bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 711: Small molecule compounds that target cell division cycle 7 (Cdc7) kinase inhibit cell proliferation and tumor growth.
Authors: Bailis Julie , Fang Li , Orf Jessica , Heller Scott , Bush Tammy , Bourbeau Matthew , Escobar Sonia , Frohn Michael , Harrington Paul , Hsieh Faye , Pickrell Alexander , Sham Kelvin , Siegmund Aaron , Tan Helming , Zalameda Leeanne , Allen John , Wickramasinghe Dineli 
Published: August 2014

Abstract
Cdc7 is an essential, serine/threonine protein kinase that activates the initiation of DNA synthesis at replication origins. Cdc7 also promotes cell cycle checkpoint activation in response to replication stress. As a key regulator of S phase entry and progression, Cdc7 kinase is a potential target for cancer therapy, with a distinct mechanism of action from known drugs that inhibit DNA replication. Following a high throughput screen for inhibitors of Cdc7 kinase activity, we investigated structure-activity relationships of azole-based compounds and optimized the compounds for potency and pharmacokinetic properties. Here we present the characterization of one of these compounds as a potent, selective, bioavailable Cdc7 kinase inhibitor. In cells, Cdc7 inhibition decreases MCM2 phosphorylation and DNA synthesis, causes DNA damage, and slows S phase progression. Cdc7 inhibition also induces chromosome missegregation leading to cell lethality in vitro and tumor growth inhibition in vivo. Cdc7 inhibition provides a new approach to target cancers, either as a single agent or in combination with chemotherapy.
Citation Format: Julie Bailis, Li Fang, Jessica Orf, Scott Heller, Tammy Bush, Matthew Bourbeau, Sonia Escobar, Michael Frohn, Paul Harrington, Faye Hsieh, Alexander Pickrell, Kelvin Sham, Aaron Siegmund, Helming Tan, Leeanne Zalameda, John Allen, Dineli Wickramasinghe. Small molecule compounds that target cell division cycle 7 (Cdc7) kinase inhibit cell proliferation and tumor growth. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 711. doi:10.1158/1538-7445.AM2013-711
Abstract 721: Multiplexed systems pathology for in-depth analysis of the tumor microenvironment: a strong correlation between pAkt and androgen receptor in the epithelial component of prostate cancer.
Authors: Blom Sami , Mäki-Teeri Petra , Mirtti Tuomas , Rannikko Antti , Säilä Jenni , Pellinen Teijo , Kallioniemi Olli 
Published: August 2014

Abstract
It is important to understand the heterogeneity across the cancer tissue as well as the spatial interactions and signaling between the different components that constitute the tumor microenvironment; epithelium, stroma, inflammatory cells, etc. The state of the tumor microenvironment and its variability within and in between tumors may give important insights on cancer initiation and progression, diagnostics, prognostics and therapeutic assessment. Thus, there is a major need to assess multiple molecular targets simultaneously, quantitatively, and within the specific tumor sub-compartments. Here, we demonstrate a systems pathology approach for quantitative detection of multiple proteins in formalin-fixed paraffin-embedded patient tissue samples using a combination of immunohistochemistry and high-throughput fluorescence imaging.
The study cohort consisted of 50 prostate cancer tissue samples from 25 patients exhibiting different disease stages in a tissue microarray (TMA) format. We developed a multiplexed assay for detecting pAkt, AR, and cytokeratin 8 (CK8) simultaneously using fluorescent nanoparticle labeling and high-throughput quantitative imaging. Fluorescent signals of pAkt and AR were automatically quantified within the segmented CK8-positive prostate epithelium. The stromal compartment and the non-malignant prostate tissue were analysed separately.
Our results showed that the expression of pAkt and AR correlated strongly in the prostate cancer epithelium (Pearson correlation coefficient 0.89, p &lt; 0.001). This suggests that the androgen-dependent signaling is strongly associated with the pAkt signaling in cancer, with potential ramifications for administrating and monitoring anti-androgens and/or Akt-inhibitor therapy. The systems pathology approach enables quantitative in situ multianalyte detection for any key cancer signaling proteins. The analyses can be readily expanded to TMAs of large prospective or clinical trial cohorts with automated imaging. The ability to quantitatively study the spatial arrangement of the tumor microenvironment could have decisive advantages and improve the diagnostic and therapeutic predictions.
Citation Format: Sami Blom, Petra Mäki-Teeri, Tuomas Mirtti, Antti Rannikko, Jenni Säilä, Teijo Pellinen, Olli Kallioniemi. Multiplexed systems pathology for in-depth analysis of the tumor microenvironment: a strong correlation between pAkt and androgen receptor in the epithelial component of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 721. doi:10.1158/1538-7445.AM2013-721
Abstract 726: Fluorophore-conjugated antibodies improve surgical resection of pancreatic cancer leading to prolonged disease-free survival and overall survival in orthotopic mouse models.
Authors: Metildi Cristina A. , Kaushal Sharmeela , Talamini Mark A. , Luiken George A. , Hoffman Robert M. , Bouvet Michael 
Published: August 2014

