bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 385: Potentiating MUC1 expression in human bronchial epithelial cells by cigarette smoke carcinogens through induction of TNF-α secretion from macrophages
Authors: Xu Xiuling , Chen Wenshu , Padilla Mabel T. , He Weiyang , Wang Qiong , Kim Kwang Chul , Lin Yong 
Published: August 2012

Abstract
Although an important role of inflammation in the development of lung cancer has been recognized, how inflammation promotes lung epithelial cell transformation and lung cancer development has not been well elucidated. Cigarette smoke (CS), the major cause of lung cancers, potently elicits chronic pulmonary inflammation. Our recent studies have found that CS significantly induces Muc1 (MUC1 for human and Muc1 for nonhuman species) expression in mouse bronchial epithelial cells and macrophages, and MUC1 facilitates Benzo(a)pyrene diolepoxide (BPDE)-induced human lung epithelial cell transformation. In this study, we investigated the role of inflammatory cells in regulating CS carcinogen-induced MUC1 expression in bronchial epithelial cells. BPDE and N-Nitroso-N-methylurea (MNU), an active CS carcinogen and a mimic, strongly induced tumor necrosis factor-alpha (TNF-α) secretion from human macrophages. The TNF-α induction was effectively blocked when ERK, JNK, and NF-κB were blocked, suggesting these pathways are involved in the induction of TNF-α from macrophages by BPDE and MNU. Interestingly, knockdown of MUC1 in macrophages suppressed BPDE- or MNU-induced TNF-α secretion, suggesting MUC1 plays a role in modulating carcinogen-induced and macrophage-mediated inflammatory responses. Conditioned media from BPDE- or MNU-treated macrophages potently induced MUC1 expression in human bronchial epithelial cells (HBECs), which was inhibited by a TNF-α neutralizing antibody, suggesting that TNF-α derived from macrophages contributes to CS carcinogen-induced MUC1 expression in HBECs. Thus, our results establish a dual role of MUC1 in CS-induced and inflammation-associated lung cancer development: to facilitate TNF-α secretion from macrophages and to potentiate transformation of HBECs. Note: This work is supported by NIH/NIEHS grant 1R01ES017328.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 385. doi:1538-7445.AM2012-385
Abstract 3871: Insulin-like growth factor 1 receptor (IGF1R) inhibitor BMS754807 is active against FLT3-ITD mutated acute myelogenous leukemia and activity is p53 dependent
Authors: Borthakur Gautam , Duvvuri Seshagiri , Tsao Twee , Zhang Weiguo , Ruvolo Vivian , Lu Hongbo , Kojima Kensuke , Konopleva Marina , Andreeff Michael 
Published: August 2012

Abstract
The Internal tandem mutation (ITD) in the FLT3 gene is associated with shorter remission duration, overall survival and relapse free survival in patients with normal karyotype acute myelogenous leukemia (AML). FLT3-ITD inhibitors are in clinical development but single agent clinical activity is of limited duration with activation of parallel signaling pathways potentially contributing to most relapses thus highlighting the need for new agents. Because common signaling pathways are activated downstream of FLT3 and IGF1R, we investigated the preclinical activity of IGF1R antagonist BMS754807 against AML cells with FLT3-ITD mutations. Results: BMS 754807 induced apoptosis (Annexin V binding by flow cytometry) in MOLM13 cells (AML cell line with FLT3-ITD mutation and wild type p53) at 48 hrs at submicromolar concentrations, while OCI AML3 cells (p53 and FLT3 wild type) were resistant. Similarly, murine BAF3 cells expressing human FLT3-ITD underwent prompt apoptosis with BMS 754807 while the same cells with human wt-FLT3 were resistant to BMS 754807(IC50s 2.5 μmol vs &gt;10 μmol). Western blot analysis confirmed reduction in FLT3, Akt, ERK, S6 ribosomal protein and GSK3 beta phosphorylation and increase in p53 levels in MOLM13 cells. Interestingly, apoptosis induction was not associated with caspase activation. Moreover, apoptosis induction by BMS 754807 appeared to be p53 dependent as MOLM13 cells with stable expression of short hairpin RNA (sh-RNA) targeting p53 (p53-shRNA) were resistant, while MOLM13 cells expressing scramble sh-RNA underwent apoptosis comparable to parental MOLM13 cells. Surface expression of IGF1R was comparable among parental and p53-shRNA MOLM13 cells. Apoptosis induction by BMS 754807 in p53-WT and FLT3-ITD cells was associated with phosphorylation of p53 at serine 15. Conclusion: BMS 754807 has selective activity against AML cells with FLT3-ITD mutation and this activity is p53 dependent and associated with phosphorylation of p53 at serine 15. Results suggest that IGF1R inhibition has therapeutic potential as novel targeted therapy for AML with FLT3-ITD mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3871. doi:1538-7445.AM2012-3871
Abstract 3884: A novel, in vitro tankyrase 1 trans-ribosylation assay
Authors: George Jay , Benton Gabriel Jon , Woodgate Sandra , Xu Hai 
Published: August 2012

