bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA18: Noncoding RNA biomarkers in gastrointestinal cancers
Authors: Goel Ajay 
Published: March 2017

Abstract
Cancer has emerged as a leading cause of mortality worldwide, claiming over 8 million lives annually. Gastrointestinal (GI) cancers account for ~35% of these mortalities. Recent advances in diagnostic and treatment strategies have reduced mortality among GI cancer patients, yet a significant number of patients still develop late-stage cancer, where treatment options are inadequate. Emerging interests in “liquid biopsies” have encouraged investigators to identify and develop clinically-relevant noninvasive genomic and epigenomic signatures that can be exploited both as biomarkers capable of detecting premalignant and early-stage cancers, and as therapeutics for targeted cancer treatment. In this context, microRNAs (miRNAs), which are small non-coding RNAs that are frequently dysregulated in cancers have emerged as promising entities for development as liquid biopsy biomarkers. Albeit the future looks promising, current approaches for detecting miRNAs in blood and other biofluids remain inadequate. This presentation will summarize an update on exploiting circulating miRNAs as cancer biomarkers and evaluating their potential as tissue-based, and more importantly as liquid biopsies in GI cancers.
Citation Format: Ajay Goel. Noncoding RNA biomarkers in gastrointestinal cancers. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA18.
Abstract IA22: Clonal evolution and drug resistance in colorectal cancers: The EGFR-RAS signaling pathway
Authors: Bardelli Alberto 
Published: March 2017

Abstract
When metastatic colorectal cancers are challenged with targeted agents almost invariably a subset of cells insensitive to the drug emerges. As a result, in most instances, targeted therapies are only transiently effective in patients. Strategies to prevent or overcome resistance are therefore essential to design the next generation of clinical trials. How can we overcome the near-certainty of disease recurrence following treatment with targeted agents? To address this question a deeper understanding of the evolutive nature of cancer cells is necessary. We used colorectal cancer (CRC) as a model system to test the hypothesis that by understanding tumor's evolution the emergence of drug resistance can be controlled. We find that clonal dynamics can be monitored in real time in the blood of patients, and liquid biopsies can be used to intercept the emergence of resistant clones before relapses are clinically manifest. We discovered that a multistep clonal evolution process driven by progressive increases in drug fitness underlies the development of resistance in cells and patient avatars. To have long-term efficacy, the use of targeted therapies must take into account the continuous evolution of cancer cells, that is to say, therapies must adapt to tumor evolution. One possibility is to anticipate the changes the tumors will make. For example, by knowing in advance how CRC cells overcome resistance to EGFR blockade, we devised further rounds of therapy. Another approach is to unleash the ability of cancer cells to be recognized by the immune system. We tested this possibility in syngeneic mouse models of colorectal tumors. Our findings indicate that inactivation of DNA repair triggers dynamic neoantigen evolution; impairs cancer growth and leads to prolonged therapeutic responses.
Citation Format: Alberto Bardelli. Clonal evolution and drug resistance in colorectal cancers: The EGFR-RAS signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA22.
Abstract IA29: Eliminating racial disparities in colorectal cancer
Authors: Grubbs Stephen 
Published: March 2017

Abstract
The Delaware Cancer Advisory Council was convened in 2001 by Governor Ruth Ann Minner to develop a statewide cancer control program. Rather than reporting a comprehensive cancer control program, the Council in 2002 recommended a limited number of achievable deliverables to reduce Delaware's high rates of cancer incidence and mortality. The Delaware Legislature and the Governor Minner accepted the recommendations and fully funded the program. Three key elements of the program include a statewide coordinated colorectal screening program with coverage of the uninsured, a cancer treatment program providing for the uninsured, and an emphasis of African American cancer disparity reduction. The screening program featured statewide nurse navigation, colonoscopy promotion, statewide marketing, and coverage for both screening and up to two years of cancer treatment for the uninsured.
Over the next ten years, the program eliminated the Caucasian and African American colorectal cancer disparities between by raising screening rates, lowering the stage at diagnosis, reducing the incidence, and finally eliminating the mortality disparity. All Delaware populations achieved improved colorectal cancer outcomes with the greatest gain in the African American community that closed the disparity gaps.
Delaware can be viewed as a model for success, achieved when all parties including government, health care systems, providers, and the public are determined together to improve health and tackle health disparities.
Citation Format: Stephen Grubbs. Eliminating racial disparities in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr IA29.
Abstract PR03: The pig as a model for colorectal cancer
Authors: Wander Carolin , Flisikowska Tatiana , Flisikowski Krzysztof , Schulze Érica , Fries Hans-Rudolf , Bauersachs Stefan , Kind Alexander , Schnieke Angelika 
Published: March 2017

