bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B21: PDE10A overexpression in colon cancer cells and tumors relative to normal colonocytes and colon mucosa
Authors: Lindsey Ashley S. , Lee Kevin , Andrews Joel , Chang Wen-Chi L. , Ramirez-Alcantara Veronica , Tan Marcus , Grizzle William , Clapper Margie L. , Piazza Gary 
Published: March 2017

Abstract
Phosphodiesterase 10A (PDE10A) is a cGMP and cAMP degrading PDE isozyme expressed in areas of the brain controlling motor function and cognition. PDE10A has been strongly linked to diseases such as schizophrenia and Huntington's disease, for which PDE10A inhibitors are currently in clinical trials and appear to be well tolerated. Although, PDE10A has limited expression and no known function in peripheral tissues, high levels were measured in colon tumor cells in vitro and in vivo compared with cells derived from normal colon and colonic mucosa (Li et al., Oncogene 2015). PDE10A inhibition by small molecules or genetic silencing attenuated colon tumor cell growth by a mechanism involving cGMP/PKG activation, the suppression of oncogenic β-catenin, and a decrease in TCF transcriptional activity (Li et al., Oncogene 2015). These observations suggest that PDE10A may play an unrecognized role in tumorigenesis and provide a novel therapeutic target for colorectal cancer chemoprevention or therapy. The human colon tumor cell lines, HCT116, HT29, Caco2, and SW480, show elevated expression of PDE10A as compared to the normal colon mucosal epithelial cell line, NCM460, and are more sensitive to PDE10 inhibitors relative to NCM460 cells. Subcutaneous tumors established from HT29 colon tumor cells in athymic mice expressed elevated levels of PDE10A as compared to normal mouse colon tissue. Colon tumors collected from heterozygous APCmin/+FCCC mice displayed an elevation in PDE10A levels as compared to uninvolved mucosa from the APCmin/+FCCC mice and wild type colon mucosa. Overexpression of PDE10A mRNA and protein levels was also observed in colon adenocarcinomas relative to uninvolved colon mucosa in specimens obtained from colorectal cancer patients. These observations, along with recent findings that a novel sulindac derivative (ADT-061) with PDE10A inhibitory activity suppresses tumor formation in the APCmin/+FCCC mouse model of colon cancer without apparent toxicity, suggests that PDE10A provides a novel therapeutic target for cancer cell specific inhibition of tumor growth.
Citation Format: Ashley S. Lindsey, Kevin Lee, Joel Andrews, Wen-Chi L. Chang, Veronica Ramirez-Alcantara, Marcus Tan, William Grizzle, Margie L. Clapper, Gary Piazza. PDE10A overexpression in colon cancer cells and tumors relative to normal colonocytes and colon mucosa. [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 B21.
Abstract B25: Black-white differences in colorectal cancer screening and incidence over time by age and sex
Authors: Fedewa Stacey A. , Corley Douglas , Jemal Ahmedin , Siegel Rebecca , Goodman Michael , Doubeni Chyke 
Published: March 2017

