bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B2-23: A Big Bang model of human colorectal tumor growth
Authors: Sottoriva Andrea , Kang Haeyoun , Ma Zhicheng , Graham Trevor A. , Salomon Matthew , Zhao Junsong , Marjoram Paul , Siegmund Kim , Press Michael F. , Shibata Darryl , Curtis Christina 
Published: May 2016

Abstract
What happens in the early and still undetectable human malignancy is unknown because direct observations are impractical. Here we present a “Big Bang” model, whereby a tumor grows predominantly as a single expansion producing numerous intermixed sub-clones, which are not subject to stringent clonal selection. In this model, both public and most detectable private mutations arise during the earliest phase of tumor growth. Multi-scale genomic profiling of 349 individual glands sampled from 15 colorectal tumors revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity, and sub-clone mixing in distant tumor regions, as postulated by the Big Bang. By integrating the data in a spatial model of tumor growth and statistical inference framework we also verified the most striking prediction of our model, namely that most detectable intra-tumor heterogeneity originates from private alterations acquired early during growth, and not from the later expansion of selected sub-clones. Hence, early sub-clones define the genomic profile of colorectal carcinomas and advanced adenomas, whereas potentially dangerous late-arising sub-clones will go undetected. Moreover, our results suggest that sub-clone mixing may be a biomarker of malignant potential. This new model provides a quantitative framework that explains the origins of intra-tumor heterogeneity and tumor growth dynamics with significant clinical implications.
Citation Format: Andrea Sottoriva, Haeyoun Kang, Zhicheng Ma, Trevor A. Graham, Matthew Salomon, Junsong Zhao, Paul Marjoram, Kim Siegmund, Michael F. Press, Darryl Shibata, Christina Curtis. A Big Bang model of human colorectal tumor growth. [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 B2-23.
Abstract B2-24: OVOL: A brake on EMT, driver of MET and expander of the hybrid E/M phenotype
Authors: Jia Dongya , Jolly Mohit Kumar , Boareto Marcelo , Parsana Princy , Mooney Steven , Pienta Kenneth J. , Levine Herbert , Ben-Jacob Eshel 
Published: May 2016

Abstract
Aberrant activation of Epithelial to Mesenchymal Transition (EMT) and its reverse MET is a hallmark of cancer metastasis. Also, the carcinoma cells can undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype, which can allow them to migrate collectively and form clusters of Circulating Tumor Cells (CTCs). These clusters can be up to 50 times more metastatic compared to cells that undergo complete EMT or individually migrating CTCs. Here, using experimental data and bioinformatics, we devised a dedicated model to study the role of transcription factor OVOL in regulating these bidirectional epithelial-hybrid-mesenchymal transitions. The new model incorporates the coupling between OVOL and miR-200/ZEB - the three-way EMT/MET decision-making switch that allows for three phenotypes (E, M and E/M). We found that OVOL operates as a brake holder of complete EMT and as an expander of the hybrid E/M phenotype (it extends the range of physiological parameters for which the cells can attain the hybrid E/M phenotype). Inhibition of OVOL, for example by Wg signaling, removes that brake and supports a complete EMT. Conversely, overexpression of OVOL, for example by BMP7/Smad4, leads to the reverse of EMT, i.e. MET. In addition, OVOL elevates the phenotypic plasticity of cells by turning both EMT and MET into a two-step process (E to E/M to M, and M to E/M to E). We show that depending on the context-specific coupling manner of OVOL with miR-200/ZEB, OVOL can shepherd cellular plasticity in multiple ways - by driving MET, by restricting EMT, and by expanding the existence of the hybrid E/M phenotype. In particular, we explain how the differences between the observed effects of OVOL in breast and prostate cancer are associated with the results of different miR-200/ZEB/OVOL couplings. Our computational framework can be tailored to include other signals such as p53, TGF-beta, inflammation and hypoxia that affect the cellular plasticity during metastasis, thus providing a platform to design novel anti-metastasis therapies.
Citation Format: Dongya Jia, Mohit Kumar Jolly, Marcelo Boareto, Princy Parsana, Steven Mooney, Kenneth J. Pienta, Herbert Levine, Eshel Ben-Jacob. OVOL: A brake on EMT, driver of MET and expander of the hybrid E/M phenotype. [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 B2-24.
Abstract B2-37: Understanding the variability in drug response in a panel of breast cancer cell lines using computational models
Authors: Thijssen Bram , Jastrzebski Katarzyna , Beijersbergen Roderick L. , Wessels Lodewyk FA 
Published: May 2016

