bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B1-29: The effect of higher-order receptor clusters on TRAIL induced apoptotic signaling
Authors: Raue Andreas , Chai Diana , Hudson Hannah , Tam Eric , Schoeberl Birgit 
Published: May 2016

Abstract
The trimeric TNF-related apoptosis-inducing ligand (TRAIL) is an endogenous ligand that binds to trimeric death receptors (DR4/5). TRAIL is known to induce apoptosis mainly in malignant cells while normal cells remain unaffected. This makes TRAIL a most interesting target for cancer therapy.
We investigate the effects of ligand valency on the degree of Caspase-8 activation and apoptosis induction. As a model system we use the semi-sensitive cell line DU145 and multivalent anti-DR5 fibronectin domains that can potentially form higher-order receptor clusters. In order to disentangle the effects of receptor clusters of different size, a dynamic model of ligand-receptor binding and Caspase-8 activation is coupled to a model of cell growth and cell death. The dynamic model is calibrated using quantitative experimental data of ligand on cell binding, Caspase-8 activity and cell viability.
Our results show that higher-order receptor clusters do amplify apoptotic signaling. The model predicts that receptor clusters of size three and six are more abundant than others, indicating the special role of preformed receptor trimers. However, Caspase-8 activation only increases after receptor clusters of size larger than three. On the cell population level, the model can quantitatively predict the induction of apoptosis in this cell line. This work is an important step towards an integrative model of TRAIL induced apoptosis that finally aims at the understanding of heterogeneity both on a single cell level across cell lines.
Citation Format: Andreas Raue, Diana Chai, Hannah Hudson, Eric Tam, Birgit Schoeberl. The effect of higher-order receptor clusters on TRAIL induced apoptotic signaling. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-29.
Abstract B1-46: How collection, processing and storage of PBL samples impact the measurement of telomerase activity
Authors: Johnson Ruth A. , Druliner Brooke R. , Alleto Jill Washechek , Devine Donna Felmlee , Ruan Xiaoyang , Vanderboom Russell , Boardman Lisa A. 
Published: May 2016

Abstract
Introduction: Activation of telomerase and telomere lengthening in patient peripheral blood leukocytes (PBL) is associated with longer survival in cancer patients. There are few studies to date that have measured telomerase activity in clinical PBL samples, and it is unclear how initial collection and processing of PBL samples impact the measurement of telomerase activity. In this study, we assessed if telomerase activity measurement varies based on the method of blood collection, processing and storage.
Methods: We first collected whole blood drawn in EDTA tubes from two healthy patients that were then processed three different ways. The first whole blood sample was spun down and the buffy coat was pipetted from the top of the red blood cells, and then placed directly into the -80°C freezer. The next two whole blood samples were isolated using an ACCUSPIN™ tube, which utilizes density gradient separation to recover the PBL without contamination of red blood cells. The resulting PBL from these two samples were suspended in freezing media containing RPMI and DMSO, with one sample also containing penicillin streptomycin glutamine, and then both samples were stored in liquid nitrogen following a slow freeze. We then measured enzymatic telomerase activity in each of the three PBL samples from the two different patients.
Results: We detected a comparable level of telomerase activity in all three PBL samples. These findings indicate that telomerase activity can be measured in buffy coat samples from patients independent of how the samples were processed and stored.
Conclusions: These findings are important because many biorepositories may not have collected or processed PBL samples by identical processes, therefore not allowing direct comparison across samples. Additionally, our finding that telomerase activity levels are comparable between PBL samples containing red blood cells and those processed using an ACCUSPIN™ tube is valuable because it eliminates the necessity for the extra cost of the ACCUSPIN™ tube, freezing media, antibiotics and use of liquid nitrogen storage tanks. Future studies will focus on the determining the relationship of telomerase activity between the PBL, normal colon and cancer tissue in colorectal cancer patients.
Citation Format: Ruth A. Johnson, Brooke R. Druliner, Jill Washechek Alleto, Donna Felmlee Devine, Xiaoyang Ruan, Russell Vanderboom, Lisa A. Boardman. How collection, processing and storage of PBL samples impact the measurement of telomerase activity. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-46.
Abstract B1-52: Analysis of the iCOGS breast cancer GWAS reveals 4 unique signals in the PTHLH region in patients of European origin
Authors: Freeman Adam N. , Martin T John , Henderson Michael A. , Makalic Enes , Kapuscinski Miroslaw K. , Schmidt Daniel F. , Hopper John 
Published: May 2016