Abstract
Introduction: Blacks have the highest colorectal cancer (CRC) burden of any racial/ethnic group and the underlying reason for this disparity has not been fully elucidated. Continued examination of incidence in relation to screening, which is recommended for men and women beginning at age 50 years, may provide valuable insights into these disparities. The present study examined black-white differences in CRC incidence and screening patterns by age and sex over time.
Methods: National Health Interview Surveys between 2000-2015 were used to estimate screening prevalence and prevalence ratios (PR) among adults 50 years and older by non-Hispanic white/black race and sex. Data from the SEER were used to estimate age-sex-specific incidence rates from 1992-2013.
Results: From 2000 to 2015, CRC screening prevalence in age 50 years and older increased by 69% in whites (from 39.4% to 66.5%) and by 98% in blacks (from 31.1% to 61.4%) on a relative scale. Increases in CRC screening were evident in both men and women. During this time period, black-white differences also narrowed, such that CRC screening in blacks was 19% lower than in whites in 2000 (PR=0.81, 95%CI 0.71,0.92) but only 6% lower in 2015 (PR=0.94, 95%CI 0.88, 1.00). Absolute black-white differences in CRC incidence rates were slightly larger for men than for women (men: 3.0-6.0 versus women: 2.8-5.4 per 100,000) in people 35-49 years old, but decreased overtime in both groups. In 50-79-year-olds, absolute black-white incidence differences were larger for men prior to 2003 (men: 19.8-28.9 versus women: 28.3-33.1 per 100,000) and during 2004-2013 (men: 27.7-53.3 versus women: 20.6-38.7 per 100,000). In 35-49-year-olds, black-white incidence rate ratios (IRR) decreased overtime from 1992-2000 to 2009-2013 in both men (1.47 to 1.19) and women (1.49 to 1.17), but increased in both men (1.06 to 1.38) and women (1.15 to 1.49) for those 50 years and older.
Conclusions: Black-white differences in CRC incidence in both absolute and relative terms are greatest in screening-eligible adults and have persisted in recent years whereas absolute differences in incidence in those younger than 50 are relatively small. These patterns may reflect racial gaps in screening uptake. However, disparities in CRC screening prevalence have narrowed in recent years and may portend convergence in CRC incidence rates.
Note: This abstract was not presented at the conference.
Citation Format: Stacey A. Fedewa, Douglas Corley, Ahmedin Jemal, Rebecca Siegel, Michael Goodman, Chyke Doubeni. Black-white differences in colorectal cancer screening and incidence over time by age and sex. [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 B25.
Abstract B26: Baseline serum albumin as a prognostic actor in patients with stage I and II colon adenocarcinoma
Authors: Gonzalez-Trejo Sagrario , Carrillo Jose F. , Carmona-Herrera Doris , Herrera-Goepfert Roberto , Ochoa-Carrillo Francisco J. , Aiello-Crocifoglio Vincenzo , Gallardo-Rincon Dolores , Onate-Ocana Luis F. 
Published: March 2017

Abstract
Background: Patients with stage I or II Colon carcinoma (CC) have a significant risk of recurrence after adequately performed curative resection. Adjuvant chemotherapy has not improved recurrence or survival in such patients. In this study, a prognostic model in patients with stage I or II CC, based on Baseline serum albumin (BSA) and other common clinical markers is presented.
Methods: Consecutive cases with CC treated at a single cancer center in Mexico City from January 1998 to December 2014, with diagnosis of adenocarcinoma by colonoscopy and biopsy were included in this cohort. Clinical history and chemistry data were registered, and patients were treated according to standard guidelines. Follow-up continued until June 2016; the Kaplan-Meier method and the Cox model were used to analyze the association of prognostic factors and overall survival (OS), and Hazard ratios (HR) were calculated.
Results: 1,259 cases of CC were treated, but only 496 patients have stage I and II CC and were included in the database: 234 women (47.2%) and 262 males (52.8%) and their mean age was 59.9 years (SD 14.9); 96, 339, 31 and 30 cases were pTNM stages I, IIa, IIb and IIc, respectively. BSA (HR 2.185), male gender (HR 1.43), baseline hemoglobin (HR 0.916), baseline platelet count (HR 0.998), baseline neutrophil count (HR 1.085), albumin/globulin ratio (HR 0.197), baseline platelet/lymphocyte ratio (HR 1.001), body mass index (HR 0.958), TNM stages (IIa HR 1.74, IIb HR 2.08, IIc HR 2.59; Stage I is the reference category), use of adjuvant chemotherapy (HR 0.465) and R classification (R1 HR 1.306, R2 HR 2.55, no resection HR 6.93; R0 is the reference category). Predicted survival functions using this model, defined 4 risk groups that showed better prognostic value than simple TNM stages I-IIc.
Conclusion: BSA is an independent, significant, simple, cheap and widely available prognostic factor in patients with CC. BSA and other clinical factors add significant prognostic information to TNM classification. Feasibly, it can be used to develop multivariate prognostic models with clinical impact defining the use of adjuvant chemotherapy. The use of histopathological and immunohistochemical markers could improve the prognostic information of this model.
Citation Format: Sagrario Gonzalez-Trejo, Jose F. Carrillo, Doris Carmona-Herrera, Roberto Herrera-Goepfert, Francisco J. Ochoa-Carrillo, Vincenzo Aiello-Crocifoglio, Dolores Gallardo-Rincon, Luis F. Onate-Ocana. Baseline serum albumin as a prognostic actor in patients with stage I and II colon adenocarcinoma. [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 B26.
Abstract IA04: The carcinogenic potential of bacterial biofilms
Authors: Sears Cynthia L. 
Published: March 2017

