bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1407: Mechanistic regulation of NFκB dependent radioprotection in human neuroblastoma
Authors: Aravindan Natarajan , Madhusoodhanan Rakhesh , Veeraraghavan Jamunarani , Herman Terence S. , Natarajan Mohan 
Published: February 2011

Abstract
Induced radio-resistance in cancer cells surviving after radiotherapy (RT) could be associated with increased radioprotection limiting the benefit of RT. Additionally, induced radioprotection may potentiate tumor re-growth at treatment site. Recently, we demonstrated that radiation (IR) induced NFκB in neuroblastoma cells and forced inhibition of NFκB enhanced IR-induced cell death. Accordingly, we investigated the downstream regulation involved in IR-induced NFκB-mediated radioprotection. Human SK-N-MC cells exposed to either low-dose IR (LDIR, 10, 50 and 100cGy), high dose IR (HDIR, 4Gy) or exposed to LDIR and challenged with HDIR after 24h were examined after 15min through 72h. EMSA analysis showed a marked and persistent activation of NFκB both in LDIR and HDIR exposed cells. Interestingly, cells primed with LDIR showed a robust NFκB activation when challenged with HDIR, as opposed to HDIR alone group. Consistently, we observed a significant suppression in HDIR induced DNA fragmentation (Tdt nick end labeling), apoptosis (Annexin V-FITC, caspase activity) and cytotoxicity (MTT) in cells primed with LDIR. Furthermore, clonogenic analysis revealed a profound attenuation of HDIR inhibited clonal expansion with preceding LDIR exposure. NFκB knockout (RelA siRNA) and over expression (p50, p65 transfection) studies demonstrate the influence of LDIR-activated NFκB in the regulation of HDIR induced DNA fragmentation and apoptosis. More importantly, LDIR significantly induced both transcriptional (QPCR) and cellular localization (immunoblotting) levels of radio-responsive TNFα, IL-1α, cMYC, MnSOD (SOD2 activity) and completely suppressed p53 in these cells. Co-culture experiments clearly portraits LDIR-influenced radioprotection and activation of radioresponsive molecules. Individual gene knockout (siRNA approach) studies exhibits that LDIR-modulated TNFα, IL-1α, cMYC, MnSOD and p53 mediates induced radioprotection. Furthermore, NFκB inhibition studies (ΔIκBα) demonstrated that TNFα, IL-1α, cMYC, MnSOD and p53 are selectively regulated by LDIR-induced NFκB. Collectively, these data strongly suggests that cells that survive a course of RT induce NFκB dependent radio-responsive TNFα, IL-1α, cMYC and MnSOD mediated radioprotection. Selectively targeting IR-induced NFκB could further potentiate the use of RT in neuroblastoma cell killing and mitigate tumor regrowth at treatment site.
Funding Support: ACS- IRG-05-066-01; Presbyterian Health Foundation
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1407.
Abstract 1408: Nicotine decreases the therapeutic efficacy of radiotherapy and chemoradiotherapy in vivo
Authors: Warren Graham W. , Randall Marcus , McGarry Ronald , Kudrimoti Mahesh , Rangnekar Vivek 
Published: February 2011

Abstract
Background: Continued tobacco use during cancer treatment has been associated with poor outcome. Nicotine replacement is currently used as a standard of care for smoking cessation in cancer patients; however, prior data demonstrates that nicotine can promote tumor growth and decrease the effectiveness of cancer treatment in vitro.
Methods: Athymic nude mice with human H460 lung cancer cell xenografts were stratified into three Groups beginning when tumors reached 5 mm in maximal dimension: control (CON), short term nicotine (STN, 60 ug subcutaneously every other day x 6 days), or long term nicotine (LTN, 60 ug SC every other day until tumor endpoint). Within each Group, mice were further stratified into three Treatments consisting of saline (SAL), radiotherapy (RT, 3 Gy daily x 5 days), or chemoradiotherapy (CRT, RT + concurrent cisplatin intraperitoneally 3 mg/kg daily x 5 days). Tumor volumes were measured and compared between Treatments and Groups (n=10 per Treatment within each Group). This protocol was approved by the Institutional Animal Care and Use Committee at the University of Kentucky.
Results: In CON animals, RT (199 uL at day 30) or CRT (100 uL at day 30) significantly prevented tumor regrowth as compared with control SAL animals (864 uL at day 10 requiring euthanasia as per protocol). As expected, CRT was more effective than RT (p&lt;0.05). Nicotine administration alone (STN or LTN) had no effect on tumor growth rate as compared with CON. In contrast, administration of LTN significantly increased tumor regrowth in RT animals (356 uL at day 30, p&lt;0.05) and CRT treated animals (170 uL ad day 30, p&lt;0.05). To eliminate the effects of nicotine on proliferation following completion of RT or CRT, animals were treated with STN. Administration of STN also significantly increased tumor regrowth in RT animals (328 uL at day 30, p&lt;0.05) and CRT animals (176 uL at day 30, p&lt;0.05) with virtually identical regrowth curves as demonstrated for LTN animals.
Conclusions: Results demonstrate that nicotine significantly reduces the efficacy of RT and CRT in vivo. Moreover, data suggest that nicotine use during treatment is the primary determinant of decreased therapeutic response. These results may significantly alter current recommendations for smoking cessation in cancer treatment populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1408.
Abstract 1410: Bmi-1 enhances the radioresistance of cells by suppressing the expression of NADPH oxidase genes
Authors: Dong Qinghua , Kim Roy , Chen Wei , Oh Ju-Eun , Shin Ki-Hyuk , McBride William , Park No-Hee , Kang Mo K. 
Published: February 2011

Abstract
Bmi-1 is a polycomb group protein necessary for cellular proliferation and maintenance of stem cell phenotype. The current study was undertaken to determine the radioprotective effects of Bmi-1 in human epithelial cells. Primary normal human keratinocytes (NHK) from oral mucosa or epidermis were infected with retroviral vectors expressing Bmi-1. NHK infected with empty virus (NHK/B0) rapidly underwent premature senescence upon exposure to 5 or 10 Gy of ionizing radiation (IR). However, the cells transduced with Bmi-1 (NHK/Bmi-1) maintained cell proliferation and clonogenicity after IR. To determine the mechanism underlying the radioresistance conferred by Bmi-1, we compared the DNA damage response (DDR), production of reactive oxygen species (ROS), and DNA repair activities in both cell types. NHK/B0 and NHK/Bmi-1 cells demonstrated rapid induction of DDR after 5 Gy irradiation. ROS production was increased by irradiation, but Bmi-1 transduction suppressed the ROS production. Irradiation strongly induced the genes encoding the enzymes involved in ROS production, mainly of NADPH oxidase subunits, but Bmi-1 completely abolished the expression of these genes. Chromatin immunoprecipitation (ChIP) revealed binding of Bmi-1 to the promoter regions of these genes in vivo, suggesting transcriptional repression by Bmi-1. In vitro DNA end joining and in vivo double strand break (DSB) repair activities were enhanced in NHK/Bmi-1 cells compared with NHK/B0. These data indicate that Bmi-1 enhances the radioresistance of NHK in part by mitigating the genotoxicity of radiation. This study was supported in part by the grants, UCLA/CBPR (U19) from NIAID and R01DE18295/K02DE18959 from NIDCR/NIH.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1410.
Abstract 142: A human DNA methylation analysis microarray
Authors: Ruvolo Michael , Wong Alexander , Ashutosh A. , Giles Shane , Yakhini Zohar , Roberts Douglas 
Published: February 2011

Abstract
CpG islands are stretches of high GC content DNA containing multiple CpG dinucleotides. When CpG dinucleotides within these islands are methylated, especially in promoter regions, expression of the corresponding downstream genes is often repressed. Aberrant CpG island methylation is implicated in cancer. We have refined a protocol for methylated DNA immunoprecipitation (mDIP) and coupled it with microarray detection. DNA isolated by mDIP is fluorescently labeled and hybridized to an oligonucleotide microarray that specifically represents putative methylation target regions in the human genome. This microarray contains ∼237,000 oligo probes tiling ∼28,000 CpG islands along with ∼5000 recently identified regions determined to be undermethylated across multiple tissue types. As proof of concept we perform mDIP and microarray analysis of human genomic DNA samples from normal tissues. We compare our mDIP array data with bisulfite sequencing data. Performing analysis with Agilent Genomic Workbench we demonstrate the ability to distinguish probes corresponding to methylated regions from probes corresponding to unmethylated regions. We then apply the assay to tumor and normal DNA and identify differential methylation patterns.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 142.
Abstract 1421: Inhibition of melanoma growth by activation of Notch pathway in stromal fibroblasts
Authors: Shao Hongwei , Cai Long , Li Yan , Velazquez Omaida C. , Liu Zhao-Jun 
Published: February 2011

Abstract
Background. Tumor microenvironment influences tumor initiation and progression. Fibroblasts are major components of tumor stroma and critically involved in regulating tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell-cell interaction. The Notch pathway regulates a variety of cellular activities. However, it is unknown whether and how manipulation of Notch signaling in stromal fibroblasts affects melanoma growth.
Objectives. This study aimed to investigate the effects of Notch-activated stromal fibroblasts on melanoma growth and elucidate the underlying mechanism.
Methods. Enforced activation of Notch pathway was achieved by transducing fibroblasts with lentiviral vector encoding activated Notch1 (NIC). The effect of Notch1-activated stromal fibroblasts on melanoma growth was tested by in vitro co-culture and in vivo co-injection approaches. The soluble factor which produced by Notch1-activated fibroblasts was identified by PCR Array and validated by Western blot analysis. Function of the candidate factor in mediating the inhibitory effect of Notch1-activated stromal fibroblasts on melanoma growth was examined through siRNA-mediated blockade approach and tested by in vitro cell co-culture and in vivo tumor xenografting animal models.
Results. Notch1-activated fibroblasts significantly inhibited melanoma growth by inducing tumor cell apoptosis and suppressing tumor angiogenesis. The inhibitory effect of NIC-engineered fibroblasts was mediated by up-regulating WISP-1 expression. Elevated WISP-1 suppressed melanoma growth while blockade of WISP-1 liberated the inhibitory effect.
Conclusions. Activation of Notch pathway in stromal fibroblasts can suppress melanoma growth, partially through WISP-1. Our study provides a novel approach to target tumor microenvironment through modulating stromal fibroblasts by manipulation of Notch signaling, and highlights WISP-1 as a potential therapeutic target in melanoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1421.
Abstract 1426: Identification of secretory stromal gene signature of the ovarian tumor microenvironment and implications for ovarian cancer progression
Authors: Thompson Melissa S. , Albitar Lina , Ghosh Sue , Wong Kwong-Kwok , Welch William R. , Birrer Michael J. , Mok Samuel C. 
Published: February 2011

Abstract
Ovarian cancer the deadliest gynecologic disease and despite the significant role of the tumor-associated stroma in cancer progression, little research has been done on the specific role of the tumor-associated stromal microenvironment on ovarian cancer progression. Our objective was to identify genes that are differentially regulated in the stromal component of high-grade late-stage serous ovarian cancer and illustrate direct and specific effects of their differential expression on ovarian cancer progression. Microarray analysis performed on RNA isolated from 10 microdissected normal ovarian fibroblasts, and the epithelial and stromal component of 16 high-grade late stage serous ovarian cancers revealed more than 40 secreted proteins that are overexpressed more than 5 fold by cancer-associated fibroblasts (CAFs) exclusively. Quantitative RT-PCR validated the overexpression of several genes, including sFRP2, by the CAFs. Clinical data correlated stromal sFRP2 overexpression with poorer overall survival and chemoresistance in patients with high-grade late stage serous ovarian cancer, suggesting that sFRP2 promotes ovarian cancer progression. In vitro functional studies illustrate increased ovarian cancer cell proliferation rates in response to recombinant sFRP2 as well as CAF-conditioned medium and pathway analysis via transcription-reporter assays revealed that recombinant sFRP2 signals through the NFκB and Wnt pathways in ovarian cancer cells, both of which affect cell growth. While not affecting cell proliferation, recombinant sFRP2 increased endothelial signaling to the NFAT pathway, which affects endothelial tubal branching. These results were corroborated in vivo such that microenvironments expressing higher levels of sFRP2 exhibited significantly higher microvessel density compared with microenvironments with lower sFRP2 expression. Our results illustrate a direct and specific signaling linkage from the tumor microenvironment to tumor cells and endothelial cells that contributes to tumor progression. In this case, sFRP2 exhibited significant influence on characteristics of tumor progression (i.e. tumor proliferation, microvessel morphology) suggesting that other differentially expressed genes identified by the microarray in CAFs may also play significant roles in this process.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1426.
Abstract 1430: Activation of WNT pathway in endometrial cancer stromal fibroblasts
Authors: Palla John , Aprelikova Olga , Yu Xiang , John Simone , Yi Ming , Stevens Robert , Risinger John , Jazaeri Amir , Niederhuber John 
Published: February 2011

Abstract
The dynamic interactions between tumor cells and their corresponding microenvironment play an important role in carcinogenesis. Fibroblasts are a dominant feature within a tumor stroma and have undergone a “reprogramming” to become cancer-activated fibroblasts (CAFs). In our study we established primary cell cultures of fibroblasts from matched pairs of normal human endometrium and endometrial cancer tissues and analyzed the differential expressions of mRNA and microRNA. We found that the WNT pathway was activated in CAFs and confirmed these results via Topflash luciferase reporter assays. Wingless-type (WNT) proteins are a highly conserved family of secreted glycoproteins that have been implicated in the carcinogenesis of many cancers. We demonstrated that one of the reasons for this WNT pathway activation was the methylation-dependent silencing of the secreted frizzled-related protein 4 (SFRP4), an antagonist to the WNT signaling pathway.
An additional reason for WNT pathway activation was found in the microRNA analysis. These experiments showed downregulation of miR-148a, which is a predicted regulator of the founder member of the WNT family, WNT1. We observed that CAFs have increased WNT1 protein expression in three of the five endometrial cancer CAFs. We confirmed that miR-148a directly targets WNT1 by cloning the WNT1 3'UTR into a luciferase reporter construct and showed that co-transfection with miR-148a results in a decrease of luciferase activity. When mutations to the miR-148a binding sites were introduced into the same luciferase reporter construct, the downregulation of luciferase activity by miR-148a was prevented. We conclude that the observed activation of the WNT pathway in endometrial cancer CAFs may be regulated by the miR-148a and contribute to the progression of the endometrial cancer tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1430.
Abstract 1432: Tnfα ablation demonstrates no suppressive effect on inflammation-related mouse colon tumorigenesis
Authors: Sakai Hiroyasu , Yamada Yasuhiro , Shimizu Masahito , Moriwaki Hisataka , Hara Akira 
Published: February 2011

