bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B1-21: Network analysis implicates Panx3 as an adipocyte associated factor important during carcinogenesis
Authors: Halliwill Kyle D. , Quigley David , Chin Douglas , Le Phuong Thuy , Rosario Reyno Del , Balmain Allan 
Published: May 2016

Abstract
Recent studies exploring risk factors for cancer have unveiled a clear association between body mass index (BMI) and tumor development. However, the mechanistic details of this relationship remain obscure, in large part because of the complexity inherent to these two traits. In order to better understand this relationship, we have undertaken an investigation aimed at identifying genetic elements that influence both BMI and tumorigenesis in a carcinogen-driven mouse model of non-melanoma skin cancer. Using gene expression correlation network analysis we have identified a novel factor associated with both tumorigenesis and BMI, pannexin 3 (Panx3). Our investigation has placed Panx3 as a pivotal regulator of adipocyte signaling, with a clear association with tumorigenesis, suggesting it may play a major role in linking these phenotypes. Further research aimed at elucidating the role Panx3 plays during tumorigenesis, and how it influences adipocyte development and signaling, will be critical to our understanding of the relationship between these two traits.
Citation Format: Kyle D. Halliwill, David Quigley, Douglas Chin, Phuong Thuy Le, Reyno Del Rosario, Allan Balmain. Network analysis implicates Panx3 as an adipocyte associated factor important during carcinogenesis. [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 B1-21.
Abstract B1-53: Inhibiting stemness and invasion property of glioma stem cells by biguanide compound
Authors: Choi Junjeong , Lee Ji-Hyun , Shim Jin-Kyoung , Kim Pilnam , Kang Seok-Gu 
Published: May 2016

Abstract
Introduction: Ever since pharmacoepidemiologic clues of antineoplastic actions of metformin were reported in 2005, potential application of biguanide for the treatment of several types of cancer has been evaluated. To overcome limited pharmacokinetic properties of prototype biguanides such as metformin and penformin, a newly developed biguanide compound HL156A was developed. In the present, we assessed the potential biologic effect of HL156A on the glioma stemness and invasion properties. Methods: Using patient derived glioma cancer stem cells (gCSCs), we assessed cell viability, AMPK-mTOR pathway, stemness, differentiation, tumor invasion and epithelial-mesenchymal properties of gCSCs. In addition, expression profiles with drug treatment were obtained using Illumina HumanHT-12 v4 Expression BeadChip and gene set enrichment analysis (GSEA) was performed with GSEA application. Orthotopic tumor model was generated and assessed for tumor margin. Results: The compound activated p-AMPK and reduced phosphorylation of mTORC-1-regulated proteins. It decreased stemness of gCSCs, proved by sphere formation assay and decreased expression of stemness markers. The invasive properties of gCSCs were inhibited on 3D invasion assay and the expression of proteins related with epithelial-mesenchymal transition was inhibited by the compound. GSEA revealed cell adhesion related gene set was altered in the compound treated groups. Orthotopic model of the tumor showed less invasive tumor margin on the treatment of the compound.
Citation Format: Junjeong Choi, Ji-Hyun Lee, Jin-Kyoung Shim, Pilnam Kim, Seok-Gu Kang. Inhibiting stemness and invasion property of glioma stem cells by biguanide compound. [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 B1-53.
Abstract B2-08: Model order reduction for cell signaling pathways: An investigation of G-protein coupled receptor signaling
Authors: Talwai Prem M. 
Published: May 2016