Abstract
Colorectal cancer is the fourth most common cancer worldwide with a mortality of more than 50%. Contrary to the increasing advances in cancer research colorectal cancer deaths are increasing in number. Most animal models also for colorectal cancer are in rodents. However, mice differ significantly in size, lifespan, physiology, anatomy and diet. Furthermore, genetically engineered mouse models for colorectal cancer show polyp development in the small intestine, contrary to the human phenotype that develops polyps in the large intestine. Therefore, a more suitable animal model is necessary. Pigs are increasingly recognized as a valuable model facilitating diagnostic and therapeutic strategies at human scale, longitudinal studies of disease initiation, progression and treatment response in preclinical trials.
We generated gene targeted cloned pigs carrying the nonsense mutation, APC1311 that is orthologous to a human mutation associated with a very severe phenotype of colorectal cancer and the inherited condition familial adenomatous polyposis (FAP). In pigs the APC1311 mutation results in multiple adenomatous polyps in the colon and rectum that, so far, have progressed to carcinoma in situ. Histological and molecular analysis show that the porcine model recapitulates all major features of early stage human FAP. Breeding and analysis of the mutant pig herd has revealed segregation of traits that affect polyposis severity in animals carrying the same APC1311 mutation. We are currently investigating the genetic basis for this effect by comparing normal mucosa samples from low and high polyp animals and have discovered some genes that are differentially expressed. A progression study comparing low-grade with high-grade adenomas also identified differentially expressed genes and miRNAs.
Further improvements of this model are targeted at generating organ/tissue specific Cre pigs to activate latent mutations such as KRAS and TP53 mutations in the colon. Additionally to encourage cancer progression we are working on the introduction of ubiquitous Cas9 expression in our APC1311 pigs to allow the activation of oncogenic pathways locally in vivo.
Our porcine model provides a powerful new resource for preclinical cancer research, including identifying and investigating novel biomarkers for early detection.
This abstract is also being presented as Poster A20.
Citation Format: Carolin Wander, Tatiana Flisikowska, Krzysztof Flisikowski, Érica Schulze, Hans-Rudolf Fries, Stefan Bauersachs, Alexander Kind, Angelika Schnieke. The pig as a model for colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr PR03.
Abstract A10: Correlating magnetic resonance and molecular imaging using three dimensional untreated virtual control
Authors: Jacobs Joshua , Hawkins-Darrud Andrea , Harrison Robert , Johnston Sandra , Kinahan Paul , Swanson Kristin 
Published: March 2017

