bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1481: Selective protein expression in tumor cells controlled by progression elevated gene-3 promoter
Authors: Pando Ruben , Shrestha Tej , Pyle Marla , Troyer Deryl 
Published: August 2018

Abstract
The progression elevated gene-3 (PEG-3) promoter is a rodent gene that has shown strong activity in tumor progression. Demonstrating tumor specificity and activity in at least five different human cancers, PEG-3 is considered a novel promoter for tumor-specific gene expression. Understanding how PEG-3 controls expression of reporter proteins is of biomedical significance because of the role it could play in new therapeutic strategies against certain types of cancer. In this study, we aim to use the PEG-3 promoter to observe the expression of firefly luciferase 2 (luc 2), a bioluminescent reporter protein, in the transfection of mammalian cells. Ultimately, we plan to use PEG-3 to express a therapeutic gene, cytosine deaminase, in cancer specific areas of breast, lung, and ovary.
Citation Format: Ruben Pando, Tej Shrestha, Marla Pyle, Deryl Troyer. Selective protein expression in tumor cells controlled by progression elevated gene-3 promoter [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 1481.
Abstract 1486: Cxcr4/Sdf-1 expression in Her2/Neu breast cancer biopsies and its relation to adjuvant treatment
Authors: Ayala Natalia C. , Campos Melina N. Lorenzini , Pescie Mariana M. Gomez , Alsina Angel E. , Zimerman Jorge R. , Zimmermann Maria C. 
Published: August 2018

Abstract
Background: Chemokines have a fundamental role in inflammation and in cancer progression. Chemokine receptor 4 (CXCR4) is a transmembrane receptor that belongs to the CXC chemokine receptor family and is the only known receptor for the Stromal Cell derived Factor-1(SDF-1). Many retrospective studies have documented that the expression of various chemokine receptors, particularly CXCR4, was associated with a poor prognosis in patients with breast cancer. In the present study, we proposed an SDF-1/CXCR4 induced expression in HER2/neu positive breast cancer biopsies. We, additionally, study its relation to patient's treatment, prior and post adjuvant therapy. Methods: Immunohistochemical staining of her2/neu and ki64 were analyzed in mammary tumor biopsies. Reduction mammoplasty of normal patients were also studied as normal controls. Stained hematoxilyn and eosin slides where previously revised to confirm histological diagnostic and tumoral classification based on established criteria. Additional information considering biological markers such as estrogen receptor (ER), progesterone receptor (PR) expression were also observed in histopathological reports. Quantitative PCR was performed by amplifying a conserved region of the CXCR-4 and SDF-1 genes, and their correlation to Her2/neu expression and adjuvant therapy were analyzed. Statistical analysis was assess using appropriate parametric and nonparametric tests. Results: Her2/neu breast tumor specimens expressed SDF-1 at varying levels and differed upon tumor classification. Expression of the receptor correlates mainly with the tumor type and degree. Quantitative PCR showed low constitutive CXCR4 expression in normal breast tissue that increased in breast tumor tissue, particularly in those expressing her2/neu. Variations upon treatment correspond to those of tumor progression to malignancies and recurrence. Conclusions: We established a correlation between the expression of SDF-1/CXCR4 and the tumoral characteristics prior and post adjuvant treatment. A more careful examination of experimental/clinical data may help to explain the mechanism(s) involving the SDF-1/CXCR4 signaling axis in the breast cancer pathophysiology.
Citation Format: Natalia C. Ayala, Melina N. Lorenzini Campos, Mariana M. Gomez Pescie, Angel E. Alsina, Jorge R. Zimerman, Maria C. Zimmermann. Cxcr4/Sdf-1 expression in Her2/Neu breast cancer biopsies and its relation to adjuvant treatment [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 1486.
