bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-317: Anti-invasive effects of saracatinib in preclinical models of luminal bladder cancer
Authors: Wehrenberg Bryan , Neal David , Ochoa Andrea , Choi Woonyoung , McConkey David 
Published: August 2018

Abstract
Bladder cancers (BC) form biologically and clinically distinct luminal and basal subtypes. In both subtypes, identifying treatments to prevent progression from non-muscle invasive to muscle invasive disease is a major clinical priority. Anti-invasive agents, such as the SRC and SRC-Family Kinase inhibitor, saracatinib, may benefit high risk non-muscle invasive BC patients. We hypothesized that SRC inhibition limits invasion in bladder tumor models. We examined SRC mRNA expression in the luminal and basal subtypes of BC using publicly available The Cancer Genome Atlas (TCGA) data. Using RNA-Seq expression data, we classified 30 human BC cell lines as luminal or basal and compared SRC expression between the subtypes. We then studied the effect of saracatinib in luminal and basal BC models. Proliferation was measured by MTT assay and invasion was measured using transwell assays. Transwells were either uncoated (modeling migration), matrigel coated (modeling basement membrane invasion) or collagen-1 coated (modeling muscle wall invasion). Luminal TCGA bladder tumors showed significantly enrichments in SRC mRNA expression (p&lt;0.001). SRC expression was significantly higher in luminal than basal cell lines (p&lt;0.05). Saracatinib had limited anti-proliferative activity in both luminal and basal models. All luminal models showed significantly decreased migration and collagen 1 invasion (p&lt;0.05). Of the subset of luminal cell lines that invade matrigel, two thirds had significantly decreased invasion (p&lt;0.05). Only one basal cell line exhibited significantly decreased invasion or migration (p&lt;0.05). Invasion and migration in other basal models were not significantly altered or, in several case, were significantly increased (p&lt;0.05), by saracatinib. Enrichment of SRC expression in luminal tumors and significant reductions in luminal cell line invasion after saracatinib treatment suggest SRC promotes invasion in luminal BC. The increase in basal cell line invasion, observed in a subset of these models, emphasizes the importance of considering subtype in studying the biology of BC. Though further validation in 3D culture and animal models is necessary, these results suggest saracatinib, and other SRC-Family Kinase inhibitors, could serve as effective anti-progression agents in luminal BC.
Citation Format: Bryan Wehrenberg, David Neal, Andrea Ochoa, Woonyoung Choi, David McConkey. Anti-invasive effects of saracatinib in preclinical models of luminal bladder 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 LB-317.
Abstract LB-318: Automated monitoring and analysis of kinetic live cell 3D spheroid-based tumor invasion within a hydrogel matrix
Authors: Larson Brad 
Published: August 2018

Abstract
Metastasis is the main cause of death in cancer patients and one of the most complex biological processes in human diseases. The development of therapies designed to forestall the metastatic activity of tumors has been met with multiple challenges. The first is the initial focus on single target remedies. As many types of cancers develop multiple mutations during tumor progression, individual cancers are often little affected by this type of drug. The advancement of novel methods that allow for the discernment of the effect a potential therapy has on the invasive phenotype of a particular type of cancer has proven invaluable to circumventing these early failures. A second hurdle is the choice of an appropriate cell model. Tumors in vivo exist as a three-dimensional (3D) mass of multiple cell types, including cancer and stromal cells. Therefore, incorporating a 3D spheroid-type cellular structure that includes co-cultured cell types forming a tumoroid, provides a more predictive model than the use of individual cancer cells cultured on the bottom of a well in traditional two-dimensional (2D) format. A third impediment is the inclusion of proper incubation time. Traditionally in vitro assessments of anti-cancer drugs have included short-term incubations, sometimes limited to 48 hours. In vivo treatments, however, can consist of a multi-week regimen. Pre-clinical tests must also, then, extend a similar length of time. A final hindrance which is necessary to overcome is the proper capture and analysis of microscopic images. The ability to monitor the entire tumoroid with a degree of sensitivity across multiple z-planes as cells invade into the matrix, as well as quantify changes over time, is critical. The information presented here will demonstrate a combined procedure for the generation of 3D spheroidal tumoroid structures, creation of a suitable invasion matrix, automated kinetic image-based monitoring of tumor invasion, and cellular analysis of captured z-stacked images.
Citation Format: Brad Larson. Automated monitoring and analysis of kinetic live cell 3D spheroid-based tumor invasion within a hydrogel matrix [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 LB-318.
Abstract LB-342: Targeted gene control with bifunctional molecules to harness endogenous chromatin-modifying activity
Authors: Chiarella Anna M. , Butler Kyle V. , Jin Jian , Hathaway Nathaniel A. 
Published: August 2018