Abstract
With mean survival from glioblastoma multiforme (GBM) barely edging over 15 months, it become imperative to develop novel tools informing on both progression and treatment efficacy. As the aggressive growth of GBM outstrips available resources, regions of hypoxia develop. Hypoxia can be clinically assessed through [18F]-flouromisonidazole (FMISO) PET. However, PET imaging suffers from low resolution and reconstruction artifact. We present the comparative and predictive results of a multi-stage model utilizing the mathematical biology of cancer and the physics of PET imaging.
Our mathematical model of GBM characterizes cancer cells into the interacting phenotypes of normoxic, hypoxic, and necrotic cells supported by vasculature. The pharmacokinetic activity of FMISO is induced in the simulated tissue then acquired and reconstructed by an analytic simulator of the PET process. This multi-stage process creates a patient-specific virtual PET images with characteristic of the clinical PET scan. Extending previous work, we model the full three-dimensional dynamics of tumor progression, pharmacokinetic activity, and FMISO PET for the tumor kinetics of six GBM patients. Virtual and clinical FMISO PET images are compared.
Overall hypoxic burden and spatial distribution show strong correspondence between virtual and clinical FMISO PET images for all six patients.
Simulated FMISO PET dynamics, with tumor kinetics derived from routine clinical MRI scans, provide a unique and evolving tool giving insight into the biological connections between magnetic resonance and molecular imaging.
Citation Format: Joshua Jacobs, Andrea Hawkins-Darrud, Robert Harrison, Sandra Johnston, Paul Kinahan, Kristin Swanson. Correlating magnetic resonance and molecular imaging using three dimensional untreated virtual control. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A10.
Abstract A20: Use of cell-free plasma DNA for dynamic monitoring of response to cytotoxic chemotherapy
Authors: Ruderman Daniel , Patsch Katherin , Matasci Naim , Soundararajan Anjana , Diaz Patricia , Gross Mitchell E. 
Published: March 2017

Abstract
Background: There is great interest in utilizing blood-based circulating biomarkers to gain molecular insight into cancer. Most of the published data examines circulating free DNA (cfDNA) obtained at a single time-point. Here, we developed and utilized an methodology for monitoring cfDNA at multiple time-points within 24 hours of cytotoxic chemotherapy infusions over sequential cycles.
Methods: To monitor the short- and long-term responses to treatment, we analyzed cfDNA from plasma drawn immediately before (baseline), 5 hours and 24 hours after administration of docetaxel chemotherapy. We quantified the extracted cfDNA via qPCR of Long interspersed nuclear elements (LINE1). We then amplified and performed targeted deep sequencing (Illumina Miseq) of androgen receptor (AR) exon 8. To reduce PCR variability, we pooled 10 technical replicate amplifications.
Results: Detailed data and time courses are presented for a patient with castrate resistant prostate cancer metastatic to bone treated with docetaxel/everolimus/bevacizumab according to a recently published trial (J Clin Oncol 33, 2015 suppl; abstr 5066). LINE1 was measured at 34.4 pg/mcl at baseline prior to treatment. Targeted deep sequencing of AR exon 8 revealed two independent mutations at 11% (H874A) and 13% (T877A), respectively. 5 hours after start of docetaxel infusion, total DNA content measured by LINE1 decreased to 0.4 pg/mcl. However, H874A and T877A mutations were observed at frequencies similar to the baseline values. A similar pattern was observed for samples obtained at Cycle 2 (21 days later). Specifically, baseline values for LINE1 (67.4 pg/mcl), H874A (3%), and T877A (7%) were noted to change to LINE1 (8.5 pg/mcl), H874A (6%), and T877A (17%) 5 hours later.
Conclusion: We conclude that cytotoxic chemotherapy can produce effects immediately observable on cfDNA markers. The generalizability and clinical relevance of these findings will require follow up studies involving more patients.
Citation Format: Daniel Ruderman, Katherin Patsch, Naim Matasci, Anjana Soundararajan, Patricia Diaz, Mitchell E. Gross. Use of cell-free plasma DNA for dynamic monitoring of response to cytotoxic chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A20.
Abstract A24: ZAP-70 and SYK regulation in the B cell receptor pathway in chronic lymphocytic leukemia
Authors: Frushicheva Maria P. 
Published: March 2017