Abstract 1498: The role of tissues specific super-enhancers in mediating the genetic risk of ovarian cancer
Authors: Vavra Kevin C. , Corona Rosario I. , Seo Ji-Heui , Coetzee Simon G. , Lee Janet M. , Freedman Matthew L. , Pharoah Paul D. , Hazelett Dennis J. , Gayther Simon A. , Lawrenson Kate 
Published: August 2018

Abstract
Super-enhancers demarcate regions of master regulators involved in cellular differentiation and tumorigenesis. While many trait-associated variants discovered through genome wide association studies are enriched in regulatory elements, the role of super-enhancers in disease susceptibility is less well understood. We evaluated the role of super-enhancers, defined by H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) analysis of epithelial ovarian cancers (EOC) and precursor cells, in mediating the genetic risk of EOC. We characterized super-enhancer-risk SNP intersections to identify a series of risk-associated loci where multiple candidate causal alleles overlap with ovarian super-enhancers (approximately 33% of candidate causal loci). In particular, a risk locus at 3q25 marked by SNP rs7651446, (odds ratio = 1.59, p = 1.5x10-34), is tagged by 79 candidate causal risk SNPs, more than half of which coincide with super-enhancers detected in EOC precursor cells (ovarian and fallopian tube epithelia) but not in ovarian cancer cell lines or primary tumors suggesting that loss of activity of this super-enhancer is associated with EOC development.
We hypothesized that SNPs at the 3q25 locus modulate activity of super-enhancers that regulate in cis the expression of genes involved in the identity of normal tissue precursors, and that these genes are downregulated during tumorigenesis. We tested the effect of decreasing the binding affinity of BRD4, a protein that binds super-enhancer regions, using a small molecule inhibitor (JQ1). We measured the expression of genes at this locus following JQ1 treatment in EOC precursor cells, identifying three candidate genes, LEKR1, SSR3, and TiPARP, that show decreased expression due to BRD4 binding inhibition. For SSR3 and TIPARP, these expression level changes mirrored the differential expression observed between normal precursor cells and primary high grade serous ovarian cancer. We then established stable shRNA-mediated knockdown models for SSR3 and TIPARP in normal EOC precursor cell lines to establish a role for these genes in ovarian cancer development. In summary, we have identified a potential role for super-enhancers at a subset of EOC risk loci, and present a functional pipeline for identification of the target gene/genes and evaluation of their role in neoplastic transformation.
Citation Format: Kevin C. Vavra, Rosario I. Corona, Ji-Heui Seo, Simon G. Coetzee, Janet M. Lee, Matthew L. Freedman, Paul D. Pharoah, Dennis J. Hazelett, Simon A. Gayther, Kate Lawrenson. The role of tissues specific super-enhancers in mediating the genetic risk of ovarian 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 1498.
Abstract 1499: Vitamin D promotes differentiation in patient-derived organoids in benign and cancer prostate models
Authors: McCray Tara N. , Lugli Giovani , Nonn Larisa 
Published: August 2018

Abstract
Deficiency in the prohormone vitamin D is associated with increased risk of lethal prostate cancer (PCa) and less-differentiated, more aggressive tumors. As cancer progresses there is aberrant expression of vitamin D metabolic genes causing dysregulation of the vitamin D pathway, indicating its role in disease. Vitamin D has many chemopreventive actions in vitro, including promotion of differentiation and apoptosis. The ability for vitamin D to drive differentiation has been explored in various cell types and cancer lines, but its mechanism of action in the prostate is not well defined. Our lab found that vitamin D treatment globally upregulates microRNAs (miRs) in prostate cell lines, primary cells and patient samples. Temporal regulation of miRs is critical for differentiation and levels of mature miRs are globally lower in PCa. Given the relationship between vitamin D and microRNAs, and their influence over differentiation, we hypothesize that vitamin D promotes differentiation in the prostate in a microRNA-dependent manner and that this process is disrupted during cancer. Here we examined organoid differentiation in the presence of 1,25D, the active metabolite of vitamin D. Organoids were grown in matrigel from human primary prostate epithelial progenitor cells. Differentiation was assessed by organoid size and branching, and by expression of epithelial markers. Organoids grown in the presence of 1,25D were strikingly larger and formed more complex branching structures than those treated with control. Whole mount immunofluorescence revealed expression of basal and luminal epithelial cells in the organoids. Flow-sorted organoids had a greater composition of basal cells when grown in the presence of 1,25D. RT-qPCR analysis of the flow-sorted epithelial populations revealed an enhancement in the WNT pathway with 1,25D, this pathway is critical in prostate development and dysregulated in cancer. The role of miRNAs was determined by reducing global miRNA levels via knockdown of Drosha, an essential miRNA-processing protein. Knockdown abrogated the effect of 1,25D, as evidenced by reduced size, round shape, and protein expression. Together our findings indicate a role of 1,25D in normal prostate development and branching, a phenotype that is lost when mature miR levels are reduced. Ongoing studies examine these phenotypes in PCa organoids.