Abstract
Epigenetic pathways are commonly found disrupted in many human diseases including cancer, yet much remains unknown about the mechanisms by which dysregulation of chromatin regulatory pathways leads to disease pathology. To investigate and control these complex interactions in live cells, we developed a novel system that will unveil the underlying mechanisms of proteins responsible for modulating chromatin states using a gene-specific manipulation strategy. To explore how dynamic changes in acetylation levels impact chromatin structure we generated an endogenous reporter system at the murine Oct4 locus with a Gal4 DNA binding array upstream of an EGFP reporter allele. In our system, a FKBP protein fused to a Gal4 DNA-binding-domain serves as a protein anchor to the DNA binding array. Next, we synthesized novel cell-permeable, bifunctional molecules that include FK506 (which binds to FKBP) linked to a component that selectively binds to a histone tail chromatin-modifying enzyme. We characterized the effects of the Chemical Epigenetic Modifiers (CEM)s using flow cytometry, high-content microscopy and chromatin immunoprecipitation. We show that our lead repressive CEM can repress GFP expression by 50%. Next, we have made our system more modular by creating a deactivated Cas9 (dCas9)-FKBP fusion protein. The FKBP portion allows us to recruit our CEMs to any region of the genome to which we design a guide RNA. To study the addition of histone acetylation we utilized our new activating, HAT-binding CEMs and designed our dCas9-FKBP to target low-expression reporters. Our lead activating CEM increases expression over 20-fold. We are now using our activating CEM system to target tumor suppressor genes in hard to treat cancers. To show proof-of-principle, we have targeted the tumor suppressor p53 in a colon cancer cell line. We hypothesize that our activating CEM platform will activate the repressed P53 allele leading to slower tumor cell proliferation and apoptosis. This work represents a novel therapeutic strategy that is capable of modulating gene expression in a reversible and dose-dependent manner.
Citation Format: Anna M. Chiarella, Kyle V. Butler, Jian Jin, Nathaniel A. Hathaway. Targeted gene control with bifunctional molecules to harness endogenous chromatin-modifying activity [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 LB-342.
Abstract LB-379: Targeted single-cell RNA expression profiling for cellular characterization of tumor microenvironment
Authors: Chenchik Alex , Makhanov Michael , Frangou Costa , Diehl Paul 
Published: August 2018

Abstract
New rapid and robust transcriptome-based methods for cellular characterization of the tumor microenvironment and biomarker discovery are required to improve prognosis and treatment of cancer and other diseases. However, challenges with current approaches for the above applications include high sample requirements, poor sensitivity, low dynamic range, and limited throughput. To address these limitations, we have developed the DriverMap™ targeted RNA expression profiling assay using a genome-wide set of 19,000 validated primer pairs that leverages the sensitivity of multiplex RT-PCR with the throughput and digital readout depth of next-generation sequencing (NGS). Starting from just 10pg (single-cell) to 100ng (10,000 cells) of total RNA is sufficient to quantify over 5 orders of magnitude variation in gene expression levels with performance similar to conventional qRT-PCR. Further, the use of gene-specific primers enables direct analysis of total RNA isolate and obviates the need for globin and rRNA depletion from whole blood samples. And, using a subset of primers empirically selected from the DriverMap™ assay, we have developed a novel single-cell targeted RNA expression (scTRex) profiling assay compatible with conventional oligo dT-molecular indexing, single- cell barcoding strategies. In this study, we present the performance of the assay to analyze the level of immune cell infiltration in tumor samples, and identify active pathways in tumor, xenograft samples and cell lines treated with small molecules. Preliminary studies demonstrate the assay's unparalleled specificity and sensitivity resulting in better detection of low abundance mRNA transcripts as well as an improved cost-effectiveness for high-throughput clinical applications.
Citation Format: Alex Chenchik, Michael Makhanov, Costa Frangou, Paul Diehl. Targeted single-cell RNA expression profiling for cellular characterization of tumor 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 LB-379.
Abstract LB-387: In vivo study on the pathological role of microRNA 155 in liver malignancy
Authors: Lee Tae Jin , Yoo Ji Young , Kaur Balveen , Croce Carlo 
Published: August 2018

Abstract
Growing body of evidence proposes that causative factor for liver damage, such as viral infection, inflammation, fatty liver and genotoxin, induces over-expression of microRNA-155 (miR-155), and increases the chance to develop hepatocellular carcinoma (HCC), where miR-155 is also found to be highly over-expressed. To understand the underlying mechanism how over-expression of miR-155 in liver induces pathologic changes linking early liver damage to malignant HCC development, we have generated conditional transgenic and knockout mice for hepatocyte-specific over-expression or deletion of miR-155 using Cre-LoxP technology. Although the miR-155 over-expressing Tg mice did not develop spontaneous HCC, they showed early inflammation in liver with elevated level of pro-inflammatory cytokines in both liver and serum through Caspase-I activation. Postnatal insulting by genotoxin, Diethylnitrosamine (DEN), has dramatically increased incidents of HCC in miR-155 Tg mice (82%) compared to wildtype mice (21%) by 9 months. Microarray analysis on whole mouse liver transcriptome has revealed that 294 genes were significantly up-regulated in the Tg mice while 147 genes were significantly down-regulated. Further pathway analysis showed that those affected genes mainly involve in acute-phase response, inflammatory response, fatty acid metabolic process, and cholesterol metabolic process, which coincides with our phenotypic observation. In addition, it was found that high incidence of HCC by DEN insult is consequence of impaired DNA damage repair and apoptosis pathways through downregulation of several genes including Foxo3a, Sirt1, C/EBP-beta and Smac by miR-155. Our in vivo study provides first insight of dysregulation of single microRNA can set forth liver damage to malignant HCC, which makes miR-155 a promising therapeutic target not only for HCC but also many type of liver damage-related liver diseases.
Citation Format: Tae Jin Lee, Ji Young Yoo, Balveen Kaur, Carlo Croce. In vivo study on the pathological role of microRNA 155 in liver malignancy [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 LB-387.
Abstract LB-389: miR133a-3p sensitizes breast cancer cells by targeting GSTP1
Authors: Chang Minsun , Liu Xiyuan , Park Eun Young 
Published: August 2018

Abstract
Breast cancer is a main threat for women's health and mammary carcinogenesis is attributed to estrogen receptor α (ERα)-mediated signaling pathways. Tamoxifen is one of the most effective ERα-targeting antiestrogen therapies to treat breast cancer. However, tamoxifen resistance remains a major hurdle in the long-term management of breast cancer. Glutathione S-transferase P1-1 (GSTP1) is one of the major non-hepatic GST family and plays important role in detoxification. Our previous study has shown that GSTP1 is a modulator for ERα signaling in tamoxifen-resistant MCF7 breast cancer cells (LCC3) and other studies have proposed that GSTP1 is one of biomarkers for the diagnosis of breast cancer risk and drug resistance. In the present study, a microRNA (miR) 133a-3p is identified as a functional modulator for GSTP1 expression and cell proliferation in LCC3 cells. We have found that level of miR133a-3p was much lower and the GSTP1 expression at both mRNA and protein was higher in LCC3 cells compared to MCF7 cells. Treatment of miR133a-3p mimics decreased the levels of GSTP1 in LCC3 cells. Finally, the miR133a-3p mimics resensitized the LCC3 cells against tamoxifen-induced cell death. Our data demonstrated that GSTP1 is the target of miR133a-3p in MCF7-derived breast cancer cells and miR133a-3p may play a critical role to overcome tamoxifen resistance in breast cancer chemotherapy.
Citation Format: Minsun Chang, Xiyuan Liu, Eun Young Park. miR133a-3p sensitizes breast cancer cells by targeting GSTP1 [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 LB-389.
Abstract LB-399: Aspirin reduces doxorubicin-induced senescence and early-aging in mice
Authors: Feng Mingxiao , Shim Minsub 
Published: August 2018

Abstract
Survivors of childhood cancers are often associated with the adverse late effects of earlier cancer treatments, including hearing loss, early menopause, osteoporosis, hypoplasia, fatigue, and infertility. While an accumulating body of evidence supports the hypothesis that cancer treatment is associated with accelerated aging, the mechanisms that lead to a functional decline or frailty remain elusive. Expression of cyclooxygenase-2 (COX2), a key enzyme in prostaglandin biosynthesis, is known to be increased in the tissues of aged humans and mice. We have previously found that transgenic expression of COX2 causes premature aging phenotypes in mice. Since it is well-known that COX2 expression is highly induced by various chemotherapeutic agents, we further investigated the possible link between COX2 and the late effects of chemotherapy. Treatment of juvenile mice with doxorubicin (DOX), an anthracycline-based chemotherapeutic agent, resulted in increased cellular senescence and premature aging in adult mice. Interestingly, tissue expression of COX2 persisted even at 11 weeks after cessation of DOX treatment. In addition, aspirin, a classical non-steroidal anti-inflammatory drug (NSAID), alleviated cellular senescence and early aging phenotypes in DOX-treated mice. Moreover, NSAIDs, either a selective or non-selective COX2 inhibitors, reduced the viability of senescent cells and down-regulated the levels of Bcl-xL and LC3b. Our results suggest that chemotherapy-induced COX2 may play an important role in the late effects of chemotherapy by inducing cellular senescence and further aging.
Citation Format: Mingxiao Feng, Minsub Shim. Aspirin reduces doxorubicin-induced senescence and early-aging in mice [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 LB-399.
Abstract PL01-02: Immune checkpoint therapy: From CTLA-4 to PD-1/PD-L1 and beyond
Authors: Sharma Padmanee 
Published: August 2018

Abstract
Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1, have led to significant clinical responses in cancer patients. However, there are still substantial numbers of patients who do not respond to anti-CTLA-4 or anti-PD-1/PD-L1. We and others have demonstrated that treatment of patients with immune checkpoint therapies impacts immune responses to enhance effector T-cell responses but also leads to increased expression of compensatory pathways or development of adaptive resistance mechanisms that act to abrogate antitumor immune responses. Rational combination strategies to address these compensatory pathways and/or adaptive resistance mechanisms, including those that permit blockade of multiple T-cell inhibitory pathways or blockade of inhibitory pathways plus targeting of co-stimulatory pathways or intervention with agents, such as epigenetic agents, to promote differentiation of effector T cells and/or M1 macrophages, are at the forefront of preclinical and clinical studies as the field of immune checkpoint therapy aims to provide benefit to even more patients. Combination therapies with anti-CTLA-4 and anti-PD-1 have already shown improved patient benefit. The next promising combinations include those with ICOS, CD47, VISTA, oncolytic viruses, and EZH2-inhibitors, to name a few. Preclinical and clinical data regarding these targets will be discussed in greater detail.
Citation Format: Padmanee Sharma. Immune checkpoint therapy: From CTLA-4 to PD-1/PD-L1 and beyond [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 PL01-02.
Abstract SY01-02: Blockade of estrogen signaling boosts antitumor immunity by dwindling cancer-promoting myelopoiesis
Authors: Svoronos Nikolaos , Perales-Puchalt Alfredo , Conejo-Garcia Jose R. 
Published: August 2018

Abstract
Although the role of estrogen signaling in the progression of breast tumors and a subset of ovarian cancer patients has been underscored by the clinical use of ER antagonists, how estrogens impact the orchestration and maintenance of protective antitumor immunity remains elusive. Here we show that estrogen signaling accelerates the progression of different estrogen-insensitive tumor models by contributing to tumor-promoting, expanded myelopoiesis. This results in increased mobilization of myeloid-derived suppressor cells (MDSCs) and also the augmentation of their intrinsic immunosuppressive activity on a per cell basis, in vivo in the bone marrow of tumor-bearing hosts. Accordingly, estrogens had a profound effect on T cell-dependent antitumor immunity and tumor-promoting inflammation, independently of the sensitivity of tumor cells to estrogen signaling. Differences in tumor growth in the presence of estrogen-insensitive tumor cells are dependent on blunted antitumor immunity and, correspondingly, disappear in immunodeficient hosts and also upon MDSC depletion. Mechanistically, estrogen receptor alpha activates the STAT3 pathway in human and mouse bone marrow myeloid precursors by enhancing JAK2 and SRC activity. Consequently, fulvestrant had significant effects in delaying the progression of estrogen-insensitive tumors, providing a rationale for blocking estrogen signals to boost the effectiveness of anticancer immunotherapies, which is currently being tested at our institution in breast cancer patients. Our data therefore provide novel mechanistic insight into how enhanced estrogenic activity contributes to malignant progression in established tumors by driving pathologic, tumor-promoting myelopoiesis. Our work suggests that new antiestrogen drugs that have no agonistic effects (different from tamoxifen) could have benefits to boost protective immunity in a wide range of cancers, while augmented estrogenic activity could contribute to tumor initiation and/or malignant progression.
Citation Format: Nikolaos Svoronos, Alfredo Perales-Puchalt, Jose R. Conejo-Garcia. Blockade of estrogen signaling boosts antitumor immunity by dwindling cancer-promoting myelopoiesis [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 SY01-02.
Abstract SY05-02: Polycomb dysregulation by oncohistones
Authors: Lewis Peter W. 
Published: August 2018

Abstract
Covalent modifications to both the DNA and the histone proteins allow chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access to the transcription machinery and ultimately establish and maintain cellular phenotypes. Moreover, there is increasing appreciation that chromatin alterations per se, including DNA and histone modifications, are involved in the pathogenesis of cancer. Nowhere is this better supported than with the groundbreaking discoveries of high-frequency, somatic mutations in histones that are drivers of oncogenesis. These mutations (collectively called "oncohistones") cause amino acid substitutions that localize to conserved residues in the N-terminal tail of histone H3 and all seem to be linked, either directly or indirectly, to disruption of normal levels and distribution of histone H3 methylation and thus genomic regulation. Specifically, oncohistones directly or indirectly promote aberrant genome-wide distribution of lysine 27 methylation on histone H3. H3K27 methylation, catalyzed by the Polycomb Repressive Complex 2 (PRC2), is mechanistically linked to establishment and maintenance of gene repression. We are currently using a combination of biochemical and genomic approaches to investigate how oncohistone-driven changes in histone H3 K27 methylation lead to altered chromatin states that profoundly influence gene expression patterns. I will discuss some of our recent mechanistic and functional work on various oncohistone mutations.
Citation Format: Peter W. Lewis. Polycomb dysregulation by oncohistones [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 SY05-02.