Abstract
Recent discoveries of inhibitors for Syk (spleen tyrosine kinase) family protein kinases provide promising therapeutic options for patients with chronic lymphocytic leukemia (CLL). However, molecular mechanisms of these inhibitors in the B cell receptor (BCR) signaling pathway are not well understood. This study investigates functionality of Syk family protein kinases and their inhibitors in the BCR signaling pathway in CLL cells. In this work, we tested several computational models of ZAP-70 (ζ chain–associated protein kinase of 70 kD) and SYK regulation in the BCR signaling pathway to explain the observed differences in the clinical behaviors of ZAP-70+ / ZAP-70- phenotypes of CLL patients. Specifically, we characterized the effects of different ZAP-70 and SYK expression and phosphorylation levels on the BCR activation threshold. Using stochastic simulations of BCR signaling network, we reproduced the correlations between the observed and calculated trends quantitatively. We find that an increased ZAP-70 expression is correlated with decreased levels of phosphorylated ZAP-70 and SYK, depending on the amount of SYK that is expressed in cells. Our calculations also show that ZAP-70 is able to compensate for a missing SYK functionality with an increased BCR activation threshold in SYK-deficient B-CLL cells, similar to SYK-deficient B cells. Furthermore, our computational model predicts a dual inhibition of ZAP-70 and SYK for the treatment of ZAP-70+ patients, as a selective inhibition of either ZAP-70 or SYK results in disease relapse. Our findings uncover molecular mechanisms of ZAP-70 and SYK regulation in the BCR signaling pathway for the development of CLL immunotherapies.
Citation Format: Maria P. Frushicheva. ZAP-70 and SYK regulation in the B cell receptor pathway in chronic lymphocytic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A24.
Abstract A25: Systems biology approach to delineating DNA damage response and R-loop dependencies in Ewing sarcoma
Authors: Gorthi Aparna , Loranc Eva , Lin Cao , Bishop Alexander JR 
Published: March 2017

Abstract
Ewing sarcoma is a rare, yet highly aggressive family of bone and soft tissue tumors that afflicts children and young adults. It is the prototypical example of mesenchymal tumors driven by a fusion oncogene involving the EWSR1 gene, most frequently EWS-FLI1. Ewing sarcoma is exquisitely sensitive to genotoxic agents, and more recently PARP1 inhibitors, predominantly when detected at an early stage. However, the molecular basis for this sensitivity is relatively under-explored. Further, the long term side effects of these drugs pose a critical barrier to effective treatment. In this study, we proposed to delineate the pathways dictating Ewing sarcoma chemosensitivity and identify alternative avenues for targeted therapy.
R-loops are three nucleic acid DNA structures consisting of an RNA:DNA hybrid and a displaced complementary DNA loop. The importance of R-loops in both being causative as well as disruptive in DNA damage as well as DNA damage response has emerged through recent studies. Our previous work has demonstrated that Ewing sarcoma cell lines have high levels of endogenous damage as well as replication stress. We observe that Ewing cell lines have elevated levels of persistent R-loops and impaired homologous recombination repair of double strand breaks. In the present study, we use a multimodal, systems biology approach involving high-throughput RNAi based survival data, time-course RNA-seq in response to two chemotherapeutics, Chromatin immunoprecipitation-seq and DNA:RNA hybrid immunoprecipitation-seq datasets across multiple Ewing sarcoma and control cell lines. Our data led to the identification of a subset of genes whose expression patterns in response to DNA damage is dysregulated in Ewing sarcoma. Predominantly, among these genes is a network of RNA binding proteins that highlights the importance of RNA metabolism in DNA damage response. We also observe a concomitant alteration in damage-dependent transcription. Finally, we identified several compensatory mechanisms that are upregulated in Ewing sarcoma (RNASEH2, FEN1, Fanconi Anemia, etc.) in order to manage the exacerbated genomic stress conditions and targeting any of these pathways leads to severe tumor cell cytotoxicity. We therefore propose the use of these pathways as potential candidates for targeted therapy.
Citation Format: Aparna Gorthi, Eva Loranc, Cao Lin, Alexander JR Bishop. Systems biology approach to delineating DNA damage response and R-loop dependencies in Ewing sarcoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A25.
Abstract A32: Tumor-matrix tnteractions in early ductal invasions: Integrating histology imaging with computational modeling
Authors: Rejniak Katarzyna A. , Lloyd Mark C. , Kasprzak Agnieszka , Bui Marilyn 
Published: March 2017