Abstract
The colonic microbiome is hypothesized to contribute to CRC pathogenesis and to potentially act as an initiator of colon oncogenesis, in part via induction of specific mucosal pro-carcinogenic immune responses. Both we and others have presented data from experimental models implicating specific bacteria in colon carcinogenesis. Enterotoxigenic Bacteriodes fragilis (ETBF), Escherichia coli containing the pks island [E. coli (pks)] and Fusobacterium nucleatum represent colon carcinogenic bacteria strongly implicated to date in both experimental models and human disease. To further address the links between the microbiota and human colon cancer, we are prospectively studying the microbial associations of human CRC together with parameters of mucosal immunity. Paired surgical CRC samples and normal colon mucosa are studied along with colon biopsies (right and left) of healthy controls undergoing screening colonoscopy. We have presented data demonstrating that sporadic colon tumors located proximal to the hepatic flexure are characterized by invasive polymicrobial biofilms that extend to normal colon tissue far distant from the tumor. In contrast, biofilm formation is infrequent in colon tumors distal to the hepatic flexure and in the mucosa of colonoscopy controls. Biofilm formation in the human colon is associated with changes in E-cadherin, IL-6 induction, activation of pStat3, colonic epithelial cell proliferation as well as polyamine metabolism. These data suggest biofilm formation promotes pro-carcinogenic immune and epithelial signaling in the human colon. We have further tested our hypothesis that biofilm formation contributes to colon carcinogenesis by examining surgically-removed colons from individuals with Familial Adenomatous Polyposis (FAP) who are destined, as Apc+/- heterozygotes, to develop colon cancer. In contrast to sporadic CRC, early stage FAP patients display patchy biofilm formation throughout the colon and the bacterial composition of FAP-associated colon biofilms differs. Murine studies support synergistic induction of colon tumor formation by select biofilm bacterial members. Together our studies provide additional support for the hypothesis that the microbiota and, specifically, biofilms are an environmental contributor to CRC pathogenesis.
Citation Format: Cynthia L. Sears. The carcinogenic potential of bacterial biofilms. [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 IA04.
Abstract A03: Formins stabilize cell-ECM adhesions during invasion onset
Authors: Fessenden Tim , Beckham Yvonne , Perez-Neut Mathew , Juan Guillermina Ramirez-San , Gardel Margaret L. 
Published: March 2017

