bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 42: Triple negative breast cancer cell heterogeneity in zebrafish-host microenvironment
Authors: Snaar-Jagalska B.Ewa , Groenewoud Arwin , Astrologo Letizia , Chen Lanpeng , Julio Marianna Kruithof-de 
Published: August 2018

Abstract
Metastatic triple negative breast cancer (TNBC) can be considered as incurable endpoint in the progression of TNBC, prevention or treatment of metastasis therefore is of paramount importance. New insights into intra-tumoral heterogeneity have cast light on the existence of multiple functionally distinct cellular entities within one tumor, among others these cells can be divided based on their metastatic potential. The zebrafish provides us with the unique opportunity to study the first steps of metastatic initiation in great detail both microscopically and transcriptionally, on the side of both the host and cancer cells. Organotropic TNBC lines engrafted into this model recapitulate the tropism found in higher vertebrates. Using our zebrafish TNBC xenograft model we study these cellular sub-populations in vivo during metastatic initiation. These small metastatic lesions can be further analyzed ex vivo through the re-isolation of novel zebrafish specific organotropic cell lines. Re-engraftment of these greatly enhances the tumorigenic potential, and transcriptional analysis reveals increased EMT plasticity and an induction of stemness markers. Engraftment of these cells into murine tibia shows a significantly increased tumorigenic and osteolytic potential, further underscoring the critical role of this sub-population in cancer initiation. To determine the genetic drivers of this process we performed whole exome sequenced (NGS) of both, in vitro cultured cancer cells (maternal and re-isolated) and micro-dissected tissue samples derived from in situ zebrafish xenograft material. We are currently in the process of evaluating the candidate genes underpinning the enhanced tumorigenic potential in both the zebrafish and murine models used.
Citation Format: B.Ewa Snaar-Jagalska, Arwin Groenewoud, Letizia Astrologo, Lanpeng Chen, Marianna Kruithof-de Julio. Triple negative breast cancer cell heterogeneity in zebrafish-host microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 42.
Abstract 4204: Structure-activity relationship of diphenylamine derivatives to target epithelial to mesenchymal transition in triple negative breast cancer
Authors: Bhatt Akshita B. , Wright Thomas D. , Anna Katie , Gupta Mohit , Flaherty Patrick , Hoang Van , Burow Matthew , Cavanaugh Jane E. 
Published: August 2018

Abstract
Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors and high invasive potential. TNBC cells express high levels of the mesenchymal markers vimentin, fibronectin, N-cadherin, and cadherin11, which are involved in cell invasion and metastasis, and low levels of the epithelial markers E-cadherin, occludins and cytokeratins, which are involved in cellular contact and stability of the cell membrane. Mitogen activated protein kinases, including ERK5 and ERK1/2 are important pro-survival proteins and are known to be upregulated in most cancers. Of these pathways, the MEK5-ERK5 pathway is understudied in triple negative breast cancer, and there are few research tools available to selectively inhibit this pathway. The diphenylamine moiety was derived from the parent molecule Trametinib, a FDA approved MEK1/2 inhibitor for melanoma. Structural modifications were made on the lead molecule to gain selectivity towards MEK. SC-1-151, one of the compounds from this diphenylamine series was identified as a dual MEK1/2 (98.6% inhibition) and MEK5 (59% inhibition) inhibitor. Additionally, we have shown that SC-1-151 attenuates tumor growth in severe combined immunodeficient (SCID) xenograft mice and causes a mesenchymal to epithelial transition (MET) in MDA-MB-231 TNBC cells. The goal of this research is to determine the structural features of diphenylamines that are responsible for MET.
E-cadherin and cadherin-11 protein expression and cell morphology were examined to study MET after the treatment of MDA-MB-231 cells with different structural analogs of SC-1-151 for 5 days. Alkyl or N-Methyl piperazine substituents on the amide of ring 1 produced similar result as SC-1-151, and substituting the amide group with acid or ester also induced MET. In contrast, ortho-fluoro, para-iodo functional groups of the arene ring 2, when replaced with a meta-bromo substituent did not induce MET. Therefore, our data suggest the necessary functional groups for inducing MET include the hydrogen atom on the amine linkage, and the iodine atom on the arene ring 2. Future studies will be performed to determine the specific protein interactions of the promising compounds.
Citation Format: Akshita B. Bhatt, Thomas D. Wright, Katie Anna, Mohit Gupta, Patrick Flaherty, Van Hoang, Matthew Burow, Jane E. Cavanaugh. Structure-activity relationship of diphenylamine derivatives to target epithelial to mesenchymal transition in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4204.
Abstract 4220: Heterogeneous distribution of prognostic protein markers in glioblastoma
Authors: Stetson Lindsay C. , Ostrom Quinn T. , Liao Peter , Sloan Andrew E. , Chance Mark R. , Barnholtz-Sloan Jill S. 
Published: August 2018