Abstract
Cancer cell lines differ widely in their sensitivity to anticancer drugs. While many oncogenic drivers and drug resistance mechanisms have been discovered, it is generally unclear how these mechanisms interact in each cell line to make the cell line sensitive or resistant to a particular drug.
We set out to explain this variability in drug sensitivity in a panel of 30 breast cancer cell lines. We characterized these cell lines at the DNA, RNA and protein level, and accurately measured the proliferation under treatment with various different kinase inhibitors. We then constructed computational models encompassing several of the important driver pathways and sensitivity mechanisms, and tested how well these models describe the available data. After selecting the well-fitting models, we could use these models to estimate the relative contribution of each of the interacting mechanisms to the proliferation of the cells under drug treatment. For example, the models indicated that FGF2 autocrine signaling contributes to fast proliferation in some cell lines; that SGK1 expression provides a bypass for Akt signaling in some cell lines; or that the expression level of 4E-BP1 is a key determinant of mTOR-inhibitor sensitivity on top of other genetic alterations in the PI3K-pathway. Additionally, we could use these models to thoroughly analyze which parts of the data cannot be explained. This greatly narrows down which follow-up studies are necessary to advance our understanding of drug response.
These results show that knowledge-based computational models can be used to systematically study drug response in cell line panels. Such systematic, quantitative understanding of drug response will be useful in working towards precision medicine for individual cancer patients.
Citation Format: Bram Thijssen, Katarzyna Jastrzebski, Roderick L. Beijersbergen, Lodewyk FA Wessels. Understanding the variability in drug response in a panel of breast cancer cell lines using computational models. [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 B2-37.
Abstract B2-48: Biological profile in invasive lobular carcinoma in medical oncology department, Algeria
Authors: Sakhri Selma 
Published: May 2016

Abstract
Background: Invasive lobular cancers(ILC) constitute 5% - 15% of all invasive breast tumors, less common than invasive ductal carcinoma(IDC), and appear to have a distinct biology. The aim of our study is to determine the ILC biological profile collected in the department ofoncology medical Tizi Ouzou hospital Algeria
Materials and Methods: We recorded the cases of 73 patients with ILC between January 2010 and January 2012. .the aim of this study is to evaluate the clinical and pathological response, molecular profiling using RE, RP, KI67, HER2, and the follow up between (2012 – 2014).
Result: The average age of patients with ILC is 52 years, 40% women have postmenopausal status, all patients underwent mammography, diagnosed by a core needle biopsy, the commonest stage at presentation was stage III (42%).10 patients (13%) underwent a breast conserving surgery, and 87 % a mastectomy
The majority of cases were histologic grade II (SBR II), 50% of the tumors were estrogen and progesterone receptor positive, Her2 neu was reported to be negative in 60 %. the treatment consisted on : neoadjuvant chemotherapy in 28 cases ( 38%) ,adjuvant chemotherapy in 42 cases (57%) , following by radiotherapy , and hormonal therapy ( HT) was given to 47 patients ( 64%) , and target therapy to 40% the follow up after 2 years , 12 % had metastatic or loco regional recurrence : bone ( 60%) , lung ( 30 %) , and liver in ( 10 %) , 88 % of the cases remain in complete remission.
Conclusion: ILC are a heterogeneous group of tumors and the management decisions should be based on individual patient and biologic characteristic of the tumor.
Citation Format: Selma Sakhri, Sr. Biological profile in invasive lobular carcinoma in medical oncology department, Algeria. [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 B2-48.
Abstract B2-49: Coupled cellular decision-making of EMT and stemness: A bottom-up regulatory model
Authors: Jolly Mohit Kumar , Huang Bin , Lu Mingyang , Mani Sendurai A , Levine Herbert , Ben-Jacob Eshel 
Published: May 2016

Abstract
Epithelial cells undergoing epithelial-to-mesenchymal transitions (EMT) have often been shown to behave as cancer stem cells (CSCs) but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit. The two switches are coupled by LIN28 being inhibited by miR-200, and ZEB being inhibited by let-7. Here, we devise a specific theoretical framework to investigate the dynamics of the LIN28/let-7 system, and show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and the hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/mesenchymal (E/M) or partial EMT phenotype, in addition to epithelial and mesenchymal ones. We find significant correspondence between the existence of the three states of the two circuits: E-D; M-U; E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (as compared to either the pure E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-kB and c-MYC, we find that NF-kB, but not c-MYC, elevates the likelihood of E/M to gain stemness. Our results are consistent with emerging concept that cells undergoing partial EMT can gain stemness.
Citation Format: Mohit Kumar Jolly, Bin Huang, Mingyang Lu, Sendurai A Mani, Herbert Levine, Eshel Ben-Jacob. Coupled cellular decision-making of EMT and stemness: A bottom-up regulatory model. [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 B2-49.
Abstract IA02: The application of integrative sequencing for precision oncology
Authors: Chinnaiyan Arul 
Published: May 2016

