bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 213: Evaluating high risk BI-RADS 4 mammographic lesions: a pilot trial of textural analysis (TA) as a supplement to digital mammography (DM)
Authors: Gordon Melissa R. , Borazanci Erkut , Maki Daniel D. , Korn Ron L. 
Published: August 2015

Abstract
Background: Although mammographic lesions classified as BI-RADS 4 are considered suspicious for carcinoma - by definition - and biopsy (bx) is therefore always recommended, only 20-30% of such lesions ultimately yield malignancy at biopsy. TA is an ancillary non-subjective quantitative analysis platform that can be performed as an add-on to routine mammographic analysis. The ability of TA to characterize lesions with high rates of heterogeneity led us to hypothesize that TA, as a supplement to routine DM analysis, might aid in selecting patients (pts) for bx vs. serial observation.
Methods: A retrospective analysis was performed on 40 screening pts with no history of cancer, with newly identified mammographic densities characterized as BI-RADS 4. Lesions measured 1-3 cm size and had no associated microcalcifications. Twenty pts had confirmed malignant biopsy while the other 20 pts served as age matched controls with similar lesion characteristics but ultimate benign biopsy result. For each lesion, TA was performed on a 1×1cm region of interest (ROI), along with a secondary control ROI of normal breast tissue.
Results: Pts with malignant and benign bx had a median age of 53 years (range 28-83) vs. 52 years (range 32-75) (p = NS) and median nodule size 1.5 cm (range 1.0-2.9 cm) vs. 1.3 cm (range 1.0-2.5 cm) (p = NS), respectively. No differences between the groups were seen in menopausal status nor parenchymal density. The mean positive pixel (MPP) value was most predictive of malignancies at a Spatial Scale Frequency (SSF) filter level of 0.8. The median MPP for malignant lesions was 577 vs 730 for benign lesions (p = 0.033). There was no difference between MPP or other TA parameters in normal tissue of either group.
Conclusion: TA, as a supplement to DM, may help stratify which women with high-risk BI-RADS 4 densities that better benefit from biopsy vs. those that might be safely followed with serial surveillance. Larger scale studies will be needed to validate these findings and are currently ongoing.
Citation Format: Melissa R. Gordon, Erkut Borazanci, Daniel D. Maki, Ron L. Korn. Evaluating high risk BI-RADS 4 mammographic lesions: a pilot trial of textural analysis (TA) as a supplement to digital mammography (DM). [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 213. doi:10.1158/1538-7445.AM2015-213
Abstract 2136: Correlating the expression of protein kinase C isozymes with the transformed phenotype in colorectal cancer
Authors: Dowling Catríona M. , Phelan James J. , Cathcart Mary Clare , Mehigan Brian , McCormick Paul , Dalton Tara , Coffey John C. , O'Sullivan Jacintha , Kiely Patrick A. 
Published: August 2015

Abstract
Protein Kinase C (PKC) is a family of serine/threonine kinases that are involved in almost every signal transduction cascade in cells. PKC enzymes are activated by second messangers and respond to specific environmental cues. The development of PKC modulators with anti-cancer therapeutic potential is a major target in cancer. However, this task is made difficult because PKC has an important role to play in normal processes and the PKC family consists of at least 9 different isozymes. Our hypothesis is that PKC expression, activity and localisation are altered as colon epithelial cells switch from normal to the transformed state. We are confident that being able to recognise these changes has the potential to be used as a biomarker and prognostic marker in the early detection of colon cancer.
Real Time PCR was utilised to compare the gene expression profile of 9 PKC isozymes in matched normal and cancer tissue samples. We found differential expression of the conventional PKCs, with PRKCB (the gene coding for PKC Beta II) being significantly downregulated in the cancer tissue of over 90% of patients (p&lt;0.01,n = 22). This change was closely linked to the progression of the disease. Using tissue microarrays, we also demonstrated significant alterations in both epithelial and stromal levels of PKC Beta II between the patients normal and diseased tissue. The level of PKC Beta II in the diseased tissue was significantly decreased across patients (p&lt;0.01,n = 164) and we associate the decreased expression with tumour stage. In conclusion we suggest that differential expression of PKC Beta II may be an important mechanism regulating the change to the transformed phenotype in colon cancer.
Citation Format: Catríona M. Dowling, James J. Phelan, Mary Clare Cathcart, Brian Mehigan, Paul McCormick, Tara Dalton, John C. Coffey, Jacintha O'Sullivan, Patrick A. Kiely. Correlating the expression of protein kinase C isozymes with the transformed phenotype in 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 2136. doi:10.1158/1538-7445.AM2015-2136
Abstract 2137: The effect of the transcription factor MAZ on kRAS transcription: a role for the G-quadruplex
Authors: Batra Harshul , Brooks Tracy A. 
Published: August 2015

