bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3519: The c-Myc oncogene over-activates dormant replication origins and sensitizes cancer cells to chemotherapy drugs
Authors: Bryant Victoria , Alexandrow Mark G. 
Published: May 2015

Abstract
Several clinical studies have shown a correlation between elevated c-Myc levels and a better response to chemotherapy. Although elevated c-Myc might indirectly cause such chemosensitivity, it is possible that a direct effect is occurring due to underlying molecular mechanisms. The purpose of the current study was to determine whether c-Myc overexpression could acutely cause chemosensitivity. The c-Myc protein is known to activate DNA replication origins, but the mechanism for this is unknown. Origins are regulated by the loading of MCM2-7 hexamers, which form the core of the helicase that starts the initiation of replication. Mammalian cells load more MCM complexes than are necessary to complete one round of replication. The excess MCM complexes function as backups to allow recovery of replication when forks stall during drug treatment. Consistent with this, we found that loss of Mcm4 or Mcm7 sensitizes PDAC cell lines to 5-FU and Gemcitabine, two S phase stress drugs that are used to treat PDAC patients but are not highly effective on their own. Similar to depletion of backup MCM complexes via loss of Mcm4 or Mcm7, elevated c-Myc expression over-activates backup MCMs, leaving fewer available to recover from drug treatment. Cells containing overexpressed c-Myc display increased chemosensitivity to Gemcitabine that is not seen in cells containing normal c-Myc levels or a non-functional c-Myc mutant. These results demonstrate that reduction in backup MCM complexes, either by direct downregulation or by oncogene driven over-activation (via c-Myc), render cells sensitive to chemotherapy drugs. These results suggest that development of drugs that target MCM functionality may be useful in combination with S-phase stress drugs currently used in the clinic. These results also demonstrate that c-Myc has the ability to acutely cause chemosensitivity and c-Myc elevated tumors may respond better to chemotherapy due to the c-Myc effects on MCM complexes.
Citation Format: Victoria Bryant, Mark G. Alexandrow. The c-Myc oncogene over-activates dormant replication origins and sensitizes cancer cells to chemotherapy drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3519. doi:10.1158/1538-7445.AM2014-3519
Abstract 352: Integrating transcriptomic data using metacore pathway analysis to identify novel biomarkers of bevacizumab target engagement
Authors: Willis Chris D. , Lafferty-Whyte Kyle , Baker Melinda , Pestell Richard G. 
Published: May 2015

Abstract
The widespread use of microarrays for gene expression studies has generated large volumes of transcriptomic data to help describe mechanisms such as drug treatment response. The drug Bevacizumab is well characterized for its ability to inhibit VEGFA pro-angiogenic signaling resulting in tumor regression for a number of cancer-related indications. However, universal mechanisms of action have remained elusive to describe changes at the mRNA level across different solid tumor types. This case study uses 3 publically available datasets related to Bevacizumab treatment and analyzes the data in a manually curated systems biology context. Using a combination of Thomson Reuters solutions including the Data Annotation and Processing tool, MetaCore Pathway Analysis and Integrity Biomarkers Module allows for a simple workflow to process omics data and identify biomarkers of target engagement through pathway analysis and data integration. This analysis identified 5 differentially expressed genes common to all treated tumors including: Basonuclin, growth arrest-specific 7, mucin 1, integrin beta-4, and dystonin. All 5 of these objects can be connected to VEGF-A in a signaling network based on previously curated interactions. These in silico results provide a strong rationale for follow up studies in the lab to validate novel biomarkers related to Bevacizumab target engagement in solid tumors.
Citation Format: Chris D. Willis, Kyle Lafferty-Whyte, Melinda Baker, Richard G. Pestell. Integrating transcriptomic data using metacore pathway analysis to identify novel biomarkers of bevacizumab target engagement. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 352. doi:10.1158/1538-7445.AM2014-352
Abstract 3547: FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2
Authors: Liu Li-Li , Lu Shi-Xun , Li Min , Fu Jia , Zhang Chris Zhiyi , Yun Jing-Ping 
Published: May 2015

Abstract
Background and Aims: microRNAs, which are frequently deregulated in human cancer, have been implicated in the progression of hepatocarcinogenesis. Our study aims to investigate the role of miR-137 in cell proliferation and metastasis of hepatocellular carcinoma and the underlying molecular mechanisms.