Abstract
We established orthotopic mouse models of human pancreatic cancer with fragments of BxPC-3-RFP tumor. Two weeks after implantation, mice were randomized to FGS or bright-field surgery (BS). FGS was performed 24 hrs after tail vein injection of anti-CEA-Alexa 488. Completeness of resection was assessed from pre- and postoperative images obtained with the OV-100 Small Animal Imaging System. Whole body images of mice were obtained postoperatively to assess for recurrence and mice were followed until premorbid to measure survival. We achieved a complete resection of pancreatic cancers in 92% of mice in the FGS group as compared to 58% in the BS group (p=0.002). Preoperative tumor burden was not significantly different between groups (p=0.424). However, FGS afforded a significantly smaller mean postoperative tumor burden compared to BS: 0.0004 ± SE 0.0003 mm2 vs. 0.0841 ± SE 0.027 mm2, p=0.004. On average, mice in the FGS experienced a greater reduction in tumor burden: 99.99% vs 97.72%, p=0.01. FGS reduced recurrence rates from 95% to 50% (p=0.002) and lengthened mean disease-free survival from 7 weeks to 30.5 weeks (p&lt;0.001). The FGS group experienced longer overall survival compared to the BS group: 16.5 weeks vs. 37 weeks (p=0.001). Cure rate was improved with FGS from 5% to 50% (p=0.003). Furthermore, FGS more than doubled the one-year postoperative survival rate from 3 mice in the BLS group to 8 mice in the FGS group (p=0.005). This novel approach has potential to improve outcomes in the surgical treatment of pancreatic cancer.
Survival and recurrence according to surgical mode. Surgical Mode Disease-Free Survival Overall Survival Recurrence Rate Bright-Field Surgery 7 weeks 16.5 weeks 95% Fluorescence-Guided Surgery 30.5 weeks 37 weeks 50%
Citation Format: Cristina A. Metildi, Sharmeela Kaushal, Mark A. Talamini, George A. Luiken, Robert M. Hoffman, Michael Bouvet. Fluorophore-conjugated antibodies improve surgical resection of pancreatic cancer leading to prolonged disease-free survival and overall survival in orthotopic mouse models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 726. doi:10.1158/1538-7445.AM2013-726
Abstract 738: Neutrophil tracking study on mammary tumors using bioluminescence imaging in vivo.
Authors: Alshetaiwi Hamad , Balivada Sivasai , Pyle Marla , Shrestha Tej B. , Bossmann Stefan H. , Troyer Deryl L. 
Published: August 2014