Citation Format: Tara N. McCray, Giovani Lugli, Larisa Nonn. Vitamin D promotes differentiation in patient-derived organoids in benign and cancer prostate models [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 1499.
Abstract 1512: Regulation of the CDC42 signaling pathway by IKZF1 in T-cell acute lymphoblastic leukemia
Authors: Soliman Mario , Song Chunhua , Payne Jonathon L. , Ge Zheng , Gowda Chandrika , Ding Yali , Payne Kimberly J. , Dovat Sinisa 
Published: August 2018

Abstract
The IKZF1 gene encodes Ikaros—a DNA-binding, Kruppel-like zinc finger protein that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). Ikaros regulates transcription of a large number of genes that are involved in control of cellular proliferation. However, the molecular mechanisms through which Ikaros regulates proliferation of T-ALL cells are still unknown. The use of quantitative chromatin immunoprecipitation (qChIP) showed that Ikaros binds to the promoter regions of CDC42 in vivo in primary T-ALL patient samples as well as in T-ALL cell lines. Ikaros overexpression in B-ALL cells via retroviral transduction results in decreased transcription of CDC42, as evidenced by qRT-PCR and Western blot. The luciferase reporter assay showed that Ikaros represses CDC42 transcription by directly binding to its promoter. The shRNA-mediated knock-down of Ikaros in T-ALL resulted in increased expression of CDC42. These results suggest that Ikaros functions as a transcriptional repressor of CDC42 in T-ALL. Next, we studied the upstream signaling pathways that regulate Ikaros-mediated control of CDC42 transcription in T-ALL. Because Ikaros activity in leukemia is regulated via direct phosphorylation by Casein Kinase II (CK2), we tested the effect of CK2 inhibition on Ikaros-mediated regulation of CDC42 expression. Treatment of T-ALL cells with a specific CK2 inhibitor, CX-4945, resulted in reduced expression of CDC42 in T-ALL cells. This was associated with an increase in DNA-binding of Ikaros to the promoter of the CDC42 gene. Ikaros knock-down restored high expression of CDC42 in T-ALL cells that were treated with CK2 inhibitors. These data suggest that transcriptional repression of the CDC42 gene by Ikaros is impaired in T-ALL due to increased CK2 activity and reduced Ikaros DNA-binding affinity toward the CDC42 gene promoter. Inhibition of CK2 restores Ikaros function and results in transcriptional repression of the CDC42 gene. In conclusion, our results suggest that Ikaros regulates CDC42 signaling pathway via transcriptional repression of the small GTPase, CDC42, in T-ALL. Ikaros-mediated repression of CDC42 in T-ALL is negatively regulated by CK2. These results suggest that regulation of CDC42 expression is one of the mechanisms through which Ikaros regulates cellular proliferation in T-ALL.
Citation Format: Mario Soliman, Chunhua Song, Jonathon L. Payne, Zheng Ge, Chandrika Gowda, Yali Ding, Kimberly J. Payne, Sinisa Dovat. Regulation of the CDC42 signaling pathway by IKZF1 in T-cell acute lymphoblastic leukemia [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 1512.