Abstract
kRAS is a GTPase protein affecting normal cell proliferation, division, and apoptosis. It is mutated in &gt;30% of all cancers, particularly in 60-90% of pancreatic cancers. Mutated kRAS leads to continuous activity and uncontrolled proliferation. To date there have been no successful clinical agents targeting mutant kRAS activity. Modulating kRAS expression has shown anti-proliferative promise as an approach in pancreatic cancer models, but is not a main avenue of pursuit for clinical development due to lack of a molecular target. Our lab is focused on the regulation of kRAS transcription through a variety of G-rich regions of DNA in the promoter capable of forming non-B-DNA structures termed G-quadruplexes (G4s). In the current study, we sought to determine the effect of the transcription factor MAZ on the regulation of kRAS, with a particular focus on the three putative G4-forming regions (herein termed near, mid, and far in reference to their relative proximity to the transcriptional start site). In a study of the kRAS promoter using a series of luciferase plasmids, MAZ expression led to a concentration-dependent decrease in promoter activity. This action was localized to interactions with the mid-G4-forming region. In the context of a more multifaceted intracellular mileu as found in the pancreatic cancer cell lines MiaPaCa-2, Panc-1, and BxPc3, the effects of MAZ were much more complex. In particular, 48 hr post-transfection with MAZ expression plasmids, monitoring of kRAS transcription revealed a cell line-specific modulation with an increase in kRAS expression in Panc-1 cells only, confirming a previous study, and no changes noted in either the MiaPaCa-2 or the Bx-Pc3 cells. Further studies are ongoing evaluating the direct binding of MAZ to the various G-rich regions in those cell lines, as well as determining the DNA structure (single-stranded, double-stranded, or G4-DNA) to which the MAZ protein is binding. Ultimately, an understanding of the regulation of this G-rich region of DNA, by MAZ or any other transcription factors such as Sp1 or p53, is an important part of the larger puzzle leading to a targeted drug discovery program focused on G4-regulation. Ultimately, G4-stabilization-mediated down regulation of kRAS has high potential for anti-cancer efficacy in pancreatic cancers, where there is a dire need for novel therapeutic development.
Citation Format: Harshul Batra, Tracy A. Brooks. The effect of the transcription factor MAZ on kRAS transcription: a role for the G-quadruplex. [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 2137. doi:10.1158/1538-7445.AM2015-2137
Abstract 2143: A 3D system to elucidate a direct role for epiregulin mistrafficking in epithelial transformation
Authors: Singh Bhuminder , Bogatcheva Galina , Coffey Robert J. 
Published: August 2015