Abstract
The onset of local invasion typically defines the transition from benign to malignant tumors. This pathological definition has clear implications for cell behaviors governing invasion onset, which nonetheless remain mysterious. Thus we asked whether established cytoskeletal regulators contributed specifically to invasion in multicellular ensembles.
We investigated roles of actin nucleators from the formin family and the Arp2/3 complex during collective invasion by two cell types: tumor explants from PyMT mice, and acini of Manin-Darby Canine Kidney (MDCK) cells, which initiate collective invasion in response to Hepatocyte Growth Factor (HGF). Contrary to our expectations, inhibition of Arp2/3 did not prevent invasion in either cell type. The pan-formin inhibitor SMIFH2, however, drastically reduced invasive fronts in both cell types. This phenotype was specific to 3D invasion, as formins were dispensable for 2D motility by single cells or cell collectives.
We identified Diaphanous 1 (Dia1) and FHOD1 as formin family members required for invasion by MDCK acini. Live imaging of Dia1 knockdown acini revealed that while they formed transient extensions into the collagen, these were too unstable to support invasion.
Despite these defects, Dia1 knockdown cells could deform the collagen matrix locally and exerted traction stresses equal to controls. Stiffer, bundled collagen gels potentiated invasion by control acini but could not rescue invasion by Dia1 knockdown acini.
We then imaged acini in which GFP-Lifeact and mCherry-Myosin Light Chain were coexpressed as they invaded into labelled collagen. During invasion onset, we observed formation of subcellular actomyosin puncta on minute timescales. These puncta could adhere stably and alter collagen even while the cell continued to change shape and migrate within the acinus. Such adhesions formed rarely and with unstable dynamics in Dia1 knockdown acini.
Thus formins may contribute to malignancy through molecular and physical mechanisms distinct from overall cell contractility. Rather, they mediate invasion in 3D contexts where competing cell-cell and cell-ECM interactions make stringent local requirements of adhesion stability. This work provides a bridge between cell motility in 3D and canonical models of 2D migration.
Citation Format: Tim Fessenden, Yvonne Beckham, Mathew Perez-Neut, Guillermina Ramirez-San Juan, Margaret L. Gardel. Formins stabilize cell-ECM adhesions during invasion onset. [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 A03.
Abstract A13: Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer
Authors: Cook Leah , Araujo Arturo , Pow-Sang Julio , Budzevich Mikalai , Basanta David , Lynch Conor C. 
Published: March 2017

Abstract
The ability to rapidly assess the efficacy of therapeutic strategies for incurable bone metastatic prostate cancer is an important and urgent need. Pre-clinical in vivo models provide insights yet are limited in their capacity to interrogate temporal multi-cellular interactions occurring in the cancer-bone microenvironment. Computational and mathematical models that integrate and, are validated experimentally, can overcome this limitation and accelerate biological research. Here, we describe how a biologically driven discrete continuum hybrid cellular automaton (HCA) model approach can dissect the pleiotropic effects of inhibiting putative therapeutic targets such as, TGFβ. Using our HCA model, we tested five different therapeutic doses delivered in two therapeutic windows. In silico results predict that TGFβ inhibition, applied prior to tumor seeding acts by directly impacting prostate cancer cell viability but also by simultaneously restricting osteoclast formation and unexpectedly, promoting osteoblast differentiation. This effect was dependent on the prostate cancer cell expression of TGFβ receptors. In silico predictions were validated with two independent in vivo models of bone metastatic prostate cancer (PAIII and C4-2B). Using immunohistochemical information from human bone metastatic prostate cancer samples, we also demonstrate how the HCA can be used to predict the evolution of heterogeneous disease in response to applied therapies. Collectively, these data underscore the power of a combined HCA/biological approach in optimizing the efficacy of applied therapies and measuring their impact on bone metastatic prostate cancer.
Citation Format: Leah Cook, Arturo Araujo, Julio Pow-Sang, Mikalai Budzevich, David Basanta, Conor C. Lynch. Predictive computational modeling to define effective treatment strategies for bone metastatic prostate cancer. [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 A13.
Abstract A17: Genomic analysis and simulation for understanding heterogenous cancer evolution
Authors: Niida Atsushi , Takahashi Yusuke , Uchi Ryutaro , Mimori Koshi , Miyano Satoru 
Published: March 2017

Abstract
A malignant tumor harbors multiple clones generated by branching evolution. This phenomenon, called intratumor heterogeneity, could foster evolutionary adaptation and presumably causes therapeutic failure. To investigate intratumor heterogeneity in colorectal cancer, we performed whole exome sequencing of samples obtained from geographically separated regions in a single colorectal tumor. The multiregional sequencing showed early-acquired mutations, which was shared by all regions as well as late-acquired mutations, which shaped extensive intratumor heterogeneity. Next, to explore the principles underlying the intratumor heterogeneity, we built a cellular automaton model, termed the BEP model, which can simulate the branching evolution in silico. We then extensively searched for conditions that reproduce the multiregional sequencing data by performing simulations with various parameter settings on a supercomputer. The simulation analysis suggested that neutral evolution boosted by high mutation rate can extensive intratumor heterogeneity. Collectively, This study identified the possible principle underlying intratumor heterogeneity, which provides novel insights into the origin of cancer robustness and evolvability.
Citation Format: Atsushi Niida, Yusuke Takahashi, Ryutaro Uchi, Koshi Mimori, Satoru Miyano. Genomic analysis and simulation for understanding heterogenous cancer evolution. [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 A17.
Abstract A29: Heterogeneity of androgen receptor dynamics and drug response in prostate cancer cells
Authors: Patsch Katherin , Soundararajan Anjana , Engeln Mark , Gross Mitchell E. , Mumenthaler Shannon M. , Ruderman Daniel 
Published: March 2017

