bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2864: Molecular imaging of early inflammatory response during hyperplasia and/or colitis in response to bacterial infection.
Authors: Papineni Rao , Ahmed Ishfaq , LeVine Steven , Bradley Kenneth , Mclaughlin William , Pizzonia John , Umar Shahid 
Published: August 2014

Abstract
Inflammatory diseases such as ulcerative colitis recruit myeloid cells and result in inflammatory responses such as generation of reactive oxygen species (ROS). Development of non-invasive luminescence imaging approaches is needed to evaluate these inflammatory responses. We developed methodologies to show that vibration induced gut inflammation can be determined using luminescence imaging approach in a non-invasive fashion (Papineni and Vizard, World Molecular Imaging Congress
2012). Citrobacter rodentium (CR) is a natural bacterial pathogen that infects the distal colon of mice and induces transmissible murine colonic hyperplasia (TMCH). Here we determined the early inflammatory response (ROS activity) to intestinal infection by CR in a longitudinal study. We further assessed the effects of allelic variation on murine chromosome 11 (B6.CAST. 11) on the inflammatory response. The ROS activity was monitored in real-time in vivo using L-012 (8-amino-5-chloro-7-phenylpyridol [3,4-d]pyridazine-1,4(2H,3H) dione), a chemiluminescence reporter, using planar multimodal imaging system. 0.1 ml of 1 mg/ml L-012 probe was injected (i.p.) in control and the experimental mice that were subjected to CR infection. Necrosis was imaged (post-infection day-19) using a fluorescent probe containing a bis (zinc2+dipicolylamine, Zn-
DPA) motif which binds with high affinity to apoptotic, necrotic, and bacterial surfaces. Significant difference in the basal gut ROS activity was found in mice with allelic variation on chromosome 11 compared to the wild type littermates. Robust elevation in ROS activity was observed in both the wild type and B6.CAST.11mice that were infected with CR (post infection 9, 12, 19 days). The variation in the levels of ROS activity however was very distinct between the wild type and B6.CAST.11 mice indicating the contribution of molecular determinants at the chromosome 11. The potential advantages in these real-time ROS monitoring methodologies by in vivo imaging, in understanding mechanisms of infection, inflammation, and development of better intervention strategies will be elaborated.
Citation Format: Rao Papineni, Ishfaq Ahmed, Steven LeVine, Kenneth Bradley, William Mclaughlin, John Pizzonia, Shahid Umar. Molecular imaging of early inflammatory response during hyperplasia and/or colitis in response to bacterial infection. [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 2864. doi:10.1158/1538-7445.AM2013-2864
Abstract 2866: Functional impairment of microRNAs induced by chronic inflammation is the cause of inflammation-associated colon tumorigenesis.
Authors: Yoshikawa Takeshi 
Published: August 2014

Abstract
Background: A widespread downregulation of microRNAs is commonly observed in human cancers and is involved in cellular transformation and tumorigenesis. Because we previously reported that microRNA functions are inhibited under various kinds of cellular stresses including inflammatory cytokines in vitro, we hypothesized that chronic inflammation in vivo may also cause chronic functional impairment of microRNAs, which mimics a global reduction of microRNA abundance, resulting in a causal role in inflammation-associated tumorigenesis. Methods & Results: 1) To examine this hypothesis, we first confirmed the functional impairment of microRNAs under inflammatory stimuli in vitro using artificial reporter constructs. The derepression of microRNA-targeting reporter activities by inflammatory stimuli could also be observed using reporter constructs containing natural 3’UTR sequences of c-myc and Lin28B genes, which are targeted by endogenous let-7. 2) Next, we constructed reporter transgenic mice bearing CMV-promoter driven GFP construct carrying target sequences of microRNAs in its 3’UTR, and monitored the changes of microRNA functions in vivo during the course of a Dextran Sulfate Sodium (DSS) induced colitis-associated colon tumor model. The expression levels of GFP were significantly increased during colitis, suggesting that microRNA functions were impaired during the chronic inflammation in vivo. The expression levels of microRNA-target oncogenes such as c-myc and Lin28B in the colonic mucosa were indeed upregulated. 3) Lastly, to determine the consequences of the global functional impairment of microRNAs during the colitis, we examined Dicer-deficient mice, which have globally low levels of microRNA expression and may mimic the functional impairment of global microRNAs induced by chronic inflammation described above. As expected, Dicer deficient mice were more liable to have the colitis-associated tumors. This indicates that the global decrease of microRNAs leads to oncogenesis, suggesting that the functional impairment of global miRNAs during chronic inflammation can also be a cause of the inflammation-associated carcinogenesis. Conclusion: In conclusion, we propose a novel concept that the attenuation of global microRNA functions by chronic inflammation is the cause of inflammation-associated tumorigenesis.