Abstract 1516: BAT-1 up-regulation decreases cell invasion and migration in vitro
Authors: Garcia-Vargas Aileen M. , Sanchez Maria , Martinez-Ferrer Magaly 
Published: August 2018

Abstract
Prostate cancer is the most common cancer in men in the United States and is the third cause of cancer related deaths in men. In Puerto Rico, prostate cancer is the most common type of cancer and the leading cause of cancer death in men. Approximately one out of seven men will be diagnosed with prostate cancer in his lifetime. The current available biomarkers are unable to predict malignant outcomes such as recurrence. Thus, there is a critical demand for the development of innovative diagnostic and prognostic tools for the management of prostate cancer. In the current study, we evaluated the biological role of BAT-1 in prostate cancer. Preliminary data from patients who had prostate cancer recurrence identified that HLA-B associated transcript 1 (BAT-1) was down-regulated in patients with prostate cancer recurrence when compared with non-recurrent patients. We up-regulated BAT-1 in androgen independent PC3 and androgen dependent 22RV1 prostate cancer cell lines using a BAT-1 recombinant protein. In vitro assays were performed to measure proliferation, migration and invasion. Proliferation assays using MTS showed no significant change in BAT-1 recombinant protein concentrations ranging from 0.25-2.0μg/mL at 12, 24 and 48hrs for PC3 and 22RV1 cells. Wound healing assay showed that cells treated with BAT-1 recombinant protein at 0.25μg/mL and 2.0μg/mL significantly decreased migration at 6, 12hrs and 24hrs in PC3 cells when compared to control. Boyden assay showed that cells treated with BAT-1 recombinant protein at 0.25μg/mL and 2.0μg/mL significantly decreased invasion in PC3 and 22RV1 cells at 24hrs when compared to control. Our results showed that BAT-1 up-regulation decreased migration and cell motility. Cells did not show a significant change in proliferation. These results were expected due to previous data showing that BAT-1 down-regulation increased cell migration and invasion, suggesting that BAT-1 expression promotes aggressiveness in prostate cancer recurrence. A possible mechanism of action for BAT1 is the modulation of cell migration and invasion.
Citation Format: Aileen M. Garcia-Vargas, Maria Sanchez, Magaly Martinez-Ferrer. BAT-1 up-regulation decreases cell invasion and migration in vitro [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 1516.
Abstract 1527: Splicing factors determine breast cancer cell mitosis through control of sister chromatid cohesion
Authors: Koedoot Esmee , Martens John , Dévédec Sylvia E. Le , Water Bob van de 
Published: August 2018

Abstract
Breast cancer is the mostly diagnosed cancer in women worldwide and is also the leading cause of death from cancer in women, mainly due to metastasis formation. Accumulating evidence suggests that RNA splicing is critical in breast cancer progression. To investigate the role of every single component of the splicing machinery (the spliceosome) in this process, we systematically evaluated the effect of siRNA-mediated knockdown of 244 splicing factors on proliferation in two highly proliferative breast cancer cell lines MDA-MB-231 and Hs578T. Hits of the primary screen were validated with single siRNAs and separated based on their effects on migration and proliferation respectively. Knockdown of nine validated proliferation hits, amongst which was SF3B1, a known breast cancer driver gene, resulted for all nine hits in a distinct poly-lobed nuclear phenotype in both cell types, accompanied by increased DNA content and higher number of cells in G1-S transition. Increased levels of phospho-Histone H3 and lack of metaphase alignment suggested a defect in mitosis, which was confirmed by decreased RNA expression of sister chromatid cohesion factors MAU2, ESPL1 and SMC1A and interestingly, increased CDCA5 RNA levels. Upon splicing factor knockdown, CDCA5 intron 1 was retained resulting in decreased CDCA5 protein levels, inaccurate metaphase alignment and finally cell death. To identify the direct partners of the splicing factors that control mitosis, we coupled pull-down of GFP fused splicing factors with mass spectrometry. Seven out of the nine splicing factors that were identified in our screen causing poly-lobed nuclear phenotypes, resided in the same protein complex together with proteins involved in snRNP assembly and some mitosis-related factors. In conclusion, we have identified several splicing factors that are critically determining breast cancer cell proliferation through modulating the expression of chromatid cohesion factors and thereby mediating the successful metaphase alignment and ultimate mitosis.