Abstract
Polymorphonuclear neutrophils (PMNs) are the most abundant circulating blood leukocytes. They are part of the innate immune system and provide a first line of defense by migrating toward areas of inflammation in response to chemical signals that have been released from the site. Like inflammation, cancer also causes activation of PMNs and release of myeloperoxidase. In this study, we demonstrate that giving a small amount of luminol to mice that have been transplanted with 4T1 mammary tumor cells allows detection of myeloperoxidase activity. Luminol allowed detection of activation of PMNs only two days after cancer cell transplantation, even though tumors were not yet palpable. In conclusion, luminol-bioluminescence imaging (BLI) can provide a way to image certain tumors at an early stage.
Citation Format: Hamad Alshetaiwi, Sivasai Balivada, Marla Pyle, Tej B. Shrestha, Stefan H. Bossmann, Deryl L. Troyer. Neutrophil tracking study on mammary tumors using bioluminescence imaging in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 738. doi:10.1158/1538-7445.AM2013-738
Abstract 740: Investigating the role of epigenetic mechanisms upon aberrant signaling network activation.
Authors: Nabet Behnam , Braun Rosemary , Popovic Relja , Licht Jonathan D. 
Published: August 2014

Abstract
Growth factor (GF) stimulation of quiescent cells activates critical receptor tyrosine kinase (RTK) signaling pathways as well as waves of downstream gene expression to drive cell proliferation, survival, and migration. Aberrant activation of RTK signaling networks is a root cause of the uncontrolled cell growth and cell survival seen in cancer. In this study, we aim to uncover the role of epigenetic mechanisms in controlling the dynamic gene expression changes that occur as a cell is activated from a quiescent state, in normal and oncogenic cellular contexts. In order to compare controlled RTK signaling with hyperactive RTK signaling cellular states, we created a cell culture system to modulate the duration and intensity of RTK activation. We genetically deleted the Sprouty (Spry) genes, a family of negative feedback inhibitors of RTK signaling that function as putative tumor suppressors. The Spry deficient cells are hypersensitive to several GFs and show significantly enhanced and prolonged activation of several critical RTK signaling pathways, including the Ras-MAPK pathway. Additionally, the Spry deficient cells possess accelerated cell growth and increased tumorigenic potential compared to their wild-type counterparts. To determine whether this deregulated signaling results in aberrant gene expression, quiescent Spry wild-type and deficient cells were stimulated with GFs, and microarrays were used to profile changes in gene expression over time. Deregulated RTK signaling due to the absence of Spry leads to abnormal expression of a large subset of genes. Specifically, many genes display display not only changes in the level of expression, but aberrant patterns of response to GF stimulation. We determined that genes with deregulated activation in Spry deficient cells display significant differences in histone tail modifications at promoter regions and distal regulatory elements. Interestingly, these changes are evident in the quiescent cellular state as well as upon GF-mediated RTK network activation. Our work suggests that dynamic changes in a cell's epigenetic landscape contribute to the deregulated activation of genes upon hyperactive RTK signaling. Our study will provide a comprehensive view of how epigenetic mechanisms contribute to aberrant gene expression in oncogenic cellular contexts.
Citation Format: Behnam Nabet, Rosemary Braun, Relja Popovic, Jonathan D. Licht. Investigating the role of epigenetic mechanisms upon aberrant signaling network activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 740. doi:10.1158/1538-7445.AM2013-740
Abstract 741: CpG methylation abrogates KLF2-mediated transcriptional repression of telomerase in human T cells.
Authors: Hara Toshifumi , Yoshita Manami , Nakamura Masataka 
Published: August 2014