Abstract
G-protein coupled receptors (GPCRs) are frequently overexpressed in human carcinomas, where they are responsible for stimulating the aberrant proliferation of cancer cells. Unfortunately, the mechanisms of this stimulation are poorly understood due to the complexity of the interactions between GPCRs and second-messenger pathways. Robust quantitative methods are therefore necessary to simplify mathematical models of GPCR-mediated signaling. Model order reduction aims to reduce the dimensionality of kinetic models of signaling pathways (such as the GPCR signal transduction system) in order to enable the computational investigation of complex signaling networks. Existing reduction procedures aim to eliminate “slaved species”, which have low net rates of formation. Unfortunately, these methods cannot be applied to reaction networks such as the GPCR system where receptor complexes exhibit high affinities for binding proteins (and therefore have low dissociation constants). This paper aims to develop a novel projection-based model reduction technique for reducing the dimensionality of kinetic models of cell signaling pathways (such as the GPCR signaling cascade). This algorithm (executed at the command-line interface) combines the techniques of proper orthogonal decomposition, trajectory piecewise linearization, and Krylov subspace reduction in an effort to identify a best-fit subspace for the model trajectories that accurately approximates the mapping between the model input and outputs. The command-line tool effectively reduced the dimensionality of a kinetic model of the GPCR network from 16 to 3. In addition, implementing the algorithm revealed strong correlations within two disjoint sets of participating species, suggesting the need to monitor the concentration of only one species from each set during a computational or experimental investigation. The model reduction procedure enables cell biologists to effectively employ kinetic models to analyze the mechanisms of uncontrolled cell proliferation. A comprehensive understanding of these mechanisms will aid pharmacologists in identifying therapeutic targets in cancer cells.
Citation Format: Prem M. Talwai. Model order reduction for cell signaling pathways: An investigation of G-protein coupled receptor 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 B2-08.
Abstract B2-12: A systems biology approach for the discovery of differentiation therapeutics
Authors: Li Yulin , Seita Jun , Felsher Dean , Dill David L. 
Published: May 2016

Abstract
Accurately assessing the changes in cellular differentiation status in response to drug treatments or genetic manipulations is crucial for understanding the tumorigenesis process and developing novel therapeutics for human cancer. Here we have developed a novel systems biology approach, called the Lineage Maturation Index (LMI), to define the changes in differentiation state of cancer cells based on their gene expression profiles. We have been focusing on hematopoietic malignancies, but this approach is applicable to many human cancer types. We define the expression profile of N genes within a cell to be a point in an N-dimensional space. A lineage vector is derived from a progenitor cell (such as a hematopoietic stem cell) to a mature cell (such as a granulocyte) based on the expression of these N genes. By projecting the expression profile of an unknown cell onto the lineage vector, an LMI can be computed for the differentiation state of this specific cell. Upon drug treatments or genetic manipulations, a shift in LMI from stem cells towards mature cell types indicates differentiation. We have confirmed that the LMI approach can track the differentiation of normal hematopoietic cells. We have further shown that differentiation is a major consequence of various targeted therapies against leukemia irrespective of the driving oncogenes. Most importantly, we have used this approach to analyze the Connectivity Map HL60 leukemia data set for drugs that can induce leukemia cells to differentiate. In addition to drugs known to have differentiation activities (such as all-trans retinoic acid and etoposide), we discovered that several novel drugs (such as dihydroergotamine, mebendazole, and clonidine) have potent differentiation activities in leukemia cells. Currently, we are expanding our study into multiple types of solid tumors, such as breast, prostate, and colon cancers. Our LMI approach is highly robust in characterizing differentiation of the cancer cells and discovering novel differentiation therapies for human cancer.
Citation Format: Yulin Li, Jun Seita, Dean Felsher, David L. Dill. A systems biology approach for the discovery of differentiation therapeutics. [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 B2-12.
Abstract B2-32: Networks dynamics and opposite effects of Wnt5a on motility in melanomas
Authors: Rasheed Mohammed , Bouaynaya Nidhal , Araysi Lita M. , Zhuo Tang , Li Mei , Zhou Ping , El-Kattan Kareem , Fathallah-Shaykh Hassan 
Published: May 2016