Abstract
The EGF receptor (EGFR) ligand epiregulin (EREG) is delivered preferentially to the basolateral cell surface of polarized MDCK cells. Previously, we showed that EREG basolateral trafficking is regulated by a conserved tyrosine residue within a YXXΦ motif (Y156ERV) in its cytoplasmic domain. Interestingly, a Y156A substitution led to apical mistrafficking of EREG and transformation of polarized MDCK cells (PNAS 110: 8960-5, 2013). We have identified an EREG mutation (R147stop) in human tumors that we now report mistrafficks to the apical surface. To test the hypothesis that apical mistrafficking of EREG can be a driver event, we have generated MDCK cells stably expressing inducible (Tet-ON) wild-type and Y156A mutant EREG. In 3D Matrigel cultures, we show that uninduced clones form normal-appearing cysts, regardless of EREG status. Induction of WT or mutant EREG leads to increased cyst diameter. However, only (Y156A)EREG-expressing cells form abnormal cysts with ectopic lumens and inward growth, features of in vivo transformation. Furthermore, we show that ligand processing and EGFR activity is required for EREG mistrafficking-induced ectopic lumen formation as preincubation with a broad-spectrum metalloprotease inhibitor, BB-94, abrogates ectopic lumen formation. We have extended these studies to polarizing human colon cancer cells, HCA-7, which preserve the trafficking fidelity of WT and mutant EREG. Furthermore, using EREG cytoplasmic domain as a bait in a yeast-2-hybrid screen, we have identified APOBEC3C as an interacting protein. APOBECs are a family of cytidine deaminases that have been identified as a major contributor to human cancer mutations. We have subsequently confirmed EREG-APOBEC3C interaction by co-immunoprecipitation. Results from MDCK cells stably expressing differentially inducible EREG (Tet-ON) and APOBEC3C (Cumate-ON) will be presented.
Note: This abstract was not presented at the meeting.
Citation Format: Bhuminder Singh, Galina Bogatcheva, Robert J. Coffey. A 3D system to elucidate a direct role for epiregulin mistrafficking in epithelial transformation. [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 2143. doi:10.1158/1538-7445.AM2015-2143
Abstract 2148: Ras-mediated evasion of detachment-induced cell death involves differential signaling pathways for metabolism and anoikis
Authors: Mason Joshua A. , Versagli Calli , Leliaert Amy , Durbin Sienna , Buchheit Cassandra , Schafer Zachary 
Published: August 2015

Abstract
In order for successful metastasis to occur, cells must overcome anoikis, a caspase-dependent cell death process triggered by detachment from the extracellular matrix (ECM). In addition, recent studies have revealed that ECM-detached cells must also rectify detachment-induced metabolic defects that compromise cell survival. However, the precise signals involved in the inhibition of anoikis and the restoration of proper cell metabolism during ECM-detachment are poorly understood. Of particular interest to our studies is the oncogene Ras, which is constitutively active in approximately 30% of all cancers and is well known to be regulate cell death pathways and metabolism. We have discovered that Ras facilitates the survival of ECM-detached cancer cells by utilizing distinct signaling pathways to block anoikis and regulate metabolism.
Using MCF-10A cells engineered to overexpress oncogenic Ras and HCT116 cells (which contain an activating Ras mutation), we investigated the signaling pathways downstream of Ras that facilitate the survival of ECM-detached cells. Interestingly, we discovered that while Ras-mediated PI(3)K signaling is critical for rectifying metabolic defects during ECM-detachment, the downstream effector is not Akt, but rather SGK-1. SGK-1 stimulates glucose uptake, enhances ATP generation, promotes luminal filling in 3-dimensional cell culture, and drives anchorage-independent growth in soft agar. Interestingly, our data also indicate that oncogenic Ras utilizes an entirely distinct signaling pathway to block anoikis. We discovered that Ras diminishes the expression of the phosphatase PHLPP1. This inhibits the dephosphorylation-induced activation of a signaling cascade that culminates in the activation of pro-apoptotic p38 MAPK. In aggregate, these data unveil a novel survival strategy utilized by ECM-detached cancer cells and implicate both SGK-1 and PHLPP1 function downstream of Ras during ECM-detachment. The molecular mechanisms unveiled here could be utilized for the design of novel therapies that eliminate ECM-detached, metastatic cancer cells with Ras mutations through simultaneous modulation of SGK-1 and PHLPP1.
Citation Format: Joshua A. Mason, Calli Versagli, Amy Leliaert, Sienna Durbin, Cassandra Buchheit, Zachary Schafer. Ras-mediated evasion of detachment-induced cell death involves differential signaling pathways for metabolism and anoikis. [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 2148. doi:10.1158/1538-7445.AM2015-2148
Abstract 2151: Development of reference reagents to accelerate research on the RAS pathway
Authors: Esposito Dominic 
Published: August 2015