Abstract
The poly (ADP-ribose) polymerase, tankyrase 1, is an encouraging pharmacological target for cancer therapy. First discovered by its association with the TRF1, tankyrase 1 plays an important role in the maintenance of telomere length, sister telomere association, and mitotic spindle organization. More recently, interactions between tankyrase 1 and axin were shown to stabilize β-catenin and modulate Wnt signaling, enabling selective targeting of the Wnt pathway with tankyrase inhibitors. In addition, tankyrase 1 has also demonstrated potential as a target for synthetic lethality for BRCA-deficient cancers. Given the effect on these cancer-associated pathways, there is a growing interest for identifying tankyrase-specific inhibitors. Historical methods to evaluate tankyrase activity are not amenable for high throughput screening. Limited availability of the full length enzyme required radioactivity to attain the needed sensitivity. Truncation of tankyrase 1 improved solubility and increased availability, but the physiological response may not be equivalent to the full length enzyme. Many of these assays have also used modified substrates where molecules such as fluorescein or biotin are linked to NAD without characterizing the effects on enzyme activity. Most historical assays have also relied on measuring autoribosylation of tankyrase 1; whereas, transribosylation may be more relevant for assessing the activity of tankyrase 1 on other molecules. To address these issues, we have developed a novel, in vitro, high throughput assay for evaluating the transribosylation activity of tankyrase 1. This is accomplished using an ELISA format which semi-quantitatively detects poly (ADP-ribose) (PAR) deposited onto immobilized histone proteins by tankyrase 1. An anti-PAR monoclonal antibody, goat anti-mouse IgG-HRP conjugate, and HRP substrate generate a colorimetric or chemiluminescent signal, and the conversion of substrate correlates with tankyrase 1 activity. This assay ensures physiological significance by utilizing the full length enzyme and unmodified substrate in a transribosylation format, providing sensitivity down to pmols of enzyme. This assay is utilized to demonstrate the specificity of the tankyrase 1 inhibitor, XAV939, for tankyrase 1 compared to PARP1 and to reveal differential effects of activated DNA for full-length tankyrase 1 compared to the truncated enzyme.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3884. doi:1538-7445.AM2012-3884
Abstract 3886: Development of a new DNA aptamer against primary cultured tumor endothelial cells by a cell-based SELEX method to discover a new drug delivery system
Authors: Ara Mst. Naznin , Hyodo Mamoru , Ohga Noritaka , Hida Kyoko , Harashima Hideyoshi 
Published: August 2012

Abstract
The purpose of the present study was to develop DNA aptamers through a spontaneous cell-based SELEX method (systemic evolution of ligands by exponential enrichment) that specifically binding to cell surface proteins or biomarkers produced by primary cultured tumor endothelial cells (TECs). In solid tumors, new blood vessels are formed through an angiogenesis process, and this plays a critical role in cancer development as well as the development of metastasis. To combat angiogenesis, an appropriate diagnosis and understanding at the molecular level of different cancer types is now a high priority. Our initial study explored the use of the cell-based SELEX method, which has been applied in TECs to generate high affinity DNA aptamers. Our selected DNA aptamer AraHH001 bound specifically and with a high affinity to TECs in the nanomolar range but did not bind to normal skin endothelial cells (skin-ECs) and tumor parenchymal OSRC-II cells. The selected DNA aptamers also bounded to primary cultured human tumor endothelial cells (hTECs) isolated from a clinical patient with a renal carcinoma. Therefore, the development of specific DNA aptamers that bind to TECs is reported here for the first time. We conclude that such new DNA aptamers promise to hold great promise as targeted molecular probes that appear to play a major role in angiogenesis, drug delivery, identification of biomarker as well as in cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3886. doi:1538-7445.AM2012-3886
Abstract 3893: Inhalational temozolomide–a new mode of treating malignant gliomas
Authors: Chen Thomas C. , Cho Heeyon , Wang Weijun , Hofman Florence M. 
Published: August 2012

Abstract
Temozolomide (TMZ) is the standard of care chemotherapy for treatment of malignant gliomas; it is currently delivered orally or intravenously. Perillyl alcohol is a monoterpene which has been used to treat patients with malignant gliomas via an intranasal delivery system. Recently, we have constructed a new chemical entity (NCE) by conjugating temozolomide to perillyl alcohol via a carbamate bond. This new compound has been named TMZ-POH (NEO212). This new compound has been tested in-vitro in a number of assays. Its mechanism of action does not appear to be MGMT mediated, as addition of O6-benzylguanine has no effect on its cytotoxicity in glioma cells regardless of their MGMT status. On the other hand, TMZ-POH appears to induce endoplasmic reticulum stress (ERS) in malignant glioma cells, as demonstrated by an increase in glucose-regulated protein 78 (GRP78) and the apoptotic protein CHOP expression. MTT assays demonstrate that TMZ-POH is effective in both temozolomide sensitive and resistant U251, U87, LN229 malignant glioma cell lines. IC50 for colony formation assays (CFA) was determined for U251 temozolomide sensitive and resistant cells to be 18 uM and not achieved (0-60 uM). TMZ-POH, on the other hand, had IC50 of 10 uM and 30 uM respectively for TMZ sensitive and resistant U251 glioma cells. MTT assays using glioblastoma cancer stem cells (CSC) demonstrated that TMZ-POH induced IC50 cytotoxicity at 200 uM, compared to no cytotoxicity in the TMZ treated CSC. Moreover, TMZ-POH demonstrated no toxicity on normal astrocytes. Treatment of glioma cells with TMZ alone, POH alone, TMZ dissolved in POH, and TMZ-POH demonstrated that TMZ-POH was two orders of magnitude more cytotoxic than TMZ dissolved in POH. These data lead us to conclude that TMZ-POH is a NCE which may be evaluated for potential intranasal drug delivery to treat patients with malignant gliomas.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3893. doi:1538-7445.AM2012-3893
Abstract 3907: Discovery and characterization of AZ285 as a potent and selective inhibitor of CK2 kinase
Authors: Dowling James E. , Alimzhanov Marat , Bao Larry , Brassil Patrick , Cooke Emma L. , Denz Christopher R. , Liu Zhong-Ying , Ye Qing , Lyne Paul D. 
Published: August 2012

Abstract
Casein Kinase 2 (CK2) is a highly conserved and ubiquitously expressed serine/threonine kinase that regulates several key oncogenic signaling pathways, including PI3K/AKT, and NFkB and Wnt, and whose targeted overexpression in transgenic animal models results in neoplastic growth. Herein we describe the identification of AZ285, a potent pyrazolo[1,5-a]pyrimidine-derived inhibitor of CK2 with a high degree of kinase selectivity. AZ285 depletes levels of the CK2 substrates pAKTS129 and PTENS370 and induces apoptosis in cells in a concentration-dependent manner. Optimization of early leads was aided in part by cell wash-out experiments and X-ray cocrystallography with huCK2a and resulted in an agent with physical properties and DMPK characteristics suitable for evaluation in disease model studies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3907. doi:1538-7445.AM2012-3907
Abstract 3927: Loss of bHLH transcription factor Id4 modulates androgen receptor activity in prostate cancer progression
Authors: Carey Jason P. , Chaudhary Jaideep 
Published: August 2012

Abstract
Inhibitor of differentiation 4 (Id4), a crucial developmental gene also expressed in the normal prostate, has been shown to act as a tumor suppressor in prostate cancer. Promoter hypermethylation of Id4 is observed in several advanced stage cancers including prostate cancer. The loss of Id4 expression correlates with androgen independent prostate cancer progression. Our studies suggest that Id4 plays a crucial role in mediating the transition from androgen dependent to androgen independent prostate cancer by mediating the AR axis potential and reprogramming several cellular mechanisms including migration, senescence and proliferation. Stable transfection of a full length Id4 plasmid into the androgen-independent prostate cancer cell line DU145 resulted in re-expression of AR and downstream AR response gene PSA. Id4 transfected cells also observed an androgen regulated rate of proliferation in responsive to treatment with AR antagonist, Casodex. AR antagonism also significantly reduced the rate of migration as observed by a scratch wound assay. Under closer observation, AR antagonist treatment with Casodex also inhibited translocation of AR to the nucleus of DU145 cells as observed by immunofluorescence. Previous studies in our laboratory have demonstrated that DU145+Id4 transfected cells undergo a significant level of senescence (∼ 32%) compared to normal DU145 cells (∼ 4%). Treatment of DU145+Id4 cells with the AR antagonist Casodex demonstrate that the rate of senescence in DU145+Id4 transfected cells is closely related to inhibition of AR activity. Our results suggest that Id4 may play a crucial role in the loss of AR activity in advanced stage prostate cancer progression. These results also suggest that the antagonism of AR nuclear translocation post Id4 induction closely regulates the rate of proliferation and the induction of a senescent phenotype. These results provide a significant correlation between Id4 expression and AR activity during prostate cancer progression. Loss of AR activity through Id4 promoter hypermethylation may play a crucial role in understanding castration resistant prostate cancer. Therefore, induction of Id4 may provide a novel therapeutic target for advanced stage prostate cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3927. doi:1538-7445.AM2012-3927
Abstract 394: Close association between subsided inflammation and the development of histologically less malignant HCC in HCV-associated LC
Authors: Tarao Kazuo , Miyakawa Kaoru , Kobayashi Satoshi , Ueno Makoto , Ohkawa Shinichi , Morinaga Soichiro , Nakamura Yoshiyasu , Miyagi Yohei , Okudaira Masahiko 
Published: August 2012