Abstract
Melanoma is an aggressive cancer whose incidence continues to rise worldwide; furthermore, metastatic melanoma is associated with poor prognosis. Wnt signaling may lead to conflicting effects on the biology of melanoma as it may either decrease or increase the incidence of metastasis. Here, we show that Wnt5a enhances motility in 3/5 cell lines and represses motility in the other two. We measured the effects of perturbations of the levels of Wnt5a, HADHB, Pirin, and Mart1 on the levels of the seven molecules, Wnt5a, HADHB, Pirin, Mart1, Ret1, Stc2, and S100B in the five cell lines. The results uncovered unanticipated nonlinear molecular dynamics. Seeking a mechanistic explanation, we built network models consisting of ordinary differential equations representing signed directed graphs of the interactions between the seven molecules in the five cell lines. Simulations validate the results of the perturbation experiments and reveal that the indirect network-mediated effects of a molecule on another may annul or reverse its direct effects. Furthermore, network analysis and biological validation link HADHB and Pirin to motility. In summary, the findings reveal: 1) opposite effects of Wnt5a on motility in melanomas, 2) HADHB and Pirin control motility through their effects on Wnt5a, and 3) molecular targeting yields nontrivial nonlinear molecular dynamics, which are not readily anticipated.
Citation Format: Mohammed Rasheed, Nidhal Bouaynaya, Lita M. Araysi, Tang Zhuo, Mei Li, Ping Zhou, Kareem El-Kattan, Hassan Fathallah-Shaykh. Networks dynamics and opposite effects of Wnt5a on motility in melanomas. [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 B2-32.
Abstract PR13: Systems and structural biology approaches to elucidate new effectors in KRAS mutant tumors
Authors: Broyde Joshua , Simpson David , Wah David A. , Giorgi Federico M. , Petrey Donald , Alvarez Mariano J. , Silkov Antonina , Lachmann Alexander , Hill David E. , Vidal Marc , Jackson Peter , Honig Barry , Sweet-Cordero Alejandro , Califano Andrea 
Published: May 2016

Abstract
Activated KRAS interacts directly and indirectly with numerous downstream effector pathways that are still elusive or poorly characterized. Furthermore, it has become clear over the past few years that the KRAS regulatory gene network (interactome) is highly cell-context dependent and thus tumor specific. We sought to computationally elucidate novel KRAS effectors, modulators, and interactors in Lung Adenocarcinomas (LUAD) and Colon Adenocarcinomas (COAD) by integrating computational and biochemical reverse engineering methods. Specifically, results from ARACNe and MINDy based analysis of KRAS networks were combined with Protein-protein interaction (PPI) predictions based on the PrePPI algorithm. These algorithms detect, respectively, transcriptional, post-translational, and protein-protein interactions respectively. The MARINa/VIPER algorithm was used to analyze the networks resulting from these analyses to identify key modulators and effectors of KRAS activity, including modulators harboring genetic alterations that phenocopy aberrant KRAS activity. In addition, we collaborated with the Jackson (Stanford) and Vidal (Harvard) labs to include high-throughput tandem affinity mass spectrometry data and yeast 2 hybrid screens in these analyses. Validation of computationally inferred effectors, using pooled shRNA silencing assays in primary lung cancer cells isolated from a KrasLSL/p53f/f mouse model of LUAD validated novel genes as likely KRASmut effectors and putative synthetic lethal genes. At least two hairpins against RNF43, E4F1, HMCN1, MYO9A, RHOT2, SETD1B and MAP3K2 scored in this assay. These results suggest that KRAS network analyses using computational methods can identify novel members of the KRAS interactome.
Citation Format: Joshua Broyde, David Simpson, David A. Wah, Federico M. Giorgi, Donald Petrey, Mariano J. Alvarez, Antonina Silkov, Alexander Lachmann, David E. Hill, Marc Vidal, Peter Jackson, Barry Honig, Alejandro Sweet-Cordero, Andrea Califano. Systems and structural biology approaches to elucidate new effectors in KRAS mutant tumors. [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 PR13.
Abstract A01: Innate lymphoid cells (ILCs) in murine melanoma: A new paradigm in cancer immunity
Authors: Christianson Blake , Walker James , Kocherla Marsha , Qin Xu , Yu Jack C. , Baban Babak 
Published: May 2016