Abstract
Many genes in tumor cells are DNA-methylated and transcriptionally repressed. Constitutive expression of the limiting catalytic subunit of telomerase, hTERT, is one of the common signatures of tumor cells, even though its promoter is DNA-methylated. On the other hand, in normal somatic cells the promoter is unmethylated and transcription of hTERT is strictly regulated. In this study, we examined transcriptional regulation of the hTERT gene in normal and tumor cells. We identified a novel promoter element, which bound the zinc-finger transcription factor Krüpple-like factor 2 (KLF2) in normal human T Lymphocytes. The binding of KLF2 to the hTERT promoter element paralleled repression of hTERT transcription in resting normal T cells. T cell growth induced KLF2 release from the element and hTERT transcription. Forced reduction of KLF2 expression by siRNA in normal resting T cells increased the level of endogenous hTERT mRNA. The hTERT promoter is methylated in the KLF2-positive human T leukemic cell line, Kit 225, and KLF2-negative human T leukemic cell line, Jurkat. Treatment with the DNA methyltransferase inhibitor, Zebularine, reduced levels of CpG methylation in the hTERT promoter, resulting in downregulation of hTERT mRNA expression in KLF2-positive Kit 225 cells, while the Zebularine treatment did not cause any appreciable effects on hTERT expression in KLF2-negative Jurkat cells. Methylation of CpG sequences in endogenous and exogenous hTERT promoter elements inhibited the KLF2 binding to the element. Furthermore, KLF2 binding to the promoter is associated with histone H3 repressive marks, indicating KLF2-mediated epigenetic silencing of the hTERT promoter. Our results suggest that KLF2 partly controls strict transcriptional regulation of the hTERT gene through association and dissociation with the promoter in normal T cells, but in tumor cells these important interactions are prevented by DNA methylation.
Citation Format: Toshifumi Hara, Manami Yoshita, Masataka Nakamura. CpG methylation abrogates KLF2-mediated transcriptional repression of telomerase in human T cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 741. doi:10.1158/1538-7445.AM2013-741
Abstract 750: Negative regulation of bcl-2 transcription by DNA damage-binding protein complex in human ovarian cancer cells.
Authors: Zhao Ran , Han Chunhua , Eisenhauer Eric , Kroger John , Gong Li , Zhu Qianzheng , Zhao Weiqiang , Yu Jianhua , Karuppaiyah Selvendiran , Liu Xingluo , Wani Altaf Ahmad , Wang Qi-En 
Published: August 2014

Abstract
Elevated expression of the anti-apoptotic factor Bcl-2 is believed to be one of the contributing factors to an increased relapse rate associated with multiple cisplatin-resistant cancers. DNA damage-binding protein 2 (DDB2) has recently been revealed to play an important role in sensitizing human ovarian cancer cells to cisplatin-induced apoptosis through the down-regulation of Bcl-2, but the underlying molecular mechanism remains poorly defined. Here, we report that DDB2 functions as a transcriptional repressor for Bcl-2. DDB2 binds to a specific response element at the 5’-end of bcl-2 P1 promoter, concomitant with marked losses of histone H3 acetylation along the bcl-2 promoter and enhancer regions. Quantitative chromatin immunoprecipitation analysis revealed that HDAC1 was locally enriched in the bcl-2 P1 core promoter following DDB2 over-expression. Lysine 244 in DDB2 is essential for the transcriptional regulation of bcl-2, evidenced by the fact that the K244E mutant failed to inhibit bcl-2 promoter activity. Interestingly, the simultaneous DDB1 knock-down and DDB2 over-expression are required to potentiate bcl-2 promoter activity in the human ovarian cancer cell line CP70, while the knockdown of DDB1 alone failed to produce any significant effect. Furthermore, quantitative analysis of DDB2 and Bcl-2 expression in ovarian cancers provides clinical evidence that DDB2 and Bcl-2 are inversely correlated. Collectively, our data supports a model in which DDB2 and DDB1 function cooperatively in repressing bcl-2 transcription by recruiting HDAC1 to deacetylate histone H3 across bcl-2 regulatory regions, with DDB2 being responsible for binding to a specific cis-acting element in the bcl-2 P1 promoter. These findings have immediate implications for clinical trial designs of DDB2-based therapies for diverse cisplatin-resistant malignancies.(Supported by NIH grant CA151248 to QEW, and CA93413 to AAW)
Citation Format: Ran Zhao, Chunhua Han, Eric Eisenhauer, John Kroger, Li Gong, Qianzheng Zhu, Weiqiang Zhao, Jianhua Yu, Selvendiran Karuppaiyah, Xingluo Liu, Altaf Ahmad Wani, Qi-En Wang. Negative regulation of bcl-2 transcription by DNA damage-binding protein complex in human ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 750. doi:10.1158/1538-7445.AM2013-750
Abstract 759: Regulation of androgenic signaling by yes-associated protein, YAP, in prostate cancer cells.
Authors: Alptekin Ahmet , Abali Gamze Kuser , Wang Qiang , Cinar Bekir 
Published: August 2014