Abstract
Background: Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. The heterogeneity of the disease leads to significant variability in response to standard therapy (surgery plus concurrent radiation and temozolomide). An accurate and reliable predictor of patient prognosis represents an unmet need to improve the care of GBM patients. While protein markers are an effective readout of cellular function, proteomics has rarely been utilized in GBM prognostic marker discovery. Experimental Procedures: GBM patients were prospectively recruited (Ohio Brain Tumor Study) and proteomics discovery using liquid chromatography mass spectrometry analysis (LC MS/MS) was performed in a discovery set of 27 patients including 13 short-term survivors (&lt; 9 months, STS) and 14 long-term survivors (&gt;= 18 months, LTS). Statistically significant proteins were evaluated in two independent datasets, including in18 samples micro-dissected from multiple tumor areas of 6 GBM patients. Results: Proteomics discovery identified 11,941 peptides in 2,495 unique proteins, with 172 proteins exhibiting significant dysregulation when comparing STS and LTS. Proteins involved in glycolysis/TCA cycle were up-regulated in STS compared to LTS by examination of individual targets as well as upon application of a novel protein and peptide pathway enrichment analysis. Validation of these dysregulated proteins and other protein markers from the literature in our first validation set (18 samples micro-dissected from n=6 patients) demonstrated that they were very unevenly distributed throughout individual patients' tumors. Several proteins overcame the heterogeneous nature of the tumors and were both prognostic markers differentially expressed between LTS and STS, as well as potential drug targets owing to their even distribution throughout the tumor. Protein abundance of significant marker proteins were verified in a second independent validation set using Western immunoblots. Conclusion: The current study verified the importance of metabolism in GBM pathology and demonstrated the heterogeneous nature of GBMs at the protein level.
Citation Format: Lindsay C. Stetson, Quinn T. Ostrom, Peter Liao, Andrew E. Sloan, Mark R. Chance, Jill S. Barnholtz-Sloan. Heterogeneous distribution of prognostic protein markers in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4220.
Abstract 4223: Personal history of non-melanoma skin cancer and the risk of death from invasive cutaneous melanoma in men
Authors: Song Fengju , Han Jiali 
Published: August 2018

Abstract
BACKGROUND: Previous studies have found an increased risk of invasive cutaneous melanoma (CM) among those with a history of non-melanoma skin cancer (NMSC). OBJECTIVE: The aim of this study is to evaluate the risk of CM death after NMSC. METHODS: The study was based on the Health Professionals Follow-up Study (HPFS). Cox proportional hazards model was used to examine the hazard ratio (HR) of CM death associated with personal history of NMSC, among the entire study population (primary analysis) and invasive CM cases (secondary analysis) respectively. RESULTS: We documented a total of 908 invasive CM cases over a total of 0.7 million person-years of follow-up. Among all participants, the risk of developing either lethal or non-lethal invasive CM increased for those with NMSC history. The risk of melanoma death based on NMSC history was non-significantly increased, with HR (95% CI) of 1.53 (0.95 - 2.46). In the case-only analysis, those with NMSC history had a significantly lower risk of melanoma death compared with those with no such history, HR=0.60 (0.35-0.94). LIMITATIONS: Because HPFS consists exclusively of male health professionals, the results of this study may not be extended to the entire population. CONCLUSION: Personal history of NMSC is associated with a decreased risk of melanoma-specific death among male patients with invasive CM. KEYWORDS: invasive cutaneous melanoma; non-melanoma skin cancer; mortality; cohort study
Citation Format: Fengju Song, Jiali Han. Personal history of non-melanoma skin cancer and the risk of death from invasive cutaneous melanoma in men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4223.
Abstract 4226: Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy
Authors: Raittinen Paavo V. , Talala Kirsi , Taari Kimmo , Tammela Teuvo L. , Ilmonen Pauliina , Auvinen Anssi , Murtola Teemu J. 
Published: August 2018

