bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4921: A new method for identifying a data-consistent self-reconfigurable predictive bio-network model of the cell cycle based on time series data and its application in cancer systems biology
Authors: Idowu Michael A. , Bown James , Zhelev Nikolai 
Published: August 2012

Abstract
A new method for (re)constructing interaction networks using a limited number of time series data has been developed. This method may provide better opportunities for immediate identification of data-consistent models of biological systems. It may serve as an alternative or complementary approach to other existing data-driven strategies for modeling or mining time-evolutionary properties of complex biological processes based on the analysis of their time series data. We present some practically useful data-mining techniques for constructing self-reconfigurable predictive models of complex biological systems, which approximate their underlying processes. These parametric models, if well reverse-engineered, may help capture key features of data relevant for the purpose of interest. To demonstrate our network inference method, we focus on analyzing time series data of cdk2, cyclinA1, cyclinD1, cycinD2, cyclinD3, E2F1, p16 and p27 obtained from real experiments. The constructed predictive model of the cell-cycle is found to be data-consistent. This model approximates the underlying biological processes hidden in the data, and may help reveal or identify key processes that may govern G1-S phase progression. Given multiple sets of time series data from a cell line, where some sets represent control conditions and other intervention conditions, the method introduced here can help construct interaction networks for each of these data sets. To investigate areas of the signaling network most affected by the intervention, critical areas that have been identified in those networks could be compared to the effects of real perturbations. This may help inform future experimental design by targeting sensitive areas in the signaling network or avoiding resistant pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4921. doi:1538-7445.AM2012-4921
Abstract 4925: The natural enzyme sequestration in signaling cascades provides inherent opportunities for off-target effects induced by kinase inhibitors
Authors: Wynn Michelle L. , Ventura Alejandra C. , Sepulchre Jacques-A. , Garcia Hector J. , Merajver Sofia D. 
Published: August 2012

Abstract
Off-target effects from targeted therapies are often attributed to cross-talk, which usually refers to inter-pathway molecular interactions that occur because of explicit regulatory feedback connections between two pathways. Recent experimental and theoretical studies have demonstrated, however, that covalently modified cascades naturally exhibit bidirectional signal propagation via a phenomenon termed retroactivity. This phenomenon arises due to enzyme sequestration where each cycle is coupled, not only to the next cycle, but also to the previous cycle. While retroactivity occurs naturally in covalently modified cascades, signaling pathways likely evolved to propagate information in a downstream manner. An important consequence of retroactivity, however, is that a downstream perturbation can induce an upstream response without the presence of regulatory feedback connections. We hypothesize that kinase inhibitors can produce off-target effects as a consequence of retroactivity alone via the following mechanism: a signal travels upstream from the site of a downstream perturbation through retroactivity and, upon reaching a shared upstream component, is delivered to an independent parallel pathway. To test the hypothesis we used a computational model to simulate the targeted inhibition of a specific kinase in a series signaling networks using physiologically and therapeutically relevant ranges for all parameters. Surprisingly, our results suggest that an off-target effect due to retroactive signaling is more likely when the first cycle in a non-inhibited cascade is “off” and not consuming large amounts of a shared up-stream activator. Our results also suggest that the kinetics governing covalently modified cycles in a cascade are more important for propagating an upstream off-target effect than the binding affinity of the drug to the targeted protein, which is a commonly optimized property in drug development. Finally, our results suggest that a single mutation has the capacity to produce a large spontaneous off-target effect without any direct regulatory connections between the targeted protein and the effected protein. Together, our results suggest that retroactivity may play an important role in the dysregulated signaling networks of cancer cells as well as the cellular response to targeted therapies. These findings have important implications for somatic evolution in cancer and the onset of therapeutic resistance, which has been widely reported for many targeted cancer therapeutics, including kinase inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4925. doi:1538-7445.AM2012-4925
Abstract 4935: A quantitative model to study cell-type-specific transcriptional regulation between MCF-7 and LNCaP
Authors: Liu Yuwen , Zhou Jie , White Kevin P. 
Published: August 2012