Citation Format: Takeshi Yoshikawa. Functional impairment of microRNAs induced by chronic inflammation is the cause of inflammation-associated colon tumorigenesis. [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 2866. doi:10.1158/1538-7445.AM2013-2866
Abstract 2871: Tumor-derived CCL2 promotes recruitment of CD11b/Gr1midmyeloid cells to sustain colorectal cancer liver metastasis.
Authors: Lim Su Yin , Zhao Lei , Gordon-Weeks Alex , Tapmeier Thomas , Muschel Ruth 
Published: August 2014

Abstract
Metastatic colorectal cancer (CRC) is one of the most prominent causes of cancer-related mortality. However, therapeutic options for patients with metastatic CRC are limited and development of new and more effective therapeutics aimed at downstaging the disease and prolonging survival is urgently required. Primary tumor dissemination to secondary sites, predominantly the liver, is a dynamic process dependent on the interactions between tumor cells and the host tissue microenvironment. Immune cells in the tumor microenvironment have been shown to play pivotal roles in the metastatic process but their pro-metastatic functions in CRC liver metastasis remains incompletely understood.
To simulate liver metastasis, MC38 colon carcinoma cells were injected into the spleen of C57BL/6 mice. A population of CD11b/Gr1mid cells, distinct from other metastasis-associated myeloid cells previously described, increased dramatically during establishment of liver metastases. Adoptive transfer of bone marrow cells confirmed that these CD11b/Gr1mid cells were derived from bone marrow progenitor cells. MC38 tumor cells expressed high levels of CCL2 and serum levels were elevated in tumor-bearing mice compared to controls. Inhibition of tumor-derived CCL2 using shRNA, and absence of its cognate receptor in CCR2 KO mice significantly diminished CD11b/Gr1mid cell infiltration into tumor-bearing livers. Importantly, inhibition of CD11b/Gr1mid cell recruitment led to a marked reduction in tumor burden. Moreover, when CD11b/Gr1mid cells were depleted in a transgenic CD11b-DTR mouse model, a striking decrease in tumor vessel density was observed, with a concomitant reduction in tumor cell proliferation.
Serum CCL2 concentrations were similarly elevated in CRC patients, including those who present metastasis, compared to normal controls. Furthermore, CD11b/CCR2 myeloid cells, analogous to the CD11b/Gr1mid population described in our mouse model, were identified in liver metastases of several CRC patients. Together, our studies demonstrate the importance of a distinct CD11b/Gr1mid myeloid subset in sustaining CRC liver metastasis and implicate a CCL2/CCR2-dependent pathway in their recruitment to metastatic sites. Our findings reinforce how tumor cells utilize host systems for successful propagation and identify a potential target for therapeutic manipulation.
Citation Format: Su Yin Lim, Lei Zhao, Alex Gordon-Weeks, Thomas Tapmeier, Ruth Muschel. Tumor-derived CCL2 promotes recruitment of CD11b/Gr1mid myeloid cells to sustain colorectal cancer liver metastasis. [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 2871. doi:10.1158/1538-7445.AM2013-2871
Abstract 2873: Epithelial NF-κB signaling is required for different functions in Kras- and EGFR-mediated lung tumorigenesis.
Authors: Ausborn Jamie A. , Sherrill Taylor , Zaynagetdinov Rinat , Polosukhin Vasiliy , McMahon Frank , Yull Fiona , Blackwell Timothy 
Published: August 2014

Abstract
The transcription factor nuclear factor-κB (NF-κB) is a key mediator of the inflammatory response, and its activation correlates with poor prognosis in non-small cell lung cancer patients. Oncogenic KRAS and epidermal growth factor receptor (EGFR) mutations occur frequently in lung adenocarcinoma and are associated with increased NF-κB activation in lung tumors. Recent papers have shown that inhibition of epithelial NF-κB signaling in a mouse model of Kras-mediated lung tumorigenesis decreases tumor formation. However, the mechanisms linking NF-κB signaling to tumor formation remain unclear. We hypothesize that epithelial NF-κB signaling is a common requirement for lung tumorigenesis. For our studies, we used mice that inducibly express oncogenic KrasG12D or EGFRL858R+T790M as well as a dominant negative inhibitor of κB signaling (DN-IκB) in Clara Cell Specific Protein (CCSP)-expressing lung epithelium (designated KrasDN or EGFRDN mice). EGFRDN mice developed smaller and fewer tumors after two months of doxycycline administration compared to mice expressing EGFRL858R+T790M alone, while KrasDN mice did not develop any tumors. In KrasDN mice, loss of Kras transgene expression and increased cell death were observed after one week of doxycycline, suggesting that NF-κB signaling may be required for survival of Kras mutant cells in vivo. In EGFRDN mice, NF-κB inhibition led to a significant reduction in the percentage of BAL neutrophils when compared to mice expressing EGFRL858R+T790M alone. In addition, NF-κB inhibition led to reduced expression of CXCR2 ligands CXCL1 and CXCL2, which are known NF-κB-regulated neutrophil chemoattractants. In vitro inhibition of CXCR2 did not affect proliferation of EGFR-mutant cells, suggesting that the critical function of CXCL1 and CXCL2 may be inflammatory cell recruitment/activation. Future studies will investigate the effects of CXCR2 inhibition and neutrophil depletion on EGFR-mediated tumor formation in vivo. Together, these results suggest that NF-κB signaling is required for both Kras- and EGFR-mediated lung tumorigenesis, but NF-κB's function in a tumor may depend on the driver mutation. From these studies, we hope to identify NF-κB-regulated genes critical for tumor formation as potential targets for the development of better therapeutic strategies for lung cancer patients.
Citation Format: Jamie A. Ausborn, Taylor Sherrill, Rinat Zaynagetdinov, Vasiliy Polosukhin, Frank McMahon, Fiona Yull, Timothy Blackwell. Epithelial NF-κB signaling is required for different functions in Kras- and EGFR-mediated lung tumorigenesis. [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 2873. doi:10.1158/1538-7445.AM2013-2873
Abstract 2906: Towards breast cancer drug repurposing based on a pathway modeling approach.
Authors: Ibrahim Sara 
Published: August 2014

Abstract
Molecular connectivity maps between drugs and proteins in specific disease contexts, especially breast cancer, can be particularly valuable, offering an opportunity to gain global perspectives on both the therapeutic and toxicological profiles of drugs. To assess drug pharmacological effects, we assume that “ideal” drugs for a patient can treat or prevent disease by modulating gene expression profiles of the patient to the similar level with those in healthy people. Starting from this hypothesis, we build comprehensive disease-gene-drug connectivity relationships with drug-protein directionality (inhibit/activate) information based on a computational connectivity maps (CMaps) platform. In this work, we develop a novel approach based on integrative pathway modeling using breast cancer as a case study. We identify and rank breast cancer related drugs/compounds with their overall drug-protein “connectivity map” profile. First, we retrieve breast cancer associated proteins through the CMaps platform by using breast cancer as a query term. Second, we retrieve breast cancer related pathways by using breast cancer associated proteins as input and searching in the Human Pathway Database (HPD), PAGED, and the PubMed. Third, we integrate the breast cancer related pathways into unified pathway models, from which we categorize the pharmaceutical effects of candidate drugs on all breast cancer associated proteins as either “therapeutic” or “toxic”. Expression values are given to all relevant proteins on the pathway. Potential drugs and targets are retrieved from C-Map, DrugBank, and MetaDrug. Finally, we transform the integrated pathway into network models and rank drugs based on the network topological features of drug targets, drug-affecting genes/proteins, and curated disease-associated proteins. The case studies correlated very well with the known pharmacological profiles of cancer drugs, highlighting the significance of the platform that we developed. Ongoing research can potentially change future drug discovery practices.
Citation Format: Sara Ibrahim. Towards breast cancer drug repurposing based on a pathway modeling approach. [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 2906. doi:10.1158/1538-7445.AM2013-2906
Abstract 2937: Dual roles of ERK2 to TRAIL sensitivity in SK-N-MC neuroepithelioma cells.
Authors: Jung Hye Lim , Lee Myoung Woo , Eom Ji Eun , Kim Dea Seong , Park Hyo-Jung , Yu Dong-Kyung , Son Meong Hi , Lee Soo Hyun , Yoo Keon Hee , Sung Ki Woong , Koo Hong Hoe 
Published: August 2014

Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a new promising agent for clinical use since it kills a wide range of tumor cells but not normal cells. It is regulated by 2 death receptors (DR), DR4 (TRAIL-R1) and DR5 (TRAIL-R2), and 2 decoy receptors (DcR), DcR1 (TRAIL-R3) and DcR2 (TRAIL-R4). However, the determining factors of the sensitivity to TRAIL cytotoxicity are not clearly understood. This study aims to elucidate the role of extracellular signal-regulated kinase (ERK) on enhancement of TRAIL cytotoxicity in cultured neuroepithelioma cell line SK-N-MC. When 1 μg/ml cisplatin-pretreated cells were exposed to 100 ng/ml TRAIL for 48 h, apoptotic cell death increased, compared with the cells treated with cisplatin or TRAIL alone (66% versus 27% or 9% apoptotic cell death). In addition, pretreatment with cisplatin in SK-N-MC cells significantly increased ERK1/2 activity and increased expression levels of DR5, but not DR4, DcR1 and DcR2, which correlated with increase of their susceptibility to TRAIL cytotoxicity. Introduction of ERK2 siRNA or ERK2 shRNA in SK-N-MC cells significantly decreased cisplatin-induced DR5 expression, suggesting that cisplatin-induced ERK2 activity is involved in DR5 expression. On the other hand, treatment with 20 μM U0126, an inhibitor of MEK, completely reduced basal ERK1/2 activity and induced cell death in SK-N-MC cells. In addition, pretreatment with U0126 increased TRAIL-mediated apoptosis via up-regulation of DR5 expression in response to the decrease in basal ERK2 activity. Because pretreatment with U0126 completely inhibited not only cisplatin-induced ERK2 activation but also basal ERK2 activity, the following treatment with TRAIL significantly increased cell death, indicating that constitutively activated ERK2 blocks DR5 expression in SK-N-MC cells. Taken together, our results implicate that basal ERK2 activity is involved in TRAIL resistance but induced ERK2 plays a role in TRAIL sensitivity, and suggest that the enhanced sensitivity of SK-N-MC cells to TRAIL is associated with an increase in DR5 expression.
Citation Format: Hye Lim Jung, Myoung Woo Lee, Ji Eun Eom, Dea Seong Kim, Hyo-Jung Park, Dong-Kyung Yu, Meong Hi Son, Soo Hyun Lee, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo. Dual roles of ERK2 to TRAIL sensitivity in SK-N-MC neuroepithelioma 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 2937. doi:10.1158/1538-7445.AM2013-2937
Abstract 2954: Novel interaction between FLIP/DAPK: role for RON in androgen-independent prostate cancer.