Citation Format: Esmee Koedoot, John Martens, Sylvia E. Le Dévédec, Bob van de Water. Splicing factors determine breast cancer cell mitosis through control of sister chromatid cohesion [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 1527.
Abstract 153: A genome-wide CRISPR screen in hESC uncovers JNK pathway mediated inhibition of human definitive endoderm formation
Authors: Li Qing , Huangfu Danwei 
Published: August 2018

Abstract
Human embryonic stem cells (hESCs) are uniquely suitable for interrogating human development and birth defects with high-throughput genetic manipulation. Using CRISPR/Cas, we have conducted a forward genetic screen for genes that regulate the formation of human definitive endoderm (DE), the first step towards the generation of cells in respiratory and gastrointestinal organs. Our screen identified both known and unknown regulators of endoderm differentiation, including a previously unrecognized inhibitory mechanism mediated by the JNK/JUN pathway. JNK inhibitor treatment significantly improves the efficiency of hESC differentiation to endoderm, leading to more efficient creation of endoderm-derived pancreatic and lung lineage cells. The AP1 transcription factor JUN co-occupies ESC enhancers with SMAD2/3 and OCT4, and impedes the re-configuration of the SMAD2/3 chromatin-binding landscape during the ESC-to-DE transition. Thus the hESC-based CRISPR screen enables unbiased interrogation of the functional genome during human development, which can inform hESC directed differentiation for regenerative medicine and disease modeling.
Citation Format: Qing Li, Danwei Huangfu. A genome-wide CRISPR screen in hESC uncovers JNK pathway mediated inhibition of human definitive endoderm formation [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 153.
Abstract 1531: A bispecific chimeric-antigen receptor T-cell factory for triple-negative breast cancer
Authors: Kuiper Emily G. , Chan Leo L. , Chang Matthew R. , Zhu Quan K. , Marasco Wayne A. 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor clinical prognosis. While treated with chemotherapies, the high incidence of relapse signifies the need for novel, targeted therapies. Immune therapies offer an exciting therapeutic option for TNBC. Our goal is to engineer a chimeric-antigen receptor (CAR) T-cell factory, a CAR T-cell that secretes immune-modulating antibodies, for TNBC.
Chimeric-antigen receptor (CAR) T-cell therapies redirect a patient's T-cells to kill tumor cells by the exogenous expression of a CAR. A CAR is a membrane spanning fusion protein that links the antigen recognition domain of an antibody to the intracellular signaling domains of the T-cell receptor and co-receptor. Solid tumors offer unique challenges for CAR-T therapies. Unlike blood cancers, tumor-associated target proteins are overexpressed between the tumor and healthy tissue resulting in on-target/off-tumor T-cell killing of healthy tissues. Furthermore, immune repression in the tumor microenvironment (TME) limits the activation of CAR-T cells towards killing the tumor.
We hypothesize that a bispecific CAR targeting two antigens on TNBC will mitigate on-target/off-tumor T-cell killing and that the secretion of a checkpoint blockade antibody will remove repression in the tumor microenvironment. Following local immune restoration, the CAR-T cells and other cells in the TME will work synergistically to shrink and clear tumors. Our current work evaluates human single-chain variable fragments (scFvs) to serve as CAR-targeting moieties. We are evaluating the efficacy of scFvs to specifically kill target cells in vitro. This work will define lead scFvs used for engineering of our bispecific CAR. Future work will evaluate this therapy in humanized mouse models of TNBC.
Citation Format: Emily G. Kuiper, Leo L. Chan, Matthew R. Chang, Quan K. Zhu, Wayne A. Marasco. A bispecific chimeric-antigen receptor T-cell factory for 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 1531.