bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 133: A microRNA contribution to aberrant Ras activation in gastric cancer
Authors: Wang Xian , Lam Emily , Jin Hongchuan 
Published: June 2012

Abstract
Oncogenic Ras mutations are rare in gastric cancer, indicating that other mechanisms may be responsible for aberrant Ras activation in this type of cancer. Ezrin is critical to Ras activation by remodeling cortical actin cytoskeleton. In this study, we aimed to illustrate the relevance and regulation of ezrin in gastric cancer. Ezrin was upregulated in gastric cancer cells. Ezrin siRNA inhibited Ras activation, cell growth and cell migration. Ezrin overexpression was correlated with a poor outcome of gastric cancer patients (n=150, p&lt;0.01). Cox regression analysis revealed a significant value of ezrin expression in prognosis prediction of gastric cancer (relative risk: 2.37, 95% confidence interval: 1.24-4.56, p&lt;0.01). MiR-204, which was predicted to target ezrin, was downregulated in gastric cancer cells and gastric carcinomas (n=22, p&lt;0.01). MiR-204 inhibited ezrin expression, Ras activation, cell growth and cell migration. Importantly, miR-204 suppressed the expression of luciferase controlled by wild-type but not mutated ezrin 3’-UTR. In conclusion, ezrin is important to Ras activation in gastric cancer. Its upregulation is an independent prognosis prediction factor for gastric cancer. By contributing to ezrin upregulation, miR-204 downregulation represents a novel mechanism for aberrant Ras activation in gastric carcinogenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 133. doi:10.1158/1538-7445.AM2011-133
Abstract 1336: Nicotine does not promote tumor growth in preclinical mouse models of lung cancer
Authors: Maier Colleen , Hollander M. Christine , Dennis Phillip 
Published: June 2012

Abstract
Nicotine replacement therapy (NRT) is a popular and effective regimen for the cessation of smoking. Expanded use of NRT is controversial based on preclinical studies that show that nicotine activates signaling pathways that promote cellular survival and proliferation. To address the tumor promoting effects of nicotine in mouse models of lung cancer, nicotine was administered in the drinking water and tested in a tobacco carcinogen-driven model (NNK), a genetically engineered model (KRasLA2), and syngeneic mouse xenografts. Pharmacokinetic analysis showed that mice had normal water consumption and achieved an average serum cotinine level of 135 ng/ml, a level comparable to that observed in NRT users. In the NNK model, nicotine was administered after 3 weekly intraperitoneal injections of NNK, and was continued for 12 wk. At the time of sacrifice, nicotine did not increase lung tumor multiplicity or size, and did not activate the Akt/mTOR pathway. In the KRasLA2 model, mice were placed on nicotine at the time of weaning. At 6 wk, there was no effect on tumor multiplicity, size, histology, or tumor biomarkers. Studies assessing the effects of nicotine on overall survival of K-RasLA2 mice are ongoing. Similar negative results were observed with nicotine administration in xenograft studies with isogenic NNK-transformed lung adenocarcinoma cell lines. To assess whether the response to nicotine might be dose-dependent, we assessed activation of the PI3K/Akt/mTOR, MEK/ERK, and JAK/STAT pathways in these cell lines using immunoblotting. Stimulation was only observed at concentrations higher than that observed with NRT. These results suggest nicotine at doses comparable to NRT does not promote lung tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1336. doi:10.1158/1538-7445.AM2011-1336
Abstract 1337: MUC1 facilitates BPDE-induced EGFR activation and malignant transformation in human bronchial epithelial cells
Authors: Xu Xiuling , Bai Lang , Chen Wenshu , Li Zi , Kim Kwang Chul , Belinsky Steven A. , Lin Yong 
Published: June 2012

Abstract
Inflammation has emerged as an important factor for the development of lung cancer. However, the gene targets and pathways that are involved in inflammation-associated lung cancer development have not been clearly elucidated. Cigarette smoke (CS), which causes chronic pulmonary inflammation, is an established risk factor for lung cancer. MUC1 (MUC in human and Muc in animals), a mucin-like glycoprotein expressed on the surface of airway epithelial cells, is inducible during lung inflammation. MUC1 is also overexpressed as a tumor antigen in lung tumors. We found that chronic CS exposure significantly increased Muc1 expression in mouse airway epithelial cells associated with infiltration of inflammatory cells to the lung. The role of MUC1 in lung epithelial cell transformation induced by benzo[a]pyrene diol epoxide (BPDE), the active form of the CS carcinogen benzo(a)pyrene (BaP), was examined in an in vitro cell transformation assay. Knockdown of MUC1 by shRNA significantly reduced the efficacy of BPDE-induced transformation of BEAS-2B, an SV40 large T antigen immortalized human bronchial epithelial cell line. BPDE strongly activated EGFR and Akt in BEAS-2B cells. Akt activation was blocked with an EGFR inhibitor, suggesting that BPDE activates the EGFR/Akt cascade. Blocking this cascade with inhibitors for either EGFR or Akt significