bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2117: Epigenetic mechanisms control switching between metastatic and proliferative subtypes in the SW13 adrenal adenocarcinoma cell line
Authors: Davis McKale R. , Hull Elizabeth E. 
Published: August 2015

Abstract
The human adrenal carcinoma SW13 cell line can switch between a subtype which expresses the tumor-suppressor gene Brahma (BRM), SW13+, and one that does not, SW13-. Unlike many tumor supressor genes, which are often mutated, loss of BRM expression occurs post-transcriptionally and BRM expression can be restored via histone deacetylase (HDAC) inhibition. However, many of the previously characterized BRM inducing HDAC inhibitors are toxic, broad-spectrum inhibitors which have limited downstream use, and provide little insight into the specificity of BRM epigenetic suppression. In this work we sought to further characterize the oncogenic potential of the two SW13 subtypes, and to investigate the potential epigenetic regulators that contribute to the subtype switching. SW13 subtype morphology and growth rates were assessed by immunofluorescence and standard growth assays. Metastatic potential was characterized by measuring anchorage-independent growth with soft agar assays, collagenase activity with fluorescein-conjugated gelatin, and invasiveness into a 3D extracellular matrix. Differences in gene expression were measured by standard qRT-PCR and pathway-specific qRT-PCR profiling arrays. The capacity of specific HDAC inhibitors for their ability to induce switching between the SW13 subtypes was assessed by immunofluorescence and gene expression analyses. BRM deficient SW13- cells have both a faster doubling time and an increased rate of anchorage-independent growth, while SW13+ cells exhibit higher collagenase activity and invasive capacity. Significant differences in the expression of multiple genes involved in epigenetic chromatin remodeling as well as epigenetic chromatin modification were observed, indicating that these two subtypes also have unique gene expression profiles that could contribute to BRM regulation. Of those tested, inhibition of HDAC1 most efficiently increased the rate of conversion between SW13- and SW13+ cells, and did so in a dose dependent manner. After conversion to SW13+ subtype there is also increased acetylation on histone H3 but not histone H4 when compared to levels in SW13-, suggesting that the role of acetylation on the H3 tail may play an essential role in the subtype switch. These studies provide new insight into the functional consequences of BRM loss in the SW13 cell type and reveal potential targets for the reversal of BRM epigenetic silencing.
Citation Format: McKale R. Davis, Elizabeth E. Hull. Epigenetic mechanisms control switching between metastatic and proliferative subtypes in the SW13 adrenal adenocarcinoma cell line. [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 2117. doi:10.1158/1538-7445.AM2015-2117
Abstract 212: Infrared spectral diagnosis for predictive cancer medicine: application to the early diagnosis and prognosis of preinvasive bronchial intraepithelial lesions
Authors: Gaydou Vincent D. , Polette Myriame , Gobinet Cyril , Kileztky Claire , Manfait Michel , Birembaut Philippe , Piot Olivier 
Published: August 2015

Abstract
This study concerns the development of a new imaging diagnostic tool for bronchial cancer. This malignancy is a wide-spread cancer in the world, with an increasing incidence. Our objective is to assess the potential of infrared (IR) spectroscopy in the early diagnosis of the bronchial cancer. Our approach is divided into two steps: the first issue aims at highlighting specific spectroscopic markers of the bronchial cancer permitting to detect unambiguously the presence of cancer cells. The second step relies on establishing a chemometric model able to estimate the tumor invasivity of these malignant cells
For our approach, we used 4 different bronchial cellular lines displaying different in vitro invasive properties assessed by a modified Boyden chamber assay : the non invasive cell line 16HBE used as a control, the moderate invasive cell line Beas2B and the two highly invasive cell lines BZR and BZRT33. Four samples of each cell line were cultured and embedded in paraffin wax. Slices of 10 μm were prepared on CaF2 windows suitable for IR measurements. The infrared acquisitions were performed with an imager (Bruker, Germany) equipped with a Focal Plane Array detector allowing to image large tissue areas with a spatial resolution of a few micrometers.
The IR spectra were processed using chemometric and statistical multivariate treatments. A first stage permitted to correct spectral interferences originated from the paraffin and optical effects. Then, supervised models were established by means of PLS-DA (Partial Least Square Discriminant Analysis) method. A first model, based on sparse-PLS method, was optimized to highlight spectroscopic markers specific of the normal and cancerous states; this model has proved effective in terms of sensibility (96%) and specificity (90%). Based on these promising results, the study will be pursued by the analysis of tissue samples from biopsies and tumor samples. Subsequently, the next investigation will rely on the construction of a second model to model and quantify the aggressiveness level of the cell lines.
Citation Format: Vincent D. Gaydou, Myriame Polette, Cyril Gobinet, Claire Kileztky, Michel Manfait, Philippe Birembaut, Olivier Piot. Infrared spectral diagnosis for predictive cancer medicine: application to the early diagnosis and prognosis of preinvasive bronchial intraepithelial lesions. [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 212. doi:10.1158/1538-7445.AM2015-212
Abstract 2140: Dual Wnt and EGFR-MAPK dependency of BRAFV600E-mutant colorectal cancer
Authors: Wang Youzhen , Palmer Michael , Jaeger Savina , Bagdasarian Linda , Qiu Shumei , Woolfenden Steve , Meyer Ronald , Yang Guizhi , Green John , Pan Shifeng , Liu Jun , Gao Hui , Cao Z. Alexander , Myers Andrea , McLaughlin Margaret E. 
Published: August 2015

Abstract
Aberrant Wnt pathway activation due to inactivating mutations in the gene encoding RNF43 (an E3 ubiquitin ligase that promotes degradation of the Wnt receptors Frizzled and LRP6) may contribute to the unresponsiveness of BRAFV600E-mutant colorectal cancer (CRC) to BRAF inhibitors. Analysis of The Cancer Genome Atlas (TCGA) CRC data set reveals a striking co-occurrence of the BRAFV600E mutation and truncating mutations in RNF43. RNF43 mutations are likely to be functionally significant, as RNF43 mutations and mutations in the β-catenin destruction complex component APC are almost completely mutually exclusive. The vast majority of BRAFV600E;RNF43-mutant CRCs are hypermutable [microsatellite instability (MSI)-high phenotype]. The mismatch repair deficiency in these tumors may directly contribute to RNF43 mutagenesis, as RNF43 mutations tend to be small insertions/deletions in homopolymeric tracts. To determine if RNF43 mutations confer Wnt dependency in BRAFV600E-mutant CRC, we treated three BRAFV600E;RNF43-mutant CRC patient-derived xenograft (PDX) models with the porcupine inhibitor WNT974 (formerly LGK974), which blocks the palmitoylation and secretion of Wnt ligands. Single agent WNT974 anti-tumor activity was observed in 2/3 PDX models, and correlated with decreased tumor cell proliferation and mucinous differentiation. Single agent anti-tumor activity with the BRAF inhibitor LGX818 was also observed in 2/3 PDX models. No single agent anti-tumor activity was observed with the EGFR inhibitor cetuximab. The double combinations of WNT974+LGX818 and LGX818+cetuximab, and the triple combination of WNT974+LGX818+cetuximab were efficacious in all three BRAFV600E;RNF43-mutant CRC PDX models. In summary, the Wnt pathway and the EGFR-MAPK pathway may jointly promote tumorigenesis of BRAFV600E-mutant CRC, providing a strong rationale to treat patients with BRAFV600E-mutant CRCs harboring upstream Wnt pathway mutations with combinations of WNT974, LGX818 and/or cetuximab.
Citation Format: Youzhen Wang, Michael Palmer, Savina Jaeger, Linda Bagdasarian, Shumei Qiu, Steve Woolfenden, Ronald Meyer, Guizhi Yang, John Green, Shifeng Pan, Jun Liu, Hui Gao, Z. Alexander Cao, Andrea Myers, Margaret E. McLaughlin. Dual Wnt and EGFR-MAPK dependency of BRAFV600E-mutant colorectal 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 2140. doi:10.1158/1538-7445.AM2015-2140
Abstract 2169: Genomic analysis of 207 rectal cancer samples
Authors: Hu Yue 
Published: August 2015

Abstract
As the 3rd most commonly diagnosed cancer, colorectal cancer makes up of about 10% of all cancer cases and afflicts 1.3million patient each year. It is also the 3rd leading cause of cancer death. Every year more than 50,000 patients die of this disease. To analyze the molecular mechanism of rectal cancer, we explore the gene expression of cancer samples of 207 patients; most of them have paired control. We also study SNPs as well as prognosis data of these patients. Rectal cancer samples show a significant downregulation of genes in metabolic pathways. The general expression pattern separates cancer samples into “control like” subgroup and “cancer like” subgroup. There is no significant prognosis difference between these two groups. We observe a strong correlation between the average gene expression and the copy number change of each chromosome of cancer samples. Several SNPs show differential survival among patients with different alleles. Clinical data shows that these SNPs affect prognosis independent of lymph node status.
Note: This abstract was not presented at the meeting.
Citation Format: Yue Hu. Genomic analysis of 207 rectal cancer samples. [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 2169. doi:10.1158/1538-7445.AM2015-2169
Abstract 2176: Joint structural variant analysis of colorectal cancer whole genome sequencing data
Authors: Pitkänen Esa , Cajuso Tatiana , Katainen Riku , Lundgren Sofie , Tuupanen Sari , Kilpivaara Outi , Aaltonen Lauri A. 
Published: August 2015

Abstract
Colorectal cancer (CRC) is one of the most common cancers, with over million cases and over 600,000 deaths each year in the world. It is estimated that a significant part of CRCs may have a hereditary compo-
nent, but majority of this heritability remains unexplained. Structural variants (SVs) comprise an important type of variation that, until the availability of deep-coverage whole-genome sequencing (WGS), has been hard to study in genome-wide scale. It has been suggested that a significant portion of unexplained, or “missing”, heritability could be explained by structural variants. Somatic structural aberrations are known to play a role in tumorigenesis and tumor progression. However, structural variation discovery is often complicated by low sequencing coverage, sequencing artifacts, repeat regions and errors of the reference genome.
To study the role of structural variation in CRC, we analyzed deep-coverage WGS data of matched tumor-normal sample pairs of 213 Finnish CRC patients and additional in-house WGS data. In these data, we identified both germline and somatic structural variants using a recent structural variant caller DELLY.
A novel algorithm was used to combine DELLY paired-end structural variant calls across normal and tumor samples to improve both sensitivity and specificity of variant detection. A total of 4,854,576 unfiltered structural events were identified, consisting of 2,912,552 deletions, 1,304,636 tandem duplications, 71,724 inversions and 565,664 interchromosomal translocations. To call high-confidence somatic events, we identified 475,902 structural events in tumors that were not present in any normal sample. Calling accuracy was further improved by annotating events by mappability and proximity to repeat regions. Our results demonstrate the applicability of integrating structural variant data across a large number of samples to obtain high-quality structural variant calls.
Citation Format: Esa Pitkänen, Tatiana Cajuso, Riku Katainen, Sofie Lundgren, Sari Tuupanen, Outi Kilpivaara, Lauri A. Aaltonen. Joint structural variant analysis of colorectal cancer whole genome sequencing data. [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 2176. doi:10.1158/1538-7445.AM2015-2176
Abstract 2194: p21Waf1/Cip1 dependent chromatin modifications in colorectal tumor cells
Authors: Lennert Pablo , Erlenbach-Wuensch Katharina , Kroeger Carsten , Steinmann Sara , Huebner Kerstin , Paul Sushmita , Rausch Felix , Hartmann Arndt , Schneider-Stock Regine 
Published: August 2015

Abstract
Objectives: The cell cycle regulator p21Waf1/Cip1 belongs to the family of cyclin-dependent kinase inhibitors (CDKIs). Depending on the cellular condition, p21Waf1/Cip1 can either, inhibit the cell cycle or promote proliferation, prohibit or induce apoptosis and increase or decrease cell differentiation. The contradictory nature of p21Waf1/Cip1 encouraged us to investigate the effects of this CDKI on the expression of chromatin modifying enzymes in colorectal tumor cells.
Methods: Three different HCT116 cell lines were used for our studies. HCT116 WT, HCT116 p21-/- and HCT116 p53-/-. The isolated RNA was analyzed via Epigenetic Chromatin Modification Enzymes RT2 Profiler PCR Arrays from Qiagen. Western Blot analysis was performed to verify the results of the PCR arrays. In addition, immunohistochemical staining of different chromatin modifiers was performed on tissue microarrays of colon cancer patients. The protein structure of p21Waf1/Cip1 was generated by computational modelling techniques to investigate possible interactions between p21Waf1/Cip1 and chromatin modifying enzymes. Ex vivo crypt organoids from WT and p21 -/- mice were studied for chromatin signature.
Results: The PCR arrays provided us with astonishing results. Compared to the wild type HCT116 cells, we could see a clear deregulation of a high number of different chromatin modifying enzymes in the two knock out cell lines. SETD1B was up-regulated 1,8 times in p21-/- and HDAC1, which is a known interaction partner of p21Waf1/Cip1, was down regulated about 2 times compared to the WT cells. This could also be proven by Western Blot and immunohistochemical analysis. The data was further processed and analyzed using an R package termed as HTqPCR and it was observed that ATF2 was up-regulated, while AURKB, different HDACs, and DNMT3B genes were down-regulated in p21-/- cells compared to the WT cells. The interaction between p21Waf1/Cip1 and HDAC1 could be analyzed on an atomic scale by molecular dynamics simulations.
Conclusion: Our data strongly suggests that p21Waf1/Cip1 is very important for chromatin regulation in colon cancer cells and that its loss induces an active histone code. Interestingly most p21-dependent effects were independent of p53. These exciting and new findings have to be further investigated.
Citation Format: Pablo Lennert, Katharina Erlenbach-Wuensch, Carsten Kroeger, Sara Steinmann, Kerstin Huebner, Sushmita Paul, Felix Rausch, Arndt Hartmann, Regine Schneider-Stock. p21Waf1/Cip1 dependent chromatin modifications in colorectal tumor cells. [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 2194. doi:10.1158/1538-7445.AM2015-2194
Abstract 2199: Evaluation of critical residues in the C-terminal binding protein (CtBP) dehydrogenase domain contributing to substrate binding, catalysis, and oncogenic activity
Authors: Morris Benjamin L. , Damle Priyadarshan , Nawaz Zaid , Grossman Steven R. 
Published: August 2015

Abstract
C-terminal binding proteins (CtBP) 1 and 2 are transcriptional coregulators that are upregulated in several cancers, including a majority of studied breast, colorectal, and ovarian tumor samples. CtBPs drive many cellular oncogenic properties, including migration, invasion, proliferation, and survival, in part through repression of tumor suppressor genes, such as E-cadherin, PTEN, BRCA1, and p16. CtBPs encode an intrinsic dehydrogenase activity regulated by both intracellular NADH concentration and the putative substrate 4-methylthio-2-oxobutyric acid (MTOB). NADH binding induces CtBP dimerization, which regulates the recruitment of transcriptional regulatory complexes. High levels of MTOB appear to inhibit CtBP dehydrogenase function and induce cytotoxicity among cancer cells in a CtBP-dependent manner. However, the function of the substrate-binding domain has yet to be examined with regard to CtBP's oncogenic activity. To this end, we have created several point mutations in the substrate-binding pocket of CtBP and have determined key residues for CtBP's enzymatic activity using an in vitro dehydrogenase assay. We have found that a conserved tryptophan in the catalytic domain, and specifically its aromatic moiety, is imperative for enzyme activity. This tryptophan is unique to CtBP family proteins and distinguishes the CtBP substrate-binding domain from that of all other families of dehydrogenases. Additionally, we found arginine and histidine residues lining the substrate pocket that are necessary for CtBP dehydrogenase function. Knowledge of these residues allows the directed synthesis of drugs with increased potency and higher CtBP specificity. Moreover, to investigate the importance of the catalytic domain on CtBP's oncogenic potential, we have transfected human cancer cell lines with several CtBP substrate-binding domain mutants and observed the effects on cellular processes, including growth, survival, migration, and recruitment of key components of the transcriptional repressor complex. From this work we have investigated the utility of CtBP, and specifically the CtBP substrate-binding domain, as a target for cancer therapeutics. We also provide preliminary insights into the function of this domain in cellular models of cancer.
Citation Format: Benjamin L. Morris, Priyadarshan Damle, Zaid Nawaz, Steven R. Grossman. Evaluation of critical residues in the C-terminal binding protein (CtBP) dehydrogenase domain contributing to substrate binding, catalysis, and oncogenic activity. [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 2199. doi:10.1158/1538-7445.AM2015-2199
Abstract 22: Genetic re-programming of the acute myeloid leukemia cell line HL-60: Regulation of cell proliferation, differentiation, and programmed cell death
Authors: Roberts Michael , Holbert Cassandra , Ghoto Mansoor , Schneider Juliana , Marriott Abigail , Forrester Jeffrey 
Published: August 2015

Abstract
The human acute myeloid leukemia cell line, HL-60, in response to phorbol esters, undergoes genetic re-programming leading to cell cycle arrest, macrophage differentiation, and apoptosis. The induced program overrides the oncogenic mutations driving the leukemia program, illustrating that changes in gene expression can reverse the cancer phenotype. Whole genome exon DNA microarray analyses identifies 1260 genes whose RNA expression levels change significantly during the reprogramming. We define a subset of 186 genes functionally assigned to the biological processes of regulation of cell proliferation, differentiation, and/or programmed cell death showing specific temporal expression patterns, and suggest that a subset of these genes, which are down-regulated during the reversal of the leukemia phenotype while showing overexpression in AML patient samples, may represent new therapeutic targets in AML. Among the genes showing immediate early up-regulation (2-fold or greater by one hour post-PMA treatment), promoter analysis reveals highly significant overrepresentation of binding sites for the transcription factors STAT5A, HIF1A and NF-kB. Delayed early up-regulated genes (2-fold or greater by three hours post-PMA treatment), have promoters highly enriched in binding sites for EGR1, SP1:SP3, ZFP206 and E2F4. A phorbol ester response “signature” related to reversal of the leukemic phenotype and initiation of apoptosis has been defined and examined in two additional AML cell lines (THP-1 and Kasumi-1). Among the significantly up-regulated genes are MCL1, CDKN1A, NR4A1, and BCL6. Down-regulated genes include MYC, KIT, LGALS12, and ZBTB16. HL-60 cell lines with CRISPR-mediated knockouts of several of these genes are currently being evaluated for their effects on the leukemic phenotype and phorbol ester-induced apoptosis.
Citation Format: Michael Roberts, Cassandra Holbert, Mansoor Ghoto, Juliana Schneider, Abigail Marriott, Jeffrey Forrester. Genetic re-programming of the acute myeloid leukemia cell line HL-60: Regulation of cell proliferation, differentiation, and programmed cell death. [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 22. doi:10.1158/1538-7445.AM2015-22