Authors: Batth Izhar S. , Gong Jingjing , Kumar A. Pratap 
Published: August 2014

Abstract
Patients with Hormone refractory metastatic prostate cancer (HRPCA) have a 5-year survival of less than 30%. Therefore, it is imperative that new therapeutic strategies targeting advanced stage prostate cancer (PCA) be developed. 2-Methoxyestradio (2-ME2) is an endogenously produced compound that has been shown to successfully treat PCA. As part of our efforts in understanding its mechanism of action, we discovered that the tyrosine kinase RON (Recepteur ‘Origine Nantais) was a target for inhibition. RON Kinase has been previously shown to be upregulated in murine PCA. RON has also been reported to mediate cell migration, and invasion in various cancers. However, the precise role of RON signaling in prostate carcinogenesis is unclear. Our data revealed that RON is upregulated in HRPCA cell lines and human prostate tumors. Using genetic approaches we found novel, causal association between RON and FLICE-like inhibitory protein, also known as FLIP (a known target of 2-ME2), and an increase in Death Associated Protein Kinase (DAPK1). Interestingly, RON overexpression in early stage PCA cell lines induced the transcriptional activation of the Androgen Receptor (AR) and FLIP. Stimulation of RON with its ligand MSP (macrophage stimulating protein) also yielded heightened promoter activity of AR and its downstream target genes including PSA and FLIP. Functionally, these responses translated to increased cell migration in RON overexpressing cells and loss of this migratory potential with RON silencing. Interestingly, 2-ME2 treatment also reduced the migration of HRPCA cells. Migration in wild-type HRPCA cells is also sensitive to regulation with 2-ME2 treatment. Overall these data suggests that RON kinase is a major player in promoting advanced-stage prostate cancer in part due to its ability to regulate apoptosis through novel FLIP/DAPK1 interaction. Supported by NIH (CA 135451, APK).
Citation Format: Izhar S. Batth, Jingjing Gong, A. Pratap Kumar. Novel interaction between FLIP/DAPK: role for RON in androgen-independent 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 2954. doi:10.1158/1538-7445.AM2013-2954
Abstract 2956: c-FLIP (L) dual function in cervical cancer.
Authors: Ili Carmen G. , Brebi Priscilla , Andana Alejandra , Garcia Patricia , Leal Pamela , Tapia Oscar , Viscarra Tamara , Weber Helga , Roa Juan 
Published: August 2014

Abstract
Cellular FLICE-like inhibitory protein (c-FLIP) is a caspasa-8/10 homolog catalytically inactive that interferes with the efficient formation of DISC. There are three isoforms of this protein: c-FLIPL (long) of 55kDa, c-FLIPS (short) of 26kDa y c-FLIPR (Raji) of 24kDa. c-FLIPS and c-FLIPR functions have been well established: both can block extrinsic pathway of apoptosis by inhibiting procaspasa-8 activation in DISC. However, c-FLIPL function still remains unclear. When c-FLIPL is overexpressed, as in some cancers, has an anti-apoptotic function very similar to c-FLIPS, but also can be a proapoptotic molecule at low concentrations. The aim of this study is to characterize c-FLIP functions in cervical uterine carcinogenesis.
Three cervical cancer cell lines were used in this study: SiHa, C-4I and C-33A. c-FLIP expression in cell lines was determined by real time PCR and western blottting. c-FLIP expression was transiently downregulated by siRNA and the silencing effects on cell viability, proliferation and apoptosis were analysed, by comparing with a control negative siRNA-transfected cells.
Using MTS analysis, SiHa and C4I c-FLIP transfected cells showed a increment of viability compared with scramble, since 24 hours after transfection in C 4I and 72 hours in SiHa (P&lt;0.05), while C-33A cells do not show differences. Ki-67 immunocitochemestry was performed to evaluate proliferation in cervical cell lines. Statistical differences were found between SiHa and C 4I c-FLIP transfected cells compared with scramble (P&lt;0.05). All three c-FLIP transfected cell lines showed a higher level of apoptosis than scramble control (P&lt;0.05), using a TUNEL-based analyzed performed by flow cytometry.
Our results suggest that c-FLIPL could be having a dual function in cervical cancer cell lines, both inhibiting proliferation and apoptosis.
Grant Support: This investigation was financed by Proyect CORFO-INNOVA N°07CN13PBT-222 and Proyect CORFO N° 09CN14-5960 (CEGIN). CI is recipient of grants from FONDECYT Postdoctoral Proyect N° 3130630. PB is recipient of grants from FONDECYT Postdoctoral Proyect N° 3120141
Citation Format: Carmen G. Ili, Priscilla Brebi, Alejandra Andana, Patricia Garcia, Pamela Leal, Oscar Tapia, Tamara Viscarra, Helga Weber, Juan Roa. c-FLIP (L) dual function in cervical 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 2956. doi:10.1158/1538-7445.AM2013-2956
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.