Abstract
Studies of the genomic landscape of human cancers have demonstrated that most solid cancers have a multitude of mutations, a subset of which may be “actionable” with current drugs. Thus, the personalization of therapy for cancer will require molecular characterization of unique and shared genetic aberrations. Patients who have advanced/refractory cancer and are candidates for clinical trials could potentially benefit by identifying eligibility for “targeted” drugs based on the “actionable” genes in their specific tumor. Growing technological advances in genomic sequencing has now made it possible to consider the use of sequence data in a clinical setting. MI-ONCOSEQ initiative brings together expertise at the University of Michigan including clinical oncology, cancer genetics, bioinformatics, clinical pathology, social and behavioral sciences, and bioethics in order to implement clinical cancer sequencing. Our study identifies patients with advanced or refractory cancers that are eligible for clinical trials, consent them to the study, obtain biospecimens (tumor tissue, germline tissue) and store clinical data. The clinical sequencing team processes biospecimens, performs comprehensive sequencing and analysis of tumors to identify point mutations, copy number changes, rearrangements/gene fusions, and aberrant gene expression. Finally, a multi-disciplinary Sequencing Tumor Board deliberates on return of actionable or incidental genomic results.
Citation Format: Arul Chinnaiyan. The application of integrative sequencing for precision oncology. [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 IA02.
Abstract IA11: Differential networks and drug networks: A computational approach to drug discovery
Authors: Bernardo Diego di 
Published: May 2016

Abstract
Genome scale expression profiles (GEPs) of tumor samples versus non-tumor sampls can be analysed via innovative computational approaches to identify altered pathways and driver genes. These results can then be used to make identify appropriate small molecule therapies.
We developed and validated computational strategy, called Differential Co-expression Analysis (DiCA), to infer metabolic, signaling and regulatory pathways which are altered across two conditions (i.e. tumor vs non-tumor). DiCA is built on the hypothesis that genes in an active pathway are more likely to be regulated and hence co-expressed. On the contrary, inactive pathways will results in uncoordinated gene expression. DiCA measures how much a set of genes is co-expressed using a multidimensional information metrics. We apply DiCA to 100 Human HepatoCarcinoma samples collected within the MODHEP European Project. We demonstrate how DMI is able to correctly identify altered pathways known to be affected by HCC and to propose new hypothesis on HCC pathogenesis, which would be missed by conventional Differential Expression. We then show how GEPs from cancer samples can be used also to query a “drug network” by comparing them to transcriptional responses induced by drug treatment. The end result is a list of drugs which induce a transcriptional response similar to that of cancer samples thus hinting at which pathways are perturbed. Analogously, drugs inducing an “anti-similar” response, i.e. up regulating genes down regulated in cancer and vice-versa, could be investigated as potentially therapeutic. We tested these hypotheses on HCC samples demonstrating their potential usefulness.
Citation Format: Diego di Bernardo. Differential networks and drug networks: A computational approach to drug discovery. [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 IA11.
Abstract IA28: Towards a therapy for Angelman syndrome by targeting a long noncoding RNA to active UBE3A
Authors: Meng Linyan , Ward Amanda J. , Bennett C. Frank , Beaudet Arthur , Rigo Frank 
Published: May 2016

Abstract
Angelman syndrome (AS) is a single gene disorder characterized by intellectual disability, developmental delay, behavioral uniqueness, speech impairment, seizures, and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition increased paternal Ube3a expression. Despite a clear understanding of the disease-causing event in AS and the potential to harness the intact paternal allele to correct disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for AS by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of UBE3A protein in an AS mouse model ameliorated some cognitive deficits associated with the disease. Although additional studies of phenotypic correction are needed, for the first time we developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.
Citation Format: Linyan Meng, Amanda J. Ward, C. Frank Bennett, Arthur Beaudet, Frank Rigo. Towards a therapy for Angelman syndrome by targeting a long noncoding RNA to active UBE3A. [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 IA28.
Abstract PR06: The enhancer landscape involves a core noncoding RNA protein interaction network for C-MYC expression
Authors: Zhang Fan , Song Won-min , Li SiDe , Ajay Vashisht , Aguilo Francesca , Bagchi Anindya , Wohlschlegel James A. , Zhang Bin , Walsh Martin 
Published: May 2016