Abstract
Introduction: Innate lymphoid cells (ILCs), have emerged as novel important immune effector cells, playing a critical role also in tumor immune-surveillance. Recently, it was shown that the number of ILCs in patients with different types of cancer is significantly reduced after chemotherapy/radiotherapy as compared to healthy donors. However, so far, no data on ILC frequency, subset distribution and function in patients with melanoma are available. Therefore, we analyzed the frequency, subset distribution and function of ILCs in a murine model of melanoma with/without treatment, a parameter that is of paramount importance to understand the role of ILCs during melanoma and to assess the impact of current treatments on this type of cancer.
Methods: C57/BL6 mice were injected with B16F10 murine melanoma cell line (1 x 106 cells/mouse, subcutaneous). Tumor growth monitored. Once tumors reached 12mm in size, the mice were sacrificed and tumor cells subjected to flow-cytometry and cell culture to identify the ILC subclasses in the tumor.
Results: Our findings establish, for the first time in melanoma at diagnosis, base-line reference values for ILC frequency and function, as well as the ILC subtype distribution.
Conclusion: Our studies extend previously published work on changes in innate lymphoid cells. Our findings will help better understanding of tumor microenvironment and its interaction with immune system. These values indicate the potential of ILCs as crucial players in the treatment of cancer, specifically melanoma.
Citation Format: Blake Christianson, James Walker, Marsha Kocherla, Xu Qin, Jack C. Yu, Babak Baban. Innate lymphoid cells (ILCs) in murine melanoma: A new paradigm in cancer immunity. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A01.
Abstract A04: Hyperactive mTOR induces neuroendocrine differentiation in LNCaP prostate cancer cell with concurrent upregulation of interferon regulatory factor 1
Authors: Kanayama Mayuko , Hayano Toshiya , Maeda Tatsuya , Horie Shigeo , Aiba Atsu 
Published: May 2016

Abstract
The PI3K-Akt-mTOR pathway is frequently activated in prostate cancer. However, the precise function of mTOR in prostate cancer progression is yet to be elucidated. Thus, in this study, we performed a gain-of-function analysis by establishing human prostate cancer LNCaP stable line that expresses hyperactive mTOR (LNCaP-mTOR). Hyperactive mTOR induced neuroendocrine differentiation (NED) that can be suppressed by an mTOR inhibitor, rapamycin. Subsequent comprehensive mass spectrometric analysis in conjunction with cascade analysis indicates that the members of interferon regulator factor (IRF) family, especially IRF1, are key transcription factors in NED of LNCaP-mTOR. Aside from its major role in immune response, IRF1 is known to be a tumor suppressor. To further investigate the function of IRF1 in NED induced by hyperactive mTOR, we disrupted the IRF1 gene in LNCaP-mTOR by CRISPR/Cas system. The disruption of the IRF1 gene resulted in an acceleration of an NED-associated morphological change, elevation of neuroendocrine cell marker, neuron specific enolase, and a partial recovery of growth arrest. These results suggest that IRF1 partially suppresses NED at downstream of hyperactive mTOR. Together, our results indicate that two seemingly contradictory events, NED and the induction of IRF1, are induced by hyperactive mTOR, giving rise to a notion that pharmacological inhibition of mTOR can be a “double-edged sword” for prostate cancer treatments.
Citation Format: Mayuko Kanayama, Toshiya Hayano, Tatsuya Maeda, Shigeo Horie, Atsu Aiba. Hyperactive mTOR induces neuroendocrine differentiation in LNCaP prostate cancer cell with concurrent upregulation of interferon regulatory factor 1. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A04.
Abstract A05: NKG2D and CD28 receptors differentially activate mTOR to alter murine effector CD8+ T cell differentiation
Authors: McQueen Bryan , Trace Kelsey , Whitman Emily , Barber Amorette 
Published: May 2016