Abstract
We study the association between non-steroidal anti-inflammatory drugs (NSAIDs), Statins, and Bisphosphonates (BPs), and prostate cancer (PCa) survival during androgen deprivation therapy (ADT). STAMPEDE trial has demonstrated better PCa-specific survival in men using combination of celecoxib (CEL) and zoledronic acid (ZA) during ADT compared to ADT alone. The mechanism is unclear. ZA inhibits mevalonate pathway (MevP) previously linked with cancer growth. We evaluated PCa survival among men on ADT and simultaneously using BPs including ZA or statins, another drug group inhibiting MevP, and NSAIDs including CEL. We hypothesized that combined use of a MevP inhibitor and NSAID would be associated with improved PCa survival.
Our study cohort includes 4,428 men from the Finnish Randomized Study of PCa Screening (FinRSPC) initiating ADT in 1995-2015. Cox proportional hazards model with adjustment for age, FinRSPC study arm, tumor clinical characteristics and co-morbidities (obtained from national registries) was used to calculate HRs and 95% CI for PCa death. Medication use was analyzed as time-dependent variable.
Compared to non-users, the risk of PCa death was increased in users of NSAIDs or acetaminophen, and lowered in statin users. Use of BPs or coxibs alone were not associated with the risk. Coxibs and statins together were associated with lowered risk to a similar degree as statins alone. No statistically significant risk differences were observed for other combinations.
Statin users with high-risk prostate cancer undergoing ADT have lowered risk of PCa death. NSAID users have increased risk of PCa death, which becomes statistically insignificant when used with statins. Statin and BP use together shows no statistically significant evidence of negating the effects of statin. No clear additive benefit was observed for statins and coxibs together over statins alone. Our findings do not support additive benefits of MevP inhibitor and NSAIDs.
Statistical significance codes: *** : p = 0.001, ** : p = 0.01, * : p = 0.1DrugHR95 % CISignificanceStatin0.780.680.90***Acetylsalisylic acid0.900.761.07Coxib1.070.941.22NSAID1.171.041.31**Acetaminophen1.661.511.82***Bisphosphonate0.790.381.64Bisphosphonate and NSAID0.890.551.42Statin and NSAID1.070.901.27Statin and Bisphosphonate1.140.861.50Coxib and Bisphosphonate0.850.421.74Coxib and Statin0.800.621.02*EAU tumor Risk Group2.662.353.00***
Citation Format: Paavo V. Raittinen, Kirsi Talala, Kimmo Taari, Teuvo L. Tammela, Pauliina Ilmonen, Anssi Auvinen, Teemu J. Murtola. Association between NSAID, statins, and bisphosphonates and prostate cancer survival during androgen deprivation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4226.
Abstract 4243: Association of oral health with lung cancer risk: Results from the Southern Community Cohort Study
Authors: Yoon Hyung-Suk , Wen Wanqing , Long Jirong , Zheng Wei , Blot William J. , Cai Qiuyin 
Published: August 2018