Methods: Real-time PCR and western blot were used to examine the expressions of miR-137, Akt2 and FoxD3 in HCC tissues and cells. The in vitro and in vivo effects of miR-137 were determined. Luciferase reporter assay was conducted to confirm the association of miR-137 and AKT2. CHIP assay was performed to test the regulation of miR-137 by FoxD3.
Results: We show that microRNA (miR)-137 is significantly down-regulated in hepatocellular carcinoma (HCC), and its decreased expression is associated with vein invasion, incomplete Involucrum, and tumour metastasis. Multivariate analysis suggests that miR-137 is an independent indicator for poor survival. To determine its role in HCC development, we showed that overexpression of miR-137 suppresses cell proliferation, invasion and metastasis in vitro. Conversely, miR-137 inhibition promoted HCC cell growth. We also identified AKT2 as a key target of miR-137 in this context. Statistical data revealed a reverse correlation of AKT2 and miR-137 expression in HCC patients. Silencing of AKT2 phenotypically copied miR-137-induced phenotypes, whereas re-expression of AKT2 reversed the suppressive effects of miR-137. Further investigation showed that miR-137 exerted its anti-tumour activity via inhibiting the AKT2/mTOR pathway. Moreover, we demonstrated that FoxD3 binds to the promoter of miR-137 and activates its transcription. In vivo studies confirmed that FoxD3-regulated miR-137 inhibition of HCC growth and metastasis via directly targeting AKT2.
Conclusions: Our findings indicated that miR-137 is a valuable biomarker for HCC prognosis and demonstrated that the FoxD3/miR-137/AKT2 regulatory network plays an important role in HCC progression.
Citation Format: Li-Li Liu, Shi-Xun Lu, Min Li, Jia Fu, Chris Zhiyi Zhang, Jing-Ping Yun. FoxD3-regulated microRNA-137 suppresses tumour growth and metastasis in human hepatocellular carcinoma by targeting AKT2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3547. doi:10.1158/1538-7445.AM2014-3547
Abstract 3548: Study of the tumor suppressive machinery of arsenic trioxide-induced glioblastoma multiforme inhibition via microRNA-182-Sestrin2 regulatory circuit
Authors: Lin Liang-Ting , Chiou Shih-Hwa , Lee Yi-Jang 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) is classified the fourth grade of human glioma that indicates the most malignant brain tumor with poor five-year survival (5%). Accumulated evidence showed that GBM cells were resistant to various therapeutic strategies. Recently, use of arsenic trioxide (ATO) to induce apoptosis and to increase the radiosensitivity was reported for the benefit in treating GBMs. However, the responsible signaling cascades are still remain investigation. MicroRNA, a category of RNA interference, regulates its downstream genes post transcriptionally by binding to the 3′untraslated region (UTR) of its targets. In this study, we used S1 and S1R1 GBM cells which were derived from the primary and the recurrent lesion respectively. Firstly, we identified that an oncogenic microRNA, miR-182, was down-regulated after the treatment of ATO in both GBM cells. In addition, one of the miR-182 targeted coding genes, Sestrin 2 (SESN2), plays an important role in relieving intracellular oxidative stress and participates in TP53 tumor suppressive pathway. Use of luciferase-based reporter assay confirmed that miR-182 directly bound to SESN2 3′UTR and interrupted the further translation. Intriguingly, the basal level of miR-182 in the primary S1 GBM was significantly lower than the recurrent S1R1 GBM, supporting the oncogenic evidence in the previous studies. The counteracted SESN2 expression was also determined by real-time qPCR and western blot. We then hypothesized that ATO may retarded the growth of GBM through a miR-182-SESN2 related regulatory axis. Overexpression of miR-182 in S1 GBM resulted in a decrease of SESN2 and insensitive to ATO treatment. On the opposite, inhibition of miR-182 in S1R1 GBM dramatically retarded the growth rate and sensitized the cells to ATO. Moreover, pretreatment of an antioxidant, N-acetyl-cysteine (NAC), rescued the miR-182 suppression, suggesting that ATO-induced oxidative stress may be dominant in this responsive axis. Concordant expression of miR-182/96/182 cassette was revealed, indicating the transcriptional regulation was unveiled. Further investigation on the detailed machinery still remain elucidating. Based on our findings, we displayed that ATO-induced oxidative stress triggered a tumor suppressive response through a miR-182-SESN2 dependent machinery.