Abstract
Memory CD8+ T cells are an essential component of anti-tumor and anti-viral immunity. Activation of the mammalian/mechanistic target of rapamycin (mTOR) pathway has been implicated in regulating the differentiation of effector and memory T cells. However, the mechanisms that control mTOR activity during immunity to tumors and infections are not well known. Activation of costimulatory receptors, including CD28 and NKG2D, activate PI3K and subsequently may activate the mTOR pathway in CD8+ T cells. Therefore this study compared the activation of the mTOR signaling pathway after costimulation through CD28 or NKG2D receptors in murine effector CD8+ T cells. Compared to CD28 costimulation, activation through CD3 and NKG2D receptors had weaker activation of mTORc1 as shown by decreased phosphorylation of mTORc1 targets S6K1, ribosomal protein S6, and 4EBP-1. NKG2D costimulation also showed increased gene expression of TSC2, a negative regulator of mTORc1, whereas CD28 costimulation increased gene expression of Rheb, an activator of mTORc1, and HIF-1α and VEGFα, pro-angiogenic factors downstream of mTORc1. Strong mTORc1 activation in CD28-costimulated cells also increased expression of transcription factors that support effector cell differentiation, namely T-bet, and BLIMP1, whereas low levels of mTORc1 activation allowed for the expression of Eomes and BCL6 during NKG2D stimulation, and increased expression of central memory markers CD62L and CD127. These data show that compared to CD28, costimulation through the NKG2D receptor leads to the differential activation of the mTOR signaling pathway and potentially supports memory CD8+ T cell differentiation.
Citation Format: Bryan McQueen, Kelsey Trace, Emily Whitman, Amorette Barber. NKG2D and CD28 receptors differentially activate mTOR to alter murine effector CD8+ T cell differentiation. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A05.
Abstract A12: Chronic Coartem treatment and hepatocarcinogenesis in male Wistars rat
Authors: Aloba Martins A. , Olotu Fisayo A. , Odunola Oyeronke A. , Gbadegesin Michael A. , Owumi Solomon E. 
Published: May 2016

Abstract
Coartem (CA) artemether/lumefantrine) is a combination therapy widely used in sub-Saharan Africa in managing uncomplicated Plasmodium falciparum-induced malaria. According to manufacturer’s literature, no long-term carcinogenicity studies have been carried out on CA. Therapy with CA places a burden on hepatic metabolism, accumulation of its metabolites (dihyroartemisinin, desbutyl-lumefantrine) induces hepatotoxicity, altering hepatic functions and formation of DNA adducts that may have implication in hepatocarcinogenesis.
Wistar rats (n=20) were treated with CA (1, 3 and 5mg/kg) twice daily, thrice weekly for 40 consecutive days exhibited symptoms such as sneezing, lethargy with no effects on final body weight, relative liver weight or mortality during the study. Histopathological examination of treated rats’ liver revealed mild portal cellular infiltration in the group administered 1mg/kg Coartem. There was mild Kupffer cells hyperplasia in the rats that received 3mg/kg Coartem and mild to moderate portal mononuclear cellular infiltration in the group that received 5mg/kg. In addition, there was severe portal congestion and hyperplasia of the bile duct, which made the portal triad very prominent. These observations were in contrast to the negative control group with no macro /microscopic visible lesion.
Serum levels of hepatotoxicity markers (γ-glutamyl-, alanine amino-, aspartate amino- transferases and alkaline phosphatase) in CA treated group showed no significant difference (p&gt;0.05) compared with controls. Means of urea, creatinine (in whole blood), albumin and total protein (liver homogenate) of the CA administered group were not different (p&gt;0.05) compared with controls. CA treatment dose dependently increased the formation of micronucleated polychromatic erythrocytes (mPCEs) in rat bone marrow cells. Although this was not statistically significant (p&gt;0.05) for the various doses of CA administered when compared with control groups.
Taken together, CA treatment (1, 3 and 5mg/kg body) for a period of 40 days had no hepatotoxic and nephrotoxic effect. Although prolonged administration may likely be toxic, Kupffer cell hyperplasia mild to moderate portal cellular infiltration of hepatic sinusoid may exacerbate drug-induced hepatocarcinogenesis over a prolonged treatment period as observed in this study. Longer-term chronic studies for 80-120 are being investigated.
Citation Format: Martins A. Aloba, Fisayo A. Olotu, Oyeronke A. Odunola, Michael A. Gbadegesin, Solomon E. Owumi. Chronic Coartem treatment and hepatocarcinogenesis in male Wistars rat. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A12.