Abstract
Androgenic signaling plays a central role in prostate tumor development, progression, and metastasis. The molecular circuitry contributing to these pathological events is still a mystery. Previously, we reported that the hippo-like protein kinase Mst1/2 antagonized androgen receptor (AR) and prostate tumor cell growth (Cinar et al., Cancer Res., 2011). Here, we studied the role of yes-associated protein (YAP) oncogene, a prominent nuclear effector of the Mst/Hippo tumor suppressor network, in regulating AR and in prostate tumor cell growth in vitro. As revealed by co-immunoprecipitation (IP) and western blot experiments, we first showed that endogenous YAP formed protein complexes with endogenous AR. The complex formation between the two proteins mainly occurred in cell nuclei was further enhanced by androgen stimulation. Our luciferase-promoter reporter analysis demonstrated that enforced YAP expression increased the androgen-mediated and AR-responsive promoter reporter gene activation, and the carboxyl-terminal site of YAP, which consists of PDZ and coiled-coiled protein-protein interaction domains, appeared to be responsible for AR transactivation. Chromatin-IP and PCR analysis of the bound and uncross-linked genomic DNA revealed that YAP interacted with the DNA regions where AR also binds, and androgen enhanced the interaction between YAP and chromatin DNA. We also provided evidence that, compared to vector control, enforced YAP expression promoted androgen-dependent and independent cell growth, and silencing YAP by RNAi reduced the growth of castration-resistant prostate tumor cells in vitro. Our findings indicate that YAP is a physiologic binding partner and positive regulator of androgenic signaling, and suggest that the Hippo-YAP pathway plays a critical role in human prostate tumor progression.
Citation Format: Ahmet Alptekin, Gamze Kuser Abali, Qiang Wang, Bekir Cinar. Regulation of androgenic signaling by yes-associated protein, YAP, in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 759. doi:10.1158/1538-7445.AM2013-759
Abstract 761: Importance of protein interactions in mediating AF9/MLLT3 function.
Authors: Malik Bhavna , Hemenway Charles S. 
Published: August 2014

Abstract
AF9/MLLT3, located on chromosome band 9p22, was first identified as a fusion partner of the Mixed Lineage Leukemia (MLL) gene in acute myeloid leukemia. The AF9 protein has been shown to play an important role in erythrocyte/ megakaryocyte development by regulating the expression of genes encoding hematopoietic transcription factors. Moreover, in hematopoietic precursor cells, expression of a chimeric protein comprised of the C-terminus of AF9 fused to the N-terminus of MLL leads to leukemic transformation. Thus AF9 contributes both to normal as well as neoplastic blood cell development. Our lab and others have shown the direct or indirect association of the C-terminus of AF9 with several distinct proteins including activators and repressors of transcription (AF4, pTEFb, DOT1L, CBX8, RING1b, and BCoR), thus suggesting that the function of AF9 can be substantially changed depending upon the nature of molecules that specifically associate with it. We hypothesize that AF9 is an important component of several distinct macromolecular complexes, each of which has a unique function. Specifically, DOT1L is a chromatin modifying enzyme that methylates histone H3 at lysine 79. CBX8 is component of the repressive Polycomb PRC1 complexes. Here, we report that the association of AF9 with CBX8 competes with DOT1L for AF9 binding and alters expression of genes regulated by DOT1L. In this context, CBX8 enhances rather than represses gene expression.
Citation Format: Bhavna Malik, Charles S. Hemenway. Importance of protein interactions in mediating AF9/MLLT3 function. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 761. doi:10.1158/1538-7445.AM2013-761
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.