Abstract
Aim: We recently demonstrated that severe inflammation in the background cirrhotic tissue correlate with the development of histologically more malignant hepatocellular carcinoma (Edmondson III HCC) in HCV-associated liver cirrhosis (LC), and that histology activity index (HAI) was the only one significant contributor to the development of Edmondson III (Ed III) HCC in small nodular HCC. There is a possibility, in the contrary of this phenomenon, that subsided inflammation correlates with the development of histologically less malignant HCC (Ed I type HCC) and that long-term subsided inflammation correlates with the development of large Ed I HCC. We examined the possibility. Methods: Curative hepatic resection for HCC with LC was performed in 264 patients during the past 10 years in Kanagawa Cancer Center hospital. Of 264 patients 197 patients were anti-HCV-positive or HCV-RNA positive. Out of the 197 patients, 32 patients whose HCC revealed only one small HCC nodule (≤ 3 cm) were selected for this study. Furthermore, the cases whose HCC nodules were large (&gt; 3 cm), but consisted of predominantly Ed I component, were also examined. For the evaluation of inflammation in the background LC, modified Knodell's histology activity index (HAI) was used. (for the evaluation of pure inflammation, items of fibrosis was omitted); piece meal necrosis (1-4), intra lobular cellular degeneration and focal necrosis (1-4), portal cellular inflammation (1-4), were estimated by two well experienced pathologist. In each case, the HAI score was estimated in five field and average HAI score was calculated. All the sections of resected HCC tissue was examined pathologically in all patients for determining the grade of malignancy according to Edmondson Steiner's classification; Ed I (well differentiated), Ed II (moderately diff.), Ed III (poorly diff.). Results: The average HAI score in 7 Ed I HCC patients was as low as 3.61 ± 0.70 (mean ± SD), and was significantly lower than that in 17 Ed III HCC patients (5.21 ± 1.15, P &lt;0.001). Furthermore, the average HAI in the 5 cases whose HCC nodules were more than 3 cm and whose major component of HCC nodules were Ed I, was also as low as 3.55 ± 0.74. Conclusions: It is suggested that subsiding inflammation in the background non-cancerous cirrhotic portion might correlate with the development of histologically less malignant HCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 394. doi:1538-7445.AM2012-394
Abstract 3942: The role of vHL and REDD1 in predicting sensitivity to targeted therapies in renal cell carcinoma
Authors: Blick Christopher , Ramachandran Anassuya , McCormick Robert , Cranston David , Harris Adrian L. 
Published: August 2012

Abstract
There are currently 6 FDA approved therapies in metastatic renal cell carcinoma and their introduction has improved both time to progression and survival in these patients. Despite treatment with targeted therapies approximately 20% of patients do not respond and the remaining patients will most likely develop resistance during the first 18 months of treatment. The aim of this study was to identify a link between differences in sensitivity to targeted therapies, the vHL status and the expression of genes involved in the mTOR pathway in both historic and primary renal cancer cell lines. Drug sensitivity and gene expression data was analysed in 6 historic and 10 primary renal cancer cell lines obtained from nephrectomy specimens. Gene expression data was also available from an additional 68 renal tumours. We found that cell lines with mutated or absent vHL showed increased sensitivity to rapamycin (p&lt;0.01) but not to other therapies. Gene expression data showed that the expression of REDD1 (regulated in development and DNA damage responses 1), a known HIF1 target gene which inhibits the mTORC1 pathway in response to hypoxic stress correlates with rapamycin sensitivity (R-squared = 0.64, p=0.05). REDD1 expression was also higher in renal tumours when compared with matched normal tissue (p&lt;0.01) and was found to correlate with CAIX expression (R-squared = 0.47, p&lt;0.01). CAIX expression is associated with reduced survival in renal cell carcinoma and so further analysis is being performed to establish a potential role of REDD1 as a prognostic marker. Our findings suggest that vHL status and the levels of REDD1 expression in renal cancer cell lines can predict sensitivity to rapamycin.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3942. doi:1538-7445.AM2012-3942