Abstract
Transcriptional regulation lies at the heart of biological processes. To further understand the regulatory mechanism, we are studying the transcriptional networks of nuclear receptors in breast cancer cell line MCF-7 and prostate cancer cell line LNCaP. Based on whole-genome gene expression microarray data, we observed very different transcriptional programs induced by ligands of nuclear receptors between these two cell lines. In order to systematically explain cell-type-specific transcriptional regulation, we are trying to build a quantitative model to predict gene expression in different cellular contexts under different ligand stimulations. The model will be trained using data including genomic binding sites of nuclear receptors (ChIP-Seq), and time-series expression of nuclear receptors, cofactors and their target genes (Nanostring). The output of the model will be gene expression trajectories after ligand treatments in the two cell lines.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4935. doi:1538-7445.AM2012-4935
Abstract 4942: Can three-dimensional cell cultures be used to predict in vivo drug response and synergistic combinations
Authors: Brightman Frances A. , Fernandez Eric , Orrell David , Fell David , Chassagnole Christophe 
Published: August 2012

Abstract
The discovery of synergistic combinations of standard-of-care drugs or new chemical or biological entities shows much promise in the treatment of cancer, and there is much interest in this strategy. However, the increasing number of possible combinations makes the task of selecting the best regimens particularly difficult. As a response to this problem, we developed a computerized PK-PD model of a growing tumor, called the Virtual Tumor™. We demonstrated that this platform can successfully simulate the outcome of various drug combination schedules in xenografts, as well as predict optimal drug schedules and combinations. Although xenografts represent a convenient and relatively inexpensive approach to assessing the likely efficacy of proposed dosing regimens in vivo, the number of permutations that can be tested is still limited by practical considerations. We have therefore explored the use of three-dimensional tumor cell cultures (microtissues) as a more cost-effective alternative to xenografts for validating Virtual Tumor™ predictions. Using the Virtual Tumor™, we previously predicted that the efficacy of a gemcitabine-docetaxel combination could vary greatly depending on the scheduling of the drug administration, and verified these findings in vivo in MX-1 xenograft mouse model. We have now conducted a comparable study using MX-1 microtissues, in which the cultures were treated with these same two drugs in isolation or in combination, according to various regimens. Here we show how the microtissue Virtual Tumor™ model can be employed to simulate microtissue growth and response to drug treatment, and the capability of this model to predict drug synergy in vivo in xenografts. Furthermore, we discuss whether microtissues can be used as a surrogate for xenografts, in conjunction with the Virtual Tumor™, for designing new drug regimens, testing possible schedules for combinations of different drugs and prioritizing the most effective drug combinations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4942. doi:1538-7445.AM2012-4942
Abstract 4943: Genetically engineered osteoprotegerin for multiple myeloma osteolytic bone damage
Authors: Higgs Jerome T. , Jarboe John , Ponnazhagan Selverangan 
Published: August 2012

Abstract
Current treatments for osteolytic cancers include a combination of radiation, chemotherapy and cytotoxic products, but toxic side effects are still of major concern. Studies have shown that osteoclast activity is increased in patients with osteolytic cancers such as Multiple Myeloma (MM), through increased expression of Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) leading to RANKL/RANK signaling, resulting in osteoclast activation and ultimately bone resorption. Moreover, Osteoprotegerin (OPG) is drastically decreased in these patients who presents with bone lesion. Thus, the use of OPG as a therapeutic molecule would greatly decrease osteolytic damage and reduce morbidity. However, despite the of OPG potential in inhibiting the activation of bone resorbing osteoclast, OPG also binds to tumor related apoptosis-inducing ligand (TRAIL) making tumor cells resistant to apoptosis. TRAIL binds to the Death Receptor 4 and 5 (DR4, DR5) and initiate cell death of Transformed cells such as MM. The present study was designed to develop a novel therapeutic approach to the treatment of osteolytic bone damage by use of genetically altered OPG retaining RANKL binding but abolished of TRAIL binding. In order to eliminate TRAIL binding while maintaining RANKL binding, we created mutant OPG-Fc constructs by site directed mutagenesis based on interactive domain identification and by superimposing structural models of TRAIL, OPG and DR5. The mutant OPGs were produced in HEK 293 cells for characterization of potential mutants and their TRAIL binding ability. We conclude that using site-directed mutagenesis at the N-terminal of OPG effectively retains RANKL binding property but abolishes TRAIL binding property as determined by osteoclast and TRAIL assays respectively.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4943. doi:1538-7445.AM2012-4943
Abstract 4948: Uncovering microRNA and transcription factor-mediated regulatory network in glioblastoma
Authors: Zhao Zhongming , Sun Jingchun 
Published: August 2012