Abstract
The Ras Reference Reagents program within the NCI national Ras mission is designed to produce and distribute qualified DNA vectors, cell lines, and viruses to supply to the external community to facilitate research into Ras biology and development of Ras cancer therapeutics. Initial sets of reagents include sequence-verified libraries of Ras mutants and Ras pathway genes in Gateway combinatorial cloning vectors in multiple formats. An associated library of combinatorial components is also available to permit simple generation of expression vectors with various promoters, fusion tags, and plasmid backbones. Additional reagents under construction validated plasmid and lentiviral reagents for shRNA and CRISPR delivery, qualified cell lines, and systems for the generation of highly purified and characterized Ras and Ras-related proteins. All of these resources are readily available to the academic community through simple mechanisms, and can be licensed to industry as well. The Ras Reference Reagents program is also interested in identifying the needs of the community for additional Ras-related resources, and is developing methods for vetting requests from the outside to provide additional reagents.
Citation Format: Dominic Esposito. Development of reference reagents to accelerate research on the RAS pathway. [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 2151. doi:10.1158/1538-7445.AM2015-2151
Abstract 2156: FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis
Authors: Huang Yuan-Ling , Chou Wen-Cheng , Hsiung Chia-Ni , Hu Ling-Yueh , Chu Hou-Wei , Shen Chen-Yang 
Published: August 2015

Abstract
Purpose: The association between breast cancer risk and genetic variants of fibroblast growth factor receptor 2 (FGFR2) has been identified and repeatedly confirmed; however, the mechanism underlying FGFR2 in breast tumorigenesis remains obscure. Given that breast tumorigenesis is particularly related to DNA double-strand-break-repair (DSBR), we examined the hypothesis that FGFR2 is involved in DSBR.
Experimental design: This study started with the demonstration that FGFR2 impaired DSBR. Subsequent screening of the expression of genes functionally related to DSBR was performed and possible signaling pathways downstream of FGFR2 were examined. Data from independent breast cancer patient cohorts was used to confirm that difference in progression of patients can be explained by the findings identified in cell model.
Results: Expression of Mre11, a vital exonuclease in DSBR, is downregulated by FGFR2, which is further linked to decreased DSBR. Analysis of the Mre11 promoter revealed that POU1F1 mediates FGFR2-induced Mre11 downregulation. Furthermore, ERK, downstream of FGFR2, directly interacts with and phosphorylates POU1F1, increasing POU1F1 binding capacity to the Mre11 promoter and repressing Mre11 expression, which consequently affects DSBR and sensitizes breast cancer cells to chemotherapeutic treatments. The importance of the FGFR2-Mre11-DSBR link in cancer progression is suggested by the finding that genotypes of FGFR2 and Mre11 are associated with survival of breast cancer patients and that FGFR2 expression correlates with cancer prognosis specifically in patients receiving chemotherapy.
Conclusion: This study yields important insight into the role of FGFR2 in breast tumorigenesis and may facilitate development of a useful therapeutic approach for breast cancer. With the move toward personalized therapy, which has gradually become a clinical reality, the findings of the present study suggest that FGFR2 expression may be a potential biomarker for selecting a suitable subgroup of breast cancer patients to receive chemotherapy or to determine the optimal chemotherapeutic dose.
Citation Format: Yuan-Ling Huang, Wen-Cheng Chou, Chia-Ni Hsiung, Ling-Yueh Hu, Hou-Wei Chu, Chen-Yang Shen. FGFR2 regulates Mre11 expression and double-strand break repair via the MEK-ERK-POU1F1 pathway in breast tumorigenesis. [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 2156. doi:10.1158/1538-7445.AM2015-2156
Abstract 2157: PI3K/AKT-induced stabilization of FUSE binding proteins (FBPs) in liver cancer cells
Authors: Samarin Jana , Stein Ilan , Horwitz Elad , Chen Xin , Malz Mona , Pikarsky Eli , Calvisi Diego , Schirmacher Peter , Breuhahn Kai 
Published: August 2015

