic mutation within a sample was 6.2% (n = 10).
Conclusions: These data indicate that early intratumoral heterogeneity arising as a consequence of multiancestral origin affects tumor formation and growth. By determining the relative fitness advantage of heterogeneous polyps, we can begin to better predict which polyps may be more likely to progress into adenocarcinomas and which patients are predisposed to developing advanced disease.
Citation Format: Chelsie K. Sievers, Perry J. Pickhardt, Kristina Matkowskyj, Dawn Albrecht, Luli Zou, David Kim, Meghan Lubner, Mark Reichelderfer, Richard Halberg. Variation in mutational landscape among small colonic polyps with differential growth rates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4799. doi:10.1158/1538-7445.AM2015-4799
Abstract 4800: Identification of candidate predisposition genes for familial uterine leiomyomas
Authors: Heinonen Hanna-Riikka , Uimari Outi , Tolvanen Jaana , Ryynänen Markku , Aaltonen Lauri A. , Vahteristo Pia 
Published: August 2015

Abstract
Uterine leiomyomas are benign smooth muscle tumors that cause considerable morbidity. They are among the most common human tumors and are the leading indication for hysterectomy. Genetic factors play an important role in the development of these hormone-dependent tumors. First-degree relatives of uterine leiomyoma patients are at increased risk for developing leiomyomas. Twin studies have shown that an inherited predisposition is likely to contribute to the formation of these lesions. Furthermore, the clinical and molecular features of familial leiomyomas differ from those of sporadic cases. Thus far, the only known high risk predisposition defect is dominantly inherited loss of function mutations in fumarate hydratase (FH) that underlie a tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC). The aim of this study is to identify novel candidate high risk susceptibility genes for uterine leiomyomas. The study material consists of five FH mutation-negative families, which have at least four individuals diagnosed with uterine leiomyomas, originating from Northern Finland. Genomic DNA extracted from peripheral blood lymphocytes from one affected individual from each family has been exome sequenced. Exome sequencing data have been analyzed for rare non-synonymous variants with allele frequencies less than 0.1% in 4 019 controls. All protein-truncating variants as well as missense and splice site variants affecting the same gene in at least two individuals that are predicted to be protein-damaging have been included for further analysis. Preliminarily 25 candidate susceptibility genes have been shortlisted. Relevant variant calls will be verified by direct sequencing, followed by segregation analysis and assessment of loss of heterozygosity in the corresponding tumor samples. Identification of novel genes predisposing to familial uterine leiomyomas may provide a better understanding into the tumorigenic mechanisms and could lead to new prevention approaches and personalized medical treatments in the future.
Citation Format: Hanna-Riikka Heinonen, Outi Uimari, Jaana Tolvanen, Markku Ryynänen, Lauri A. Aaltonen, Pia Vahteristo. Identification of candidate predisposition genes for familial uterine leiomyomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4800. doi:10.1158/1538-7445.AM2015-4800
Abstract 4802: Transcriptional landscape of lung squamous cell carcinoma in Northeast Asian patients
Authors: Rhie Arang , Cho Hyesun , Son Min Hwan , Yoo Seong-Keun , Shin Jong-Yeon , Seo Jeong-Sun 
Published: August 2015

Abstract
Lung Squamous Cell Carcinoma (LSCC), the second most prevalent type of lung cancer, is known to have different genetic and epigenetic characteristics from lung adenocarcinoma. Molecular pathogenesis remains to be elucidated to identify therapeutic targets, especially for patients with no driver mutations identified in previous studies. In this study, we obtained RNAs from fresh tissue of 101 patients of LSCC, and its paired normal site. RNA-seq was performed with paired-end sequencing of HiSeq2000. The average throughput uniquely mapped to the human genome reference was 10Gbp per sample. Differentially expressed genes showed higher expression in HOX families, FOXL2, SOX2, FGFR3, JAK3, and ALK. In contrast, WIF1, RSPO2, ROS1, TAL1, PRDM16 was down regulated in tumor cells. To subgroup patients with their driver mutation, somatic mutation have been detected with comparison to normal paired samples, filtering with MAF&lt;0.01 of Northeast Asian Population, 1KG, and ExAC 65000 exomes. The average number of nonsynonymous somatic mutation was 49.63 per sample. Sixty-seven patients had somatic mutation in TP53, CDKN2A, NFE2L2, and PIK3CA. This was relatively small compared to patients from TCGA, mainly consisting of Western population. After excluding 4 patients identified to be close to normal cells by PCA analysis of expression pattern, and 2 other patients suspected to be false classified from adenocarcinoma presenting mutation in EGFR (L858R) and KRAS (G12D), 28 patients remained to be elucidated. No EGFR, ALK, RET, FGFR3, TACC fusion have been found, suggesting novel isoform of transcripts or other mechanisms driving carcinogenesis.
Citation Format: Arang Rhie, Hyesun Cho, Min Hwan Son, Seong-Keun Yoo, Jong-Yeon Shin, Jeong-Sun Seo. Transcriptional landscape of lung squamous cell carcinoma in Northeast Asian patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4802. doi:10.1158/1538-7445.AM2015-4802
Abstract 4809: Validation of molecular subtypes of urothelial carcinoma of bladder in multi-institutional and public cohorts
Authors: Dadhania Vipulkumar , Guo Charles G. , Majewski Tadeusz , Zhang Li , Bondaruk Jolanta , Zhang Shizhen , Choi Woonyoung , McConkey David , Dinney Colin , Baggerly Keith , Czerniak Bogdan A. 
Published: August 2015