Abstract
Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from that in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. In this study, we systematically explored the combinatory regulation of miRNAs and transcription factors (TFs) impacting GBM genes. We compiled GBM-related miRNAs, genes, and TFs and then identified 1,128 3-node feed-forward loops (FFLs) and 805 4-node FFLs with statistical significance. These FFLs were converged to construct a comprehensive GBM-specific miRNA-TF mediated regulatory network and, from which, an essential GBM-specific regulatory network. To further identify critical miRNA components in the GBM regulatory network, we specifically extracted a subnetwork for Notch signaling pathway. Our follow up network and functional association analyses revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some supported by previous studies. This study has generated the first comprehensive miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. Our findings of important miRNAs in the Notch signaling pathway, with partial verification by previous studies, demonstrates that our network-based approach is promising for identifying new and important miRNAs in GBM and, potentially, other cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4948. doi:1538-7445.AM2012-4948
Abstract 4949: A dynamic TGFBR3-JUND expression circuit in single basal-like breast epithelial cells
Authors: Wang Chun-Chao , Jamal Leen , Bajikar Sameer S. , Atkins Kristen A. , Janes Kevin A. 
Published: August 2012

Abstract
Basal-like carcinoma is a subtype of breast cancer that is characterized by poor prognosis and high intratumor heterogeneity. In basal-like breast epithelia, we have identified two anticorrelated gene-expression programs that arise among single extracellular matrix (ECM)-attached cells during organotypic 3D culture. The first program contains multiple TGFβ-related genes including TGFBR3, and its heterogeneous induction is critical to suppress ductal branching. The second program contains JUND together with the basal-like marker, KRT5. Homogenizing JUND expression in single cells leads to 3D acini with bridged lumina that are similar to cribiform ductal carcinoma in situ. TGFBR3 and JUND together comprise a circuit that is interconnected via four negative-feedback loops. Computational modeling of the circuit predicts damped, antiphase oscillations upon stimulation with endogenous impulses of TGFβ-like ligand, and we directly observe these spontaneous responses in 3D culture by live-cell imaging. The TGFBR3-JUND circuit and its ECM-dependent regulation are remarkably conserved in early basal-like tumors that heterogeneously express KRT5, suggesting that asynchronous circuit dynamics are active in this patient subset. Preliminary studies suggested this intrinsic single-cell expression circuit might be regulated by a transcription factor, Nrf2, and a tumor suppressor, menin. Together, breast tumor heterogeneity need not stem from partial basal-like differentiation and could instead reflect dynamic toggling of individual cells between expression states.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4949. doi:1538-7445.AM2012-4949
Abstract 4953: Interaction of vitamin E compounds with docosahexaenoic acid on induction of apoptosis in human triple negative breast cancer cells
Authors: Xiong Ailian , Yu Weiping , Sanders Bob , Kline Kimberly 
Published: August 2012

Abstract
Successful treatment of triple negative (ER-, PR-, HER2-) breast cancers (TNBC) remains elusive because of the limitations of currently available chemotherapeutic agents for TNBC, drug resistance and drug toxicities. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has been shown to exhibit anticancer actions both in vitro and in vivo in a variety of cancers, including human breast cancer. Here, we report that DHA induces apoptosis in TNBC cell lines, which is associated with cleavage of caspase-8 and -9. DHA induces endoplasmic reticulum (ER) stress evidenced by the increased levels of ER stress markers, GRP78, CHOP, and spliced XBP-1, and induced increased levels of death receptor DR5 protein expression. siRNAs to CHOP and DR5 blocked DHA-induced apoptosis and siRNA to CHOP blocked DHA-induced upregulation of DR5, indicating that DHA induces ER stress mediated death receptor dependent apoptosis in TNBC cells via CHOP. Furthermore, our data show that DHA mediated increases in levels of reactive oxygen species (ROS), apoptosis and ER stress can be blocked by antioxidants; N-Acetyl Cysteine (NAC) and alpha-tocopherol (αT) indicating that ROS plays a critical role in DHA-induced apoptosis and ER stress. In contrast to αT, gamma-tocotrienol (γT3), another form of vitamin E, cooperated with DHA to induce apoptosis and ER stress in TNBC cells. siRNAs to CHOP and DR5 blocked the combination effects mediated by DHA + γT3 on induction of apoptosis and ER stress. Taken together, our data, for the first time, demonstrate that DHA induces apoptosis in TNBC cells via activation of an ER stress mediated DR5 dependent pro-apoptotic pathway. Our data also show that different forms of vitamin E exhibit different combinational effects on DHA-induced apoptosis; namely, blockage by αT and enhancement by γT3. (Funding for these studies was provided by the Clayton Foundation for Research).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4953. doi:1538-7445.AM2012-4953
Abstract 4956: Regulation of anoikis by DBC1 (Deleted-In-Breast Cancer 1) through NF-kB
Authors: Park Sun , Riley Philip A. , Cieply Benjamin , Frisch Steven M. 
Published: August 2012