Abstract
Background: Recent studies suggest that the spatio-temporal dynamics of critical signaling molecules can mediate heterogeneous response to therapeutic intervention. Here, we set out to apply live cell imaging of single cells in high throughput to correlate the dynamics of androgen receptor (AR) with response to taxane chemotherapy in heterogeneous prostate cancer (PCa) cell populations.
Methods: We previously developed a 3-step high throughput imaging and data analysis workflow to improve measurements of the dynamic phenotype in heterogeneous populations. We treated PCa cells stably expressing GFP-AR with AR ligand and quantified nuclear/cytoplasmic GFP intensity to measure nuclear translocation of AR over a 30 min time course. Then we treated cells with paclitaxel and tracked cells' response for 24h.
Results: Applied to PCa cell lines stably expressing GFP-AR, we measured considerable heterogeneity of AR translocation in response to ligand stimulation. We quantified populations of non-responders and classified responding cells based on the dynamics of AR. Evaluation of cell morphology revealed a fraction of relatively large cells to be exclusively slow responders to AR ligand. We measured heterogeneous response to treatment with paclitaxel that correlated with cell phenotype.
Conclusion: We conclude that cell morphology features in heterogeneous PCa cell populations correlate with AR translocation dynamics and drug response. Future experiments will include expression of the constitutively active AR variant AR-v7 to analyze its effect on the dynamics of wild-type AR and on single cell response to paclitaxel chemotherapy.
Note: This abstract was not presented at the conference.
Citation Format: Katherin Patsch, Anjana Soundararajan, Mark Engeln, Mitchell E. Gross, Shannon M. Mumenthaler, Daniel Ruderman. Heterogeneity of androgen receptor dynamics and drug response in prostate cancer cells. [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 A29.
Abstract A31: Early signaling dynamics of the epidermal growth factor receptor
Authors: Reddy Raven J. 
Published: March 2017

Abstract
Despite extensive study of the EGF receptor (EGFR) signaling network, the immediate posttranslational changes that occur in response to growth factor stimulation remain poorly characterized; as a result, the biological mechanisms underlying signaling initiation remain obscured. To address this deficiency, we have used a mass spectrometry-based approach to measure system-wide phosphorylation changes throughout the network with 10-s resolution in the 80 s after stimulation in response to a range of eight growth factor concentrations. Significant changes were observed on proteins far downstream in the network as early as 10 s after stimulation, indicating a system capable of transmitting information quickly. Meanwhile, canonical members of the EGFR signaling network fall into clusters with distinct activation patterns. Src homology 2 domain containing transforming protein (Shc) and phosphoinositol 3-kinase (PI3K) phosphorylation levels increase rapidly, but equilibrate within 20 s, whereas proteins such as Grb2-associated binder-1 (Gab1) and SH2-containing tyrosine phosphatase (SHP2) show slower, sustained increases. Proximity ligation assays reveal that Shc and Gab1 phosphorylation patterns are representative of separate timescales for physical association with the receptor. Inhibition of phosphatases with vanadate reveals site-specific regulatory mechanisms and also uncovers primed activating components in the network, including Src family kinases, whose inhibition affects only a subset of proteins within the network. The results presented highlight the complexity of signaling initiation and provide a window into exploring mechanistic hypotheses about receptor tyrosine kinase (RTK) biology.
Note: This abstract was not presented at the conference.
Citation Format: Raven J. Reddy. Early signaling dynamics of the epidermal growth factor receptor. [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 A31.