Abstract
Progression from a ductal carcinoma in situ (DCIS) to an invasive tumor is a major step initiating a devastating and often lethal metastatic cascade. One sentinel event that initiate this process is the development of ductal microinvasions, i.e., small cohorts of tumor cells that breach the basement membrane surrounding the duct, and migrate through the extracellular matrix (ECM). This process is difficult to reproduce experimentally and investigate in a fully controlled way. However, mathematical modeling based on physical principles and medical imaging can shed light on interactions between tumor cells and the surrounding stroma during the spread of microinvasions.
We used a combination of advanced image analysis techniques applied to patients' histology data, that include both tissue regions and single cells segmentation, with multi-factorial classification to extract feature data which identifies specific properties of individual tumor cells inside the duct and on the invasive front. These histology-based quantitative data were then used to calibrate a hybrid agent-based mathematical model of DCIS-ECM interactions that takes into account both individual tumor cells and the underlying ECM fibril structure. The model was employed in a computational simulation study to delineate physical properties of the matrix fibers that can facilitate and/or prevent formation and progression of ductal microinvasions.
Our integrated approach incorporating medical imaging and computational modeling, allowed us to predict the dynamics of emerging ductal microinvasions that are consistent with the observed clinical data. We showed how changes in the local microenvironmental niche near the DCIS edge leads to initiation of ductal microinvasions. We identified physical properties of the matrix that can facilitate or prevent the progression of such microinvasions. Our methods also provide a tool for quantifying morphological and immunohistochemical properties of individual cells within the mammary ducts and ductal microinvasion, as well as a tool for testing biomechanical hypotheses of tumor cell-tumor matrix interactions.
These findings can be directly compared to the patient histology samples and can lead to development of new prognostic methods and therapeutic interventions by targeting the tumor preinvasive niche.
Citation Format: Katarzyna A. Rejniak, Mark C. Lloyd, Agnieszka Kasprzak, Marilyn Bui. Tumor-matrix tnteractions in early ductal invasions: Integrating histology imaging with computational modeling. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A32.
Abstract A37: ‘Touch-and-go' behavior of cancer cells in spatially-confined, fiber-like microenvironments
Authors: Milano Daniel , Muthuswamy Senthil , Asthagiri Anand 
Published: March 2017

Abstract
In a crowded, fibrillar tumor microenvironment (TMEN), invading cancer cells encounter and interact with many other cells and cell types. Whether cancer cells stop migrating or reverse direction at every encounter with another cell, or circumnavigate and slide around the encounter, will affect the efficiency of the invasion process. We find that breast cancer cells migrating along fiber-like micropatterns (FLMs) respond differently to cell-cell encounters than what is expected based on the classically-established phenotype of contact-inhibition of locomotion (CIL). Cancer cells are remarkable efficient at sliding around other cancer cells, even along FLMs much narrower than their own cell body. In contrast, non-transformed breast epithelial cells reverse direction upon encountering other normal cells. Differences in cell size fail to predict these outcomes. Interestingly, the participation of normal cells in invasive sliding behavior increases when interacting with a cancer cell rather than another a normal cell. This induction of cancer-like behavior in normal cells suggests that heterotypic interactions between disparate cell types in the TMEN may produce synergistic, disease-promoting collective behaviors. Furthermore, using a series of individual and combinatorial genetic perturbations, we show that genetic factors (ErbB2, E-cadherin, PARD3, TGFbeta) quantitatively shift the ability of normal cells to slide. Specifically, successive genetic perturbations enable normal cells to slide on progressively narrower FLMs. These results suggest that as fibers align and mature during cancer progression, coincident genetic perturbations enable cells to take advantage of the widening fibrillar tracks to execute slides and achieve more efficient dispersion in a crowded microenvironment.
Citation Format: Daniel Milano, Senthil Muthuswamy, Anand Asthagiri. ‘Touch-and-go' behavior of cancer cells in spatially-confined, fiber-like microenvironments. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A37.