Abstract
Cancer cells that undergo epithelial-to-mesenchymal transition (EMT) evade anoikis, apoptosis induced by detachment from extracellular matrix. The mechanism of anoikis-resistance is an area of ongoing research. The gene Deleted in Breast Cancer 1, DBC1, is found in chromosomal region 8p21, which is deleted in some breast cancers, while several other cancers show DBC1 overexpression. DBC1 interacts with various proteins, such as SIRT1, ERα, RARα and SUV39H1 in a cancer context dependent manner. We found that depletion of DBC1 sensitized MCF10-A mammary epithelial cells to anoikis both in two-dimensional and three dimensional culture models. This effect was also observed in several breast cancer cell lines. Microarray analysis showed that DBC1 regulates the level of the c-FLIP in MCF10a cells, which was confirmed by RT-PCR. In addition, real time PCR studies showed that DBC1 induces other NF-kB transcription factor target genes such as Bcl2 and XIAP, some of which are known suppressors of anoikis. Luciferase assays demonstrated that DBC1 induces NF-kB transcriptional activity. NF-KB is a transcription factor that regulates genes involved in inflammatory response, cell survival and death. We found, through the use of the NF-kB inhibitors BAY 117082 and curcumin, that NF-kB suppressed anoikis. Conversely, SIRT1 –a deacetylase that inhibits NF-kB and that is itself inhibited by DBC1– promoted anoikis. The pathway in which DBC1 regulates anoikis through NF-κB will be further investigated in the future, with a view toward understanding the role of DBC1 in modulating the inflammatory signaling pathways that control anoikis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4956. doi:1538-7445.AM2012-4956
Abstract 4959: Osteoprotegerin mediates resistance to TRAIL-induced apoptosis in pancreatic ductal adenocarcinoma
Authors: Kanzaki Hirotaka , Otaki Akashi , Greene Mark I. , Murali Ramachandran 
Published: August 2012

Abstract
[Purpose] Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) has been shown to have great potential for the treatment of most human tumor cells without harming normal cells. However, some cancers show resistance to TRAIL induced apoptosis. The poor prognosis of both pancreatic ductal adenocarcinoma (PDAC) is likely due to the absence of valid approaches for early detection, the frequency of its metastases at the time of diagnosis, frequent recurrence after surgery, and poor responsiveness to chemotherapy. PDAC is also known as the most common resistant cells to TRAIL. Since osteoprotegerin (OPG) is known as a decoy receptor that binds to TRAIL and inhibits TRAIL-induced apoptosis, we hypothesized that OPG might play a role in mediating resistance to apoptosis in PDAC cells. [Methods and Results] To investigate the expression of OPG in PDAC cells, RT-PCR, Western blot and ELISA were performed. From the results, we found significant expression of OPG in both cell and cell culture medium. To investigate the apoptotic activity of TRAIL, we performed cell viability assay and apoptosis assay with or without siRNA against OPG. We found that PDAC cells showed significantly resistance to TRAIL induced apoptosis and knocking down of OPG sensitized TRAIL induced apoptosis in PDAC cells. [Conclusion] This study demonstrated that OPG played a role in resistance to TRAIL-induced apoptosis in PDAC cells. Expression of OPG might provide PDAC cells with an essential growth advantage through resistance to TRAIL-induced apoptosis. Inhibition of OPG expression and blocking OPG function might be a new therapeutic approach for the treatment of pancreatic cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4959. doi:1538-7445.AM2012-4959