Citation Format: Liang-Ting Lin, Shih-Hwa Chiou, Yi-Jang Lee. Study of the tumor suppressive machinery of arsenic trioxide-induced glioblastoma multiforme inhibition via microRNA-182-Sestrin2 regulatory circuit. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3548. doi:10.1158/1538-7445.AM2014-3548
Abstract 3554: Gene and miRNA expression networks specific to never smoker lung adenocarcinoma
Authors: Kusko Rebecca , Garrison Carly , Wang Teresa , Campbell Josh , Perez-Rogers Joseph , Luo Lingqi , Beane Jennifer , Liu Gang , Kadara Humam , Belinsky Steven , Lenburg Marc E. , Spira Avrum 
Published: May 2015

Abstract
While smoking is well recognized as a major risk factor for lung cancer, there is a growing incidence of lung cancer in never smokers which is in turn the fifth leading cause of cancer-related death worldwide. Never smokers (NS) who develop lung cancer exhibit disparate profiles of somatic mutations and clinical responses to targeted therapy relative to lung cancer arising in current or former “ever” smokers (ES), suggesting that ES and NS lung cancer arise through distinct molecular processes. We therefore sought to characterize mRNA and miRNA expression differences specific to NS adenocarcinoma (AdC) to gain insights into the molecular differences underlying NS and ES AdC carcinogenesis.
Total RNA was isolated from matched pairs of lung AdC tumor and adjacent histologically normal tissue obtained from 22 subjects (8 NS, 14 ES). Large and small RNA libraries were sequenced on the Illumina HiSeq 2000. Tumor-specific gene and miRNA expression differences between NS and ES were identified using linear mixed-effects ANOVA. MiRConnx was used to construct miRNA-mRNA networks.
We identified 120 mRNA and 15 miRNA whose expression was modified uniquely in NS lung AdC. In the predicted miRNA-mRNA regulatory network, additional analysis pinpointed modulation of the development and cellular metabolism canonical pathway within genes connected to several of the differentially expressed miRNA (GATHER, p&lt;0.001). Several of the differentially expressed mRNA and miRNA were validated by qRT-PCR in samples from an independent cohort.
In summary, the construction of a miRNA-mRNA regulatory network has enabled us to identify molecular alterations that may be specific to NS lung AdC. Ultimately, these findings may serve to broaden the landscape of personalized therapeutic and treatment options by identifying targetable molecular interactions and therapeutic drug candidates for lung AdC in never smokers.
Citation Format: Rebecca Kusko, Carly Garrison, Teresa Wang, Josh Campbell, Joseph Perez-Rogers, Lingqi Luo, Jennifer Beane, Gang Liu, Humam Kadara, Steven Belinsky, Marc E. Lenburg, Avrum Spira. Gene and miRNA expression networks specific to never smoker lung adenocarcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3554. doi:10.1158/1538-7445.AM2014-3554
Abstract 3571: mRNA spike-in control materials for cancer fusion gene detection assays
Authors: Liang Winnie , Pond Stephanie J. , Tembe Waibhav D. , Chuang Han-Yu , Legendre Christophe , Kim Nancy , Montel Valerie , Wong Shukmei , McDaniel Timothy K. , Craig David , Carpten John 
Published: May 2015

Abstract
Oncogenic fusion genes underlie the mechanism of several common cancers and also constitute or encode important diagnostic and therapeutic targets. Studies using next-generation sequencing technologies, particularly RNA sequencing (RNA-seq), have revealed a growing number of recurrent fusions in a variety of cancers. As such, establishing analytic parameters, including the limit of detection, sensitivity, and specificity of detecting fusions in tumor RNA specimens is important. We have developed reference materials useful in assessing the ability to detect fusion events in RNA or DNA samples. These consist of a set of nine synthetic poly-adenylated RNA transcripts that correspond to common cancer fusion gene sequences. These synthetic fusion RNAs can be spiked at known concentrations into total RNA in the first stage of the mRNA sample prep and used as in-line controls to evaluate the sensitivity and specificity of the detection of these mutations. As a demonstration of the utility of these controls, we performed a series of spike-in experiments to investigate performance characteristics of three commonly used fusion-detection software algorithms. Our results show all three algorithms to be capable of detecting fusions in a dose-dependent manner. The results also show differences in performance among the algorithms for detecting specific fusions.