Abstract
Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in breast cancer. Its expression is thought to favour and, potentially, facilitate metastasis to bone. Paradoxically, a prospective clinical study clinical suggests that its production in primary breast cancers is actually protective, affording a better prognosis than its absence. Multiple recent Genome-Wide Association Studies (GWAS) have confirmed a single susceptibility locus immediately upstream of the PTHLH gene to be associated with breast cancer. This was again reproduced in the recent iCOGS GWAS, which involved over 90,000 European subjects. In spite of a single SNP, rs10771399, being uniquely reported and reproduced by prior studies, we demonstrate 4 discrete overlapping signals by utilising forward selection logistic regression and LASSO techniques. Two of these signals are centred and superimposed around rs10771399, ~40kbp upstream of PTHLH, a third lies a further 100kbp upstream, and the fourth lies a further 250kbp upstream over the next gene, CCDC91. While the causation of this signal remains elusive, multiple putatively contributory variations are captured by these signals.
Citation Format: Adam N. Freeman, T John Martin, Michael A. Henderson, Enes Makalic, Miroslaw K. Kapuscinski, Daniel F. Schmidt, John Hopper. Analysis of the iCOGS breast cancer GWAS reveals 4 unique signals in the PTHLH region in patients of European origin. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-52.
Abstract B2-03: Inferred miRNA activity identifies miRNA-mediated regulatory networks underlying multiple cancers
Authors: Lee Eunjee , Ito Koichi , Schadt Eric E. , Irie Hanna Y. , Zhu Jun 
Published: May 2016

Abstract
MicroRNAs (miRNAs) play a key role in regulating tumor progression and metastasis. However, miRNA's activity can't be measured by its expression level. We developed a computational approach, ActMiR, for identifying active miRNAs and miRNA-mediated regulatory mechanisms. Applying ActMiR to four cancer datasets in The Cancer Genome Atlas (TCGA), we showed that (1) miRNA activity was tumor subtype specific; (2) genes correlated with inferred miRNA activities were more likely to enrich for miRNA binding motifs; (3) expression levels of these genes and inferred miRNA activities were more likely to be negatively correlated. For the four cancer types in TCGA we identified 64~203 key miRNAs for each cancer subtype and annotated their biological functions. For ER-/HER2- breast cancers we identified activities of key miRNAs let-7d and miR-18a as potential prognostic markers and validated them in two independent ER-/HER2- breast cancer data sets. We experimentally validated their causal relationships with their target genes. Similarly, we showed that key miRNA activities but no miRNA expression level were consistently associated with clinical outcomes for other cancer types. Taken together, the inferred activity of key miRNA provided a functional link to its mediated regulatory network, and can be used to robustly predict patient's survival.
Citation Format: Eunjee Lee, Koichi Ito, Eric E. Schadt, Hanna Y. Irie, Jun Zhu. Inferred miRNA activity identifies miRNA-mediated regulatory networks underlying multiple cancers. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-03.
Abstract B2-10: Systems biology reveals role of cholesterol homeostasis in breast cancer metastasis
Authors: Zhao Weina , Sara Prijic , Urban Bettina , Tisza Michael , Mani Sendurai A. , Chang Jeffrey T. 
Published: May 2016

Abstract
New therapeutic targets that can inhibit cancer metastasis are desperately needed. To address this issue, we have leveraged a computational approach and performed an unbiased screen for therapies that can inhibit an epithelial-to-mesenchymal transition (EMT) gene expression profile, a phenotype that is believed to promote metastases. This yielded predictions of drugs that can both promote and inhibit an EMT transcriptional profile. Following up on these predictions, we confirmed experimentally that these drugs can induce or repress an EMT in a range of breast cancer cell lines. Furthermore, we discovered that they do so by altering the fluidity of the plasma membrane. An increase in plasma membrane fluidity is necessary and sufficient to induce and maintain an EMT state, increased motility, and increased mammosphere forming ability. Finally, we found that human cancers can regulate their membrane fluidity through cholesterol homeostasis pathways. Human breast tumors with altered cholesterol profiles have a significantly shorter time to metastasis. These data demonstrate that an unbiased systems approach can be used to discover novel pathways that underlie metastasis. Our multidisciplinary approach combining computational, cell biology, and mouse models reveal that plasma membrane fluidity is a cellular attribute that is leveraged by human tumors to increase metastatic capacity, and that it can, in principle, be targeted by therapeutics to prevent metastasis.
Citation Format: Weina Zhao, Prijic Sara, Bettina Urban, Michael Tisza, Sendurai A. Mani, Jeffrey T. Chang. Systems biology reveals role of cholesterol homeostasis in breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-10.
Abstract B2-29: The reverse control of colorectal tumorigenesis based on Boolean network modeling of human signaling network
Authors: Sung-Hwan Cho , Sang-Min Park , Ho-Sung Lee , Hwang-Yeol Lee , Kwang-Hyun Cho 
Published: May 2016