Abstract
Many long non-coding RNAs (lncRNAs) that regulate the capacity of cells to undergo oncogenic transformation still remain unknown. However, their involvement in chromatin organization has been an emerging principle in cancer epigenomics. This recent concept has been documented through recent studies of the gene -poor chromosomal region 8q24 surrounding the C-MYC locus to understand the mechanisms enforcing or suppressing tumor cell growth from C-MYC transcription levels. In light of such examples informing us of the DNA elements and the epigenomic composition that become integrated into molecular programs that regulate C-MYC, some lncRNAs in non-genic regions are considered landmarks that enforce chromatin state changes to accommodate C-MYC expression. Here, we use an integrative genomic and proteomic approach to gain insight of how an endogenously tagged lncRNA PCAT-1 utilizes the chromatin and biochemical context to shape C-MYC locus topology to promote tumor cell growth, survival and fitness. Our results now find that WDR74 forms an integrative hub involving recognition of the m7G cap of lncRNA transcripts along with, RNMT, RAM, BRD4, β catenin, EZH2 that assist in a program that enforce C-MYC transcription and stabilize transcripts through utilizing a comprehensive mixture of cis-acting DNA elements, lncRNAs and trans functioning transcriptional and RNA capping complexes for prostate tumor cell growth. Our results now place the lncRNA PCAT-1 and the novel interacting WD40 repeat protein WDR74 at the axis along with β catenin, BRD4 and EZH2, and additional RBPs as a non -canonical chromatin complex to shape the chromosomal topology that benefit prostate cancer cell growth.
Citation Format: Fan Zhang, Won-min Song, SiDe Li, Vashisht Ajay, Francesca Aguilo, Anindya Bagchi, James A. Wohlschlegel, Bin Zhang, Martin Walsh. The enhancer landscape involves a core noncoding RNA protein interaction network for C-MYC expression. [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 PR06.
Abstract OT2-01-04: E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group
Authors: Connolly R , Zhao F , Miller K , Tevaarwerk A , Wagner L , Lee M , Murray J , Gray R , Piekarz R , Zujewski JA , Sparano J 
Published: May 2016

Abstract
Background:
A potential mechanism of resistance to endocrine therapy in breast cancer involves changes in gene expression secondary to epigenetic modifications, which might be modulated with the use of histone deacetylase (HDAC) inhibitors such as entinostat. ENCORE 301, a phase II study evaluating the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with hormone receptor (HR)-positive advanced breast cancer who had experienced disease progression after a non-steroidal AI (NSAI), showed a significant improvement in progression-free survival (PFS), and overall survival (OS). Entinostat has been designated a Breakthrough Therapy by the FDA.
Methods:
E2112 is a multicenter randomized double-blind placebo-controlled phase III study (NCT02115282) enrolling patients with advanced HR-positive, HER2-negative breast cancer with prior disease progression on a NSAI (n=600). Patients receive exemestane 25mg po daily and entinostat/placebo 5mg po every week. Eligibility: Postmenopausal women and men, ECOG 0-1, locally advanced/metastatic invasive adenocarcinoma of the breast: ER/PR-positive, HER2-negative, measurable or non-measurable (20% cap) disease. Disease progression after NSAI use in the metastatic setting OR relapse while on or within ≤ 12 months of end of adjuvant NSAI therapy.
Statistics: Both PFS (central review) and OS are primary endpoints, and the study is designed to show an improvement in either PFS or OS. Secondary endpoints include: Safety and tolerability, objective response rate, changes in lysine acetylation status in peripheral blood mononuclear cells, patient-reported symptom burden and treatment toxicities, adherence. One-sided type 1 error 0.025 split between two hypotheses tests: 0.001 for PFS test and 0.024 for OS. PFS is tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS 4.1 to 7.1 months); OS is tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS 22 to 29.3 months).
E2112 was activated in March 2014 and accrual is anticipated to complete in 40 months.
Citation Format: Connolly R, Zhao F, Miller K, Tevaarwerk A, Wagner L, Lee M, Murray J, Gray R, Piekarz R, Zujewski JA, Sparano J. E2112: Randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group. [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 OT2-01-04.