Abstract
Increasing evidence suggests that oral health may be associated with cancer and other chronic diseases. Oral bacterial infections, which induce inflammation of the gums and tooth loss, can progress to systemic inflammation. In addition, poor oral health is often the result of smoking and/or limited access to regular dental care. Previous studies have suggested that poor oral health may increase the risk of lung cancer among individuals of European and Asian descent, but the evidence remains elusive. In this nested case-control study, we investigated whether oral health status was associated with lung cancer risk among African Americans and European Americans and whether the association varied by race and smoking habits. A total of 403 incident lung cancer cases and 1,612 matched controls from the Southern Community Cohort Study were included in the current study. The controls were matched to cases on age, sex, race, and recruitment site. Multivariate conditional logistic regression models were fitted to evaluate the risk of lung cancer linked to tooth loss, tooth decay, and history of periodontal disease (gingivitis or periodontitis). Stratified analyses were conducted by race, smoking status, and pack-years, and the interactions of these variables with oral health were further evaluated. Tooth loss was significantly associated with an increased risk of lung cancer. Compared to those without any loss of teeth, the odds ratio (OR) of loss of &gt;10 teeth was 1.64 (95% confidence interval [CI]: 1.00-2.69) after adjusting for confounders. Tooth decay was also significantly associated with increased lung cancer risk. Those with ≥ 6 decaying teeth had an OR of 1.65 (95% CI: 1.18-2.31), compared to those with no tooth decay. An increased lung cancer risk was significantly associated with a history of periodontal disease (OR: 1.44, 95% CI: 1.09-1.19). While there was no evidence of interaction by race, the increase in risk associated with tooth loss, tooth decay, and periodontal disease was observed only among smokers who had smoked more than the race-specific median pack-year. Results from our study indicate that poor oral health, as measured by tooth loss, tooth decay, and periodontal disease is associated with an increased risk of lung cancer and that this association is more evident among heavy smokers.
Citation Format: Hyung-Suk Yoon, Wanqing Wen, Jirong Long, Wei Zheng, William J. Blot, Qiuyin Cai. Association of oral health with lung cancer risk: Results from the Southern Community Cohort Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4243.
Abstract 4251: Neighborhood data system to enable health disparities research in Chicago
Authors: Press David J. , Gomez Scarlett Lin , Aschebrook-Kilfoy Briseis , Ahsan Habibul 
Published: August 2018

Abstract
Background: Chicago has become the focus of national concern following findings of striking disparities in cancer incidence and mortality, with worse outcomes for Non-Hispanic Black persons. Chicago also has communities with very high crime rates, racial/ethnic segregation, and resource-poor communities. Social stressors, including crime, social isolation, low socioeconomic status (SES), interpersonal and institutional discrimination, and residence in resource-poor settings intersect at individual- and neighborhood- levels across the lifespan and are associated with poor health outcomes. However, the extent to which these social determinants separately and together contribute to cancer health disparities is unclear.
Purpose: To elucidate health disparities attributable to neighborhood social stressors in the Chicago setting, a pilot Chicago Neighborhood Data System (ChNDS) is currently in production, using the Chicago Police Department crimes database, data from the 2010 Census short form, 2008-2012 American Community Survey (ACS), University of Chicago MAPSCorps project, and Environmental Systems Research Institute (ESRI) geodatabases.
Approach: We use principal components analysis (PCA) to generate composite indices of neighborhood-level factors at the small area level (census tract or block group): racial/ethnic composition; SES; immigration/ acculturation; other sociodemographic characteristics; crime; and community assets including density/proximity to types of businesses, retail food, and recreational facilities.
Future directions: Data record linkages at the small area-level will be performed between the pilot ChNDS and observational and population-based datasets to examine the impact of neighborhood-level characteristics on research study participation, disease occurrence, healthcare utilization, and disease outcomes in Chicago.
Citation Format: David J. Press, Scarlett Lin Gomez, Briseis Aschebrook-Kilfoy, Habibul Ahsan. Neighborhood data system to enable health disparities research in Chicago [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4251.
Abstract 4260: Dynamic modeling of macrophage plasticity in bone metastatic prostate cancer
Authors: Baratchart Etienne A. , Lo Chen Hao , Lynch Conor , Basanta David 
Published: August 2018