Abstract
The intracellular processes are governed by a signal transduction network composed of complex interactions of a number of signaling proteins and various human diseases including cancer are known to be caused by the rewiring of the complex signaling network owing to the individual genetic mutations. There have been many studies on the dynamical analysis of the human signaling network to investigate the progression mechanism of human diseases, but most of the results were limited to small-scale signaling pathways. In this study, we have reconstructed a large-scale signaling network model composed of 197 nodes and 745 relations based on Boolean modeling and performed attractor landscape analysis to uncover the mechanism of colorectal tumorigenesis caused by driver mutations. In addition, we have investigated the reverse control of tumorigenesis by changing the attractor landscape of colorectal cancer state that has been deformed by the driver mutations. Our results show that colorectal tumorigenesis can occur by the expansion of the cancer attractor basin due to the accumulation of driver mutations. We found a minimal control set of network components that can reverse the cancerous state into a normal state. Together, these results suggest a new therapeutic strategy for the treatment of colorectal cancer and provide a new insight into the drug target excavation.
Acknowledgement: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Government, the Ministry of Science, ICT & Future Planning (2014R1A2A1A10052404, 2013M3A9A7046303, and 2010-0017662).
Citation Format: Cho Sung-Hwan, Park Sang-Min, Lee Ho-Sung, Lee Hwang-Yeol, Cho Kwang-Hyun. The reverse control of colorectal tumorigenesis based on Boolean network modeling of human signaling network. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-29.
Abstract IA24: Computational dissection of phenotypic and functional heterogeneity in cancer
Authors: Pe'er Dana 
Published: May 2016

Abstract
Cells within a single tumor are known to display extensive phenotypic and functional heterogeneity. Many life-threatening features of cancer, including drug resistance, metastasis and relapse, are facets of intratumor heterogeneity. With emerging single-cell measurement technologies, the field is poised to make important strides in understanding and controlling this heterogeneity. However, these technologies require advances in analytical methods to interpret the complex data they produce. Using mass cytometry, which measures single cells in ~31 simultaneous proteomic features, we developed novel methods for analyzing phenotypic heterogeneity in cancer. We use AML as an example to demonstrate the power of our approach. The heart of our approach is Phenograph, a graph-based representation of single-cells which represents the phenotypic structure of the sample and can be partitioned into subsets of densely interconnected nodes, called communities. Using Phenograph, we deconstructed several AML samples into discrete phenotypes. Analyzing the resulting subpopulations provided insights into functional heterogeneity of AML. Phenograph can be applied to characterize heterogeneity and primitive subpopulations in additional cancers.
Citation Format: Dana Pe'er. Computational dissection of phenotypic and functional heterogeneity in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr IA24.
Abstract PR06: Nucleation of transcriptional super-enhancers at tumor oncogenes
Authors: Abraham Brian J. , Kwiatkowski Nicholas , Weintraub Abraham S. , Hnisz Denes , Hannett Nancy , Young Richard A. 
Published: May 2016

Abstract
Transcriptional super-enhancers drive expression of oncogenes in many cancers and are being targeted with novel transcriptional and epigenetic therapeutics (1,2,3,4). Super-enhancers are acquired in cancers through multiple mechanisms, including DNA translocation of an extant super-enhancer and focal amplification. We recently discovered a novel mechanism by which super-enhancers are nucleated in T cell acute lymphoblastic leukemias (T-ALLs) (5). In this case, a small, monoallelic insertion creates a DNA binding site for a master transcription factor protein, which binds and recruits additional factors to nucleate the super-enhancer, which in turn drives high levels of the TAL1 transcription factor. We describe here a method for unbiased identification of similar genomic insertions that nucleate potentially oncogenic regulatory elements in cancers. This approach uses data from genome-wide ChIP-Seq studies that map locations of enhancer-binding proteins to identify sequences missing from reference genomes. We have found many additional genomic insertions in many additional cancers. I will describe new insights into the regulation of cancer that occur due to nucleation of novel regulatory elements.
1 Hnisz, Abraham, Lee, et al., Cell 2013
2 Loven, Hoke, Lin, et al., Cell 2013
3 Kwiatkowski, et al., Nature, 2014
4 Chipumoro, et al., Cell, 2014
5 Mansour et al., Science 2014
Citation Format: Brian J. Abraham, Nicholas Kwiatkowski, Abraham S. Weintraub, Denes Hnisz, Nancy Hannett, Richard A. Young. Nucleation of transcriptional super-enhancers at tumor oncogenes. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr PR06.
Abstract IA02: Genome regulation by long noncoding RNAs
Authors: Chang Howard Y. 
Published: May 2016