Abstract
Colorectal cancer (CRC) is one of the most serious complications of inflammatory bowel disease. Tumor necrosis factor-α (Tnfα) is a major mediator of inflammation and there is increasing evidence that Tnfα/Tnf-receptor-1 (Tnfr1) signaling may act as an endogenous tumor promoter for colon carcinogenesis. In fact, a previous study revealed that mice lacking Tnfr1 develop significantly fewer colonic tumors in the inflammation-related CRC model. Apc Min/+;Tnfα -/- mice were treated with 2% dextran sodium sulfate (DSS) and the tumor development was compared with Apc Min/+;Tnfα +/+ control mice in order to investigate the role of Tnfα by itself in the inflammation-related CRC. Surprisingly, there were no significant differences in either the severity of colonic inflammation or the expression of DSS-induced chemokines and cytokines (Ccl2, Cxcl1, Tnfβ, Il1β, Il6, and Cox-2) that relate to the colonic inflammation and tumorigenesis between these two groups. Furthermore, the genetic ablation of Tnfα did not suppress the colon tumorigenesis in comparison to the wild-type mice. These observations suggest that redundant inflammatory responses other than the Tnfα-mediated inflammation promote tumorigenesis in the colon. These results also suggest that Tnfα alone may not be an efficient target for the prevention/ treatment of inflammation-related colon tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1432.
Abstract 1437: Laminin-1 confers Bleomycin-resistance through poly(ADP-ribose) polymerase activation in 3D culture
Authors: Benton Gabriel , Xu Hai 
Published: February 2011

Abstract
The purpose of this study is to examine the role of extracellular matrix proteins in regulating Bleomycin resistance and to evaluate the potential role of poly(ADP-ribose) polymerase (PARP) in modulating drug resistance in MDA-MB-231 breast cancer cells. These phenomenons were investigated using a 3D culture model where the MDA-MB-231 cells were cultured on either collagen I or laminin-1. Cells were evaluated for viability as a dose-response to the chemotherapeutic agent, Bleomycin. Cell lysates were also evaluated for PARP expression as a consequence of the 3D culture environment. Cells were then treated with the PARP inhibitor, PJ-34, and evaluated for viability as a dose-response to Bleomycin in the 3D cultures. PARP activity was assessed using a pharmacodynamic ELISA. For the first time, this study presents evidence that the basement membrane protein, laminin-1, induces Bleomycin resistance, that laminini-1 induces PARP expression and activity, and that PARP inhibition sensitizes breast cancer cells to Bleomycin treatment. In conclusion, this data provides a mechanism for ECM-mediated Bleomycin-resistance and the potential therapeutic application for PARP inhibitors to sensitize tumors to Bleomycin treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1437.
Abstract 1442: Prognostic value of Dicer expression in human breast cancers and association with the mesenchymal phenotype
Authors: Moyret-Lalle Caroline , Grelier Gael , Lasset Christine , Voirin Nicolas , Chabaud Sylvie , Treilleux Isabelle , Puisieux Alain 
Published: February 2011

Abstract
Introduction:
Dicer, a ribonuclease, is the key enzyme required for biogenesis of miRNAs and small interfering RNAs (siRNAs). It was previously shown that Dicer is essential for mammalian development and cell differentiation. Recent evidence indicates that Dicer may be involved in tumorigenesis. However, no studies have examined the clinical significance of Dicer at both RNA and protein levels in breast cancer.
Methods:
In this study, the biological and prognostic value of Dicer expression was assessed in breast cancer cell lines, breast cancer progression cellular-models, and in two independent and well-characterised set of breast carcinomas with long term follow-up using tissue microarray and quantitative reverse transcription-PCR.
Results:
We have found that Dicer protein expression is significantly associated with hormone receptors status in breast tumours. Dicer mRNA expression appeared to have an independent prognostic impact in metastatic disease. In the breast cancer cell lines, lower Dicer expression was found in cells harbouring a mesenchymal phenotype and in metastatic bone derivatives of a breast cancer cell line. These findings suggested that down-regulation of Dicer expression may be related to metastatic spread of tumours.
Conclusions:
Assessment of Dicer expression may facilitate prediction of distant metastases for patient suffering from breast cancer.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1442.