Citation Format: Winnie Liang, Stephanie JK Pond, Waibhav D. Tembe, Han-Yu Chuang, Christophe Legendre, Nancy Kim, Valerie Montel, Shukmei Wong, Timothy K. McDaniel, David Craig, John Carpten. mRNA spike-in control materials for cancer fusion gene detection assays. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3571. doi:10.1158/1538-7445.AM2014-3571
Abstract 3585: Metastasis of 4T1 murine breast cancer cells to the lung is dependent on the chemokine CCL2/MCP-1 produced by stromal cells in the primary tumor
Authors: Yoshimura Teizo , Howard O.M. Zack , Ito Toshihiro , Kuwabara Masaki , Matsukawa Akihiro , Chen Keqiang , Liu Ying , Liu Mingyong , Wang Ji Ming 
Published: May 2015

Abstract
The chemokine CCL2, also known as MCP-1, plays an important role in the initiation and progression of cancer. Since tumor cells produce CCL2, they are considered to be the main source of this chemokine. Here, we examined the capacity of CCL2 produced by non-tumor cells to affect the growth and lung metastasis of 4T1 mouse breast cancer cells. Primary tumors formed in the mammary pad of WT or CCL2-/- mice grew at a similar rate; however, lung metastases were markedly reduced in CCL2-/- mice, with significantly longer mouse survival. High levels of CCL2 mRNA were detected in tumors growing in WT, but not CCL2-/- mice. Serum CCL2 levels were increased in tumor-bearing WT, but not CCL2-/- mice. Transplantation of CCL2-/- bone marrow cells into WT mice did not alter the incidence of lung metastasis, but transplantation of WT bone marrow cells into CCL2-/- mice increased lung metastasis. The primary tumors of CCL2-/- mice consistently developed necrosis earlier than those of WT mice and showed decreased infiltration by macrophages and reduced angiogenesis. Interestingly, 4T1 cells that metastasized to the lung constitutively expressed elevated levels of CCL2. Intravenous injection of 4T1 cells producing a high level of CCL2 resulted in increased tumor foci in the lung of CCL2-/- mice. Finally, the culture supernatants of 4T1 cells markedly induced CCL2 production in mouse macrophages. Thus, CCL2 produced by tumor cell-activated stromal cells in the primary tumors promotes lung metastasis of 4T1 cells, while tumor cell-derived CCL2 also contributes to the metastasis once tumor cells enter the circulation. A greater understanding of the source and role of CCL2 during tumor progression and the mechanisms by which stromal cells produce this chemokine may lead to novel strategies for cancer treatment.
Citation Format: Teizo Yoshimura, O.M. Zack Howard, Toshihiro Ito, Masaki Kuwabara, Akihiro Matsukawa, Keqiang Chen, Ying Liu, Mingyong Liu, Ji Ming Wang. Metastasis of 4T1 murine breast cancer cells to the lung is dependent on the chemokine CCL2/MCP-1 produced by stromal cells in the primary tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3585. doi:10.1158/1538-7445.AM2014-3585
Abstract 3632: Targeting of tumor myeloid suppressor cells by Salmonella bacteria causes a shift to M1 phenotype and leads to inhibition of tumor growth
Authors: Al-Ramadi Basel K. , Kaimala Suneesh , Mohamed Yassir A. , Issac Jincy M. , Elkord Eyad , Chouaib Salem , Fernandez-Cabezudo Maria J. 