Abstract
Far upstream element-binding proteins (FBPs) represent a family of transcription factors, which are highly overexpressed in the majority human liver cancer (hepatocellular carcinoma; HCC). Nuclear accumulation of FBP-1, -2, and -3 in HCC cells support cell proliferation and migration. However, the mode of FBP dysregulation in HCC cells has not been defined so far.
Genomic alterations of the fubp (FBP-1; chr. 1p31.1), khsrp (FBP-2; chr. 19.p13.3), and fubp3 (FBP-3; 9p34.11) gene loci in primary human HCCs were determined by matrix-comparative genomic hybridization (CGH). In order to identify specific stimuli of FBP enrichment, different human HCC cell lines were cultured under different cell density and hypoxic conditions or treated with growth factors (e.g., TGFß, IGF-II), chemical inhibitors (e.g., AG1478, SB203580, MEK1/2, sorafenib, and PI3K inhibitors), and gene-specific siRNAs (e.g., Akt1-3, rictor, raptor). The in vivo relevance of the findings was confirmed using HCC mouse models (e.g., Mdr2-/- animals) and human HCC tissue specimens (immunohistochemistry and western blotting).
Only few genomic gains were found for all FBP family members in human HCC samples (e.g., 6% for fubp). In vitro, inhibition of EGFR (by AG1478) or administration of the multi-kinase inhibitor sorafenib reduced FBP protein levels. Furthermore, inhibition of the PI3K/Akt/mTOR pathway revealed strong effects on FBP protein half-live without significant impact on FBP transcription. Other pathways or stimuli only caused minor effects on FBP expression (e.g., p38 or Raf1 inhibition). These findings were confirmed in mouse HCC models with high-level expression of FBPs, where injection of sorafenib or rapamycin significantly diminished FBP amounts. Reduction of FBP concentrations after inhibition of the PI3K/Akt/mTOR pathway was rescued after inhibition of caspase-3/-7 activity. Lastly, a significant correlation between pAkt and nuclear FBP expression was detected in human HCC tissues.
These results demonstrate that activation of the PI3K/Akt/mTOR signalling axis is responsible for increased stabilisation of FBPs in human HCC cells. Elevated FBP half-live is at least partly mediated through crosstalk between the PI3K/Akt/mTOR pathway and caspase activity. These data are important for a deeper understanding of how druggable upstream regulators may affect FBP bioavailability in hepatocarcinogenesis.
Citation Format: Jana Samarin, Ilan Stein, Elad Horwitz, Xin Chen, Mona Malz, Eli Pikarsky, Diego Calvisi, Peter Schirmacher, Kai Breuhahn. PI3K/AKT-induced stabilization of FUSE binding proteins (FBPs) in liver cancer 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 2157. doi:10.1158/1538-7445.AM2015-2157
Abstract 2173: Robust estimation of mutation burden
Authors: Westesson Oscar , Nielsen Rasmus , St John John , Caulin Aleah , Hahner Nicholas , Stewart Stewart , Foo Catherine , Lung Kimberly , Catalano Jeff , Lee Mandy , Giannikopoulos Petros , Polkinghorn Will , Wiessman Jonathan , Regev Aviv , Bivona Trever 
Published: August 2015

Abstract
Developing a more robust approach to measure mutational burden is of central importance to improving the characterization of the molecular profile of tumor and may improve our ability to predict tumor progression or response to therapy in patients. Mutational burden is typically calculated as a direct enumeration of called somatic mutations per megabase covered. However, there is a growing appreciation that tumor purity, variable sequencing coverage, and copy number alterations can substantially impact the accurate identification any specific somatic mutation. Furthermore, population genetic theory and empirical data indicate that in many cases the vast majority of somatic mutations appear in only a small subpopulation of tumor cells, a context in which there is a high likelihood that an individual subclonal mutation may not be identified by conventional analysis. This tendency to miss low frequency mutations is highly variable and dependent, in part, upon sample purity and results in a strong source of bias not addressed in existing methods to measure variant allele frequencies.
We present a novel computational method that incorporates these sources of bias in a coherent probabilistic framework that enables maximum-likelihood inference of relevant population parameters such as mutation burden. We apply our method to simulated data as well as patient tumor samples diluted with varying known proportions of normal DNA. We show that our approach allows us to generate estimates of mutation burden that are robust to the substantial variations in purity and sequencing coverage that are frequently encountered in patient tumor analysis. Hence, our novel method may improve the accurate detection and quantification of variant alleles in patient tumors to better understand their genetic landscape and guide clinical management.
Citation Format: Oscar Westesson, Rasmus Nielsen, John St John, Aleah Caulin, Nicholas Hahner, Stewart Stewart, Catherine Foo, Kimberly Lung, Jeff Catalano, Mandy Lee, Petros Giannikopoulos, Will Polkinghorn, Jonathan Wiessman, Aviv Regev, Trever Bivona. Robust estimation of mutation burden. [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 2173. doi:10.1158/1538-7445.AM2015-2173