Abstract
Tumor-associated macrophages, particularly those with an anti-inflammatory phenotype, have long been implicated in the progression of primary solid malignancies, including prostate cancer. Metastatic prostate cancer typically manifests in the bone where it induces painful osteogenic lesions that are incurable. Bone is naturally rich in myeloid-derived macrophages whose temporal polarization into pro- (M1) and anti-inflammatory (M2) phenotypes is critical for regulating the bone repair program mediated by bone-resorbing osteoclasts and bone-building osteoblasts. However, the dynamics of macrophage polarization in the context of bone metastatic prostate cancer are underexplored and difficult to address with traditional biologic approaches. To address the role of macrophage polarization in the context of bone metastatic prostate cancer, we first investigated the macrophage polarization temporal dynamics in normal bones and analyzed macrophage plasticity in vivo subsequent to intratibial injury. Bone marrows were isolated at several time points and profiled by flow cytometry for pro- and anti-inflammatory monocyte macrophage content. Contralateral tibias were analyzed for bone volume, osteoblast and osteoclast numbers. We then designed a mathematical model describing the different cell population dynamics in the bones. Generation of the model required testing a number of assumptions regarding macrophage polarization behavior. For example, it is unknown whether M1 resolves at the initial stages of bone injury repair through death or by repolarizing into M2. For each aspect, competing mechanistic assumptions were proposed and simulated by sets of ODEs. The best-fitting assumptions for each aspect were integrated into a single comprehensive ODE model to fully describe the dynamics of the bone resident cell populations during bone remodeling. This experimentally validated model is now being used to address how bone resident cells respond to metastatic prostate cancer cells. In conclusion, we have generated an ODE model that describes macrophage polarization over time during bone repair and how pro- and anti-inflammatory macrophages interact with bone stromal cells. The mathematical model predictions are in agreement with our biologic experiments in vivo and will allow us to interrogate how macrophage polarization impacts the behavior of metastatic prostate cancer cells in the bone microenvironment.
Citation Format: Etienne A. Baratchart, Chen Hao Lo, Conor Lynch, David Basanta. Dynamic modeling of macrophage plasticity in bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4260.
Abstract 4290: Mad1 promotes tumor progression through destabilization of p53
Authors: Wan Jun , Weaver Beth A. 
Published: August 2018

Abstract
Mitotic arrest deficient 1 (Mad1) plays a well-characterized role in the mitotic checkpoint. However, interphase roles of Mad1 that do not impact mitotic checkpoint function are still largely uncharacterized. We have found that upregulation of Mad1, which is common in human breast cancer, results in decreased protein stability of the tumor suppressor p53 in multiple cell types. To gain mechanistic insight into this process, we first determined whether increasing expression of Mad1 alters its localization. Upregulated Mad1 localizes to puncta within interphase nuclei in both breast cancer tissue and cultured cells. We found that upregulated Mad1 localizes to ProMyelocytic Leukemia Nuclear Bodies (PML NBs), which have been implicated in the stabilization of p53. Immunoprecipitation results indicate that Mad1 and PML interact and that the C-terminal domain (CTD) of Mad1 and the N-terminal domain of PML are required for this interaction. Within the CTD of Mad1, the SUMO-Interacting Motif (SIM) is critical for the localization of Mad1 to PML NBs. MDM2 is an E3 ubiquitin ligase that targets p53 for degradation. In response to DNA damage, PML sequesters Mdm2 to the nucleolus, which stabilizes p53. In cells with elevated levels of Mad1, Mad1 interrupts the interaction between PML and MDM2. Mad1, rather than MDM2, is sequestered to the nucleolus after DNA damage, and Mad1 displaces MDM2 from PML. The displaced MDM2 is no longer sequestered in the nucleolus, freeing it to ubiquitinate p53, resulting in p53 destabilization. Upregulation of Mad1 promotes the growth of orthotopic mammary tumors. Mammary tumors with upregulated Mad1 show decreased levels of p53 and its downstream effector p21. Our results show that, in addition to causing a low rate of chromosome missegregation, Mad1 upregulation has an unexpected interphase role in promoting tumor formation and progression by destabilizing p53. Thus, Mad1 upregulation promotes tumors in through at least two distinct pathways.
Citation Format: Jun Wan, Beth A. Weaver. Mad1 promotes tumor progression through destabilization of p53 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4290.