Published: May 2015

Abstract
Tumor development is associated with changes in hematopoiesis that lead to an increase in myelomonocytic cells in systemic sites as well as within the tumor tissue. The accumulation of myeloid cells within tumors not only promotes angiogenesis and tissue remodeling required for tumor growth but also maintains the tumor milieu as an immunosuppressive environment. We have previously shown that attenuated strains of the facultative anaerobic bacteria, Salmonella enterica serovar Typhimrium, can effectively retard tumor growth in a therapeutic melanoma model. Given that Salmonella organisms utilize host macrophages as their primary niche for survival, we investigated the consequences of Salmonella treatment on myeloid cell recruitment, phenotypic characteristics and functional activation within tumor tissue of B16.F1 melanoma-bearing animals. Treatment with Salmonella led a preferential expansion, within spleen and tumor tissues, of CD11b+Gr-1+, but not CD11b+Gr-1-, myeloid cells. Using 6-color FACS analysis, CD11b+Gr-1+ cells were shown to exhibit significant up-regulation in the expression of activation markers, including MHC class II, CD80, and Sca-1/Ly6A proteins. Moreover, the functional activities of total tumor infiltrating cells or CD11b-purified cells from tumor tissue were assessed by qRT-PCR. Salmonella treatment induced a dramatic increase in iNOS and IFN-g gene expression but inhibited ARG1 and IL-4 genes. Further, while expression of TGF-b and VEGF was reduced, the level of inflammation-related S100A9 gene was increased. Our findings demonstrate that systemic administration of attenuated Salmonella leads to phenotypic and functional changes in tumor myeloid suppressor cells, with a shift from a predominantly M2 phenotype to an activated, effector macrophage phenotype.
Citation Format: Basel K. Al-Ramadi, Suneesh Kaimala, Yassir A. Mohamed, Jincy M. Issac, Eyad Elkord, Salem Chouaib, Maria J. Fernandez-Cabezudo. Targeting of tumor myeloid suppressor cells by Salmonella bacteria causes a shift to M1 phenotype and leads to inhibition of tumor growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3632. doi:10.1158/1538-7445.AM2014-3632
Abstract 3633: Combination of innate immune activators stimulates leukocyte populations in the tumor microenvironment
Authors: Shahar Ehud , Gorodetsky Raphael , Aizenshtein Elina , Pitcovski Jacob 
Published: May 2015

Abstract
Tumor microenvironment (TME) harbors a multitude of immune cells which can comprise up to 50% of the tumor. The most abundant cells in the TME often are tumor associated macrophages (TAM) and tumor associated neutrophils (TAN). These cells potentially possess anti-tumoral cytotoxic effects, and have the potential to induce a broad range of cellular immune responses. However, in the developing tumor, due to elements secreted by the tumor cells, TAM and TAN are altered to act in a pro-tumor manner. The purpose of our study was the optimization and characterization of a treatment aimed at inducing an anti-tumoral response of innate immune cells in the TME. In a melanoma B16 mice model, micro-particles carrying targeting and induction components were injected intra-tumorally and the responses of the tumors, including immune cells populations were monitored. Without treatment the CD45+ cells ratio of total TME decreased as tumor progressed. Particles carrying Toll-like receptor ligands inhibited tumor growth, inducing significant elevation of CD45+ cells in the TME. Using different inducing molecules (inducers) or simultaneous use of several inducers enabled the stimulation of specific immune cell populations within the tumor. The current study suggests that by using tumor targeted particles with adequate inducers, one could change the tumor microenvironment innate immune cells toward an anti-tumor response.
Citation Format: Ehud Shahar, Raphael Gorodetsky, Elina Aizenshtein, Jacob Pitcovski. Combination of innate immune activators stimulates leukocyte populations in the tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3633. doi:10.1158/1538-7445.AM2014-3633