Abstract
The discovery of extensive transcription of long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation. I will discuss genome-scale strategies to discover and characterize lncRNAs. Genome-wide mapping of RNA secondary structures, termed the structurome, provides important clues to potential functions of regulatory RNAs. An emerging theme from multiple model systems is that lncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators, and target these enzymatic activities to appropriate locations in the genome. Consistent with this notion, long noncoding RNAs can function as modular scaffolds to specify higher order organization in RNP complexes and in chromatin states. The importance of these modes of regulation is underscored by the newly recognized roles of long RNAs in developmental patterning and cancer.
Citation Format: Howard Y. Chang. Genome regulation by long noncoding RNAs. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr IA02.
Abstract P1-11-01: Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients
Authors: Yi HW , Nam SJ , Kim SW , Lee JE , Lee SK , Bae SY , Park S , Paik H-J , Ryu JM 
Published: May 2016

Abstract
Purpose
The results of the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) showed that ovarian function suppression (OFS) in premenopausal early breast cancer patients improves disease control. However, mood swings after OFS is one of the chief complaints to make patients stop undergoing endocrine therapy. Studies about complications of OFS in breast cancer patients are not established well. We designed this randomized controlled trial to evaluate psychological functioning of patients after undergoing adjuvant OFS by goserelin.
Patients and Methods
We randomly assigned 64 premenopausal women with hormone receptor positive early breast cancer to the tamoxifen or tamoxifen plus goserelin group for a period of 1 year. Participants were screened for depression and generalized anxiety disorder using Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAM-A), Anxiety Sensitivity Index (ASI) and Albany panic and phobia questionnaire (APPQ) at baseline, 6 months and 12 months. Brain-derived Neurotrophic Factor (BDNF) levels were measured, as well. The results were analyzed by using a linear mixed model and a generalized linear mixed model.
Results
Thirty two patients were distributed in each group, equally. Linear mixed-mixed model analyses revealed that, compared with HAM-A scores of each group at baseline, HAM-A scores at 12 months showed increments (p=0.0078). Among HAM-A questions, Questions for intellectual, sensory and autonomic status were scored significantly high at 12 months (p=0.0018, p=0.0132, p=0.0006). Platelet BDNF levels reported a statistically significant rise at 12 months (p=0.0006). There was no significant time-by-study group effect in all scales.
Conclusion
Compared with the patients without OFS, patients with Goserelin showed no difference in anxiety or depression scales. Thought the levels of anxiety of each group at 12 months were increased, they do not indicate medical interventions. Patients with increased levels of BDNF at 12 months are expected to have good recovery from anxious and depressive symptoms.
Citation Format: Yi HW, Nam SJ, Kim SW, Lee JE, Lee SK, Bae SY, Park S, Paik H-J, Ryu JM. Depression and anxiety after adjuvant ovarian function suppression in premenopausal breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-11-01.
Abstract P2-03-08: miR-621 suppresses the metastatic cascade in breast cancer patients
Authors: Xue J , Chi Y , Chen J , Yang B , Wu J 
Published: May 2016

Abstract
Purpose: In previous study, we had shown that miR-621 could sensitize breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity. In this study, we aimed to define miR-621 prognosis value in breast cancer patients, and to explore the potential molecular mechanisms.
Experimental Design: 70 patients with stages II and III breast cancer were included as validation set. The correlation between miR-621 expression level and prognosis in breast cancer patients was confirmed. In parallel, in vitro and in vivo analyses were carried out to determine the potential mechanisms of miRNA-dependent prognosis.
Results: We validated that lower than higher miR-621 expression level was markedly associated with poor metastasis-free survival in breast cancer patients(P=0.03). In breast cancer cell lines, ectopic overexpression of miR-621 inhibited proliferation, migration, invasion, and metastasis both in vitro and in vivo. The potential miR-621-target genes were determined by TargetScan and miRNA CLIP-seq database. Among those, PAK7 was verified as one of the direct targets of miR-621 in breast cancer cells, whose expression level positively associated with recurrence and metastasis in breast cancer patients. The molecular mechanisms by which miR-621/PAK7 axis regulates recurrence and metastasis may involve regulation of epithelial-mesenchymal transition (EMT) in breast cancer cells.
Conclusions: Our study revealed a strong correlation between miR-621 expression and metastasis in breast cancers. High level of miR-621 was negatively associated with poor metastasis-free survival. The increased metastasis-free survival may be mediated by down-regulation of PAK7 gene, which leads to reduced EMT in breast cancer cells. Therefore, miR-621 may represent a therapeutic target for early metastasis breast cancer.
Citation Format: Xue J, Chi Y, Chen J, Yang B, Wu J. miR-621 suppresses the metastatic cascade in breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-03-08.