Abstract
BACKGROUND: Recently we have proposed a molecular sub-classification of conventional urothelial carcinoma which could be divided into two major categories designated as basal and luminal similar to the ones defined for breast cancer. In addition, luminal cancers contain a group of cases characterized by upregulation of p53 regulatory genes and is referred to as p53-like. The purpose of this project is to verify whether such subtypes can be identified in several large independent cohorts of bladder cancers.
DESIGN: Gene expression profiles and molecular subtyping were performed by using previously described analytical algorithms on the following bladder cancer patient cohorts: (1) The Cancer Genome Atlas (TCGA) cohort containing tumor tissues from muscle invasive high grade urothelial carcinomas of 129 patients; (2) the MD Anderson Cancer Center (MDA) cohort of fresh frozen tumor tissues which included 65 superficial papillary carcinomas and 77 invasive carcinomas; (3) the Swedish cohort containing fresh frozen tumor samples of 116 superficial papillary tumors and 192 invasive tumors.
RESULTS: The three distinct molecular subtypes defined as luminal, p53-like and basal were identified in all three cohorts. The distribution of molecular subtypes in individual cohorts was as follows: the TCGA cohort contained 50 (39%) luminal, 30 (23%) p53-like and 49 (38%) basal tumors; the MDA cohort contained 54 (38%) luminal, 61 (43%) p53-like and 27 (19%) basal; the Swedish cohort contained 102 (33%) luminal, 129 (42%) p-53 like and 77 (25%) basal tumors. Interestingly, in the MDA and Swedish cohorts virtually all superficial tumors, of either low or high grade, were of luminal type.
CONCLUSION: The conventional bladder cancer can be separated into three distinct molecular subtypes with luminal phenotype defining the vast majority of superficial bladder cancers while muscle invasive tumors can be separated into luminal and basal forms. A subset of luminal cancers is characterized by upregulation of p53 regulatory genes. The identification of subtypes may help to stratify the patients for targeted therapies.
Citation Format: Vipulkumar Dadhania, Charles G. Guo, Tadeusz Majewski, Li Zhang, Jolanta Bondaruk, Shizhen Zhang, Woonyoung Choi, David McConkey, Colin Dinney, Keith Baggerly, Bogdan A. Czerniak. Validation of molecular subtypes of urothelial carcinoma of bladder in multi-institutional and public cohorts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4809. doi:10.1158/1538-7445.AM2015-4809
Abstract 4821: Association of polymorphisms in TP53, CXCL2, MDM2, MDM4 and BCL2 genes and proliferative prostate diseases among Lebanese men
Authors: Kuddus Ruhul H. , El Ezzi Asmahan A. , El-Saidi Mohammed A. , Baker Scott , Zaidan Wissam 
Published: August 2015

Abstract
Specific Aims: To investigate possible relationships between certain polymorphisms in p53 protein (TP53) gene, chemokine (C-X-C motif) ligand 2 (CXCL-2) gene, mouse double minute 2 homologue (MDM2) gene, MDM4 protein (MDM4) gene and B cell lymphoma 2 protein (BCL2) gene and benign prostate hyperplasia (BPH) and prostate cancer (PCa) among middle-aged Lebanese men.
Methods: Blood was collected from volunteer prostate disease screening campaign participants ages 50-70. DNA was extracted from peripheral blood leucocytes of 85 donors diagnosed with clinical PCa, 178 donors diagnosed with BPH, and 140 donors with no prostrate-related pathologies. The 72 Arg/pro polymorphism of TP53 gene, 801 G/A polymorphism of CXCL2 gene, 309 G/T polymorphism of MDM2 gene, 103 T/C and D153G polymorphisms of MDM4 gene and 938 C/A polymorphism of BCL2 genes was investigated by polymerase chain reaction/restriction fragment-length polymorphism analysis. The genotype of the subjects for each of the genes was determined and allelic frequency was calculated. Association between the genotypes and PCa and BPH was estimated by calculating the odds ratio (OR) and 95% confidence intervals (CI). The relative risk (RR) of PCa or BPH for having a particular genotype was also calculated using MedCalc statistical software. The null hypotheses were rejected with a p value of &lt;0.05%.
Results: There is no association between the examined polymorphisms of the TP53 gene, CXCL2 gene, MDM2 gene and BCL2 gene and BPH or PCa. The ratio of C/T alleles for the 103 T/C locus and the ratio of D/G alleles for D153G locus of MDM4 are lower for subjects with PCa and BPH compared to the controls (p&lt;0.01 for both loci). The ratio of (CC+CT)/TT is lower for subjects with PCa compared to the control (OR = 0.12, 95% CI = 0.06-0.22, RR = 0.39, p&lt;0.01), and BPH compared to the controls (OR = 0.17, 95% CI = 0.10-0.28, RR = 0.50, p&lt;0.01); and the ratio of (GG+GD)/DD is higher for subjects with PCa compared to the control (RR = 1.86, p&lt;0.01) and subjects with BPH compared to the controls (RR = 1.85, p&lt;0.01).
Conclusions: There is no statistically significant association between polymorphisms in TP53 gene, CXCL2 gene, MDM2 gene and BCL2 gene and PCa or BPH but the C allele of 103 T/C locus and the G allele of the D153G locus of MDM4 are risk factors for both PCa and BPH among Lebanese men.
Citation Format: Ruhul H. Kuddus, Asmahan A. El Ezzi, Mohammed A. El-Saidi, Scott Baker, Wissam Zaidan. Association of polymorphisms in TP53, CXCL2, MDM2, MDM4 and BCL2 genes and proliferative prostate diseases among Lebanese men. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4821. doi:10.1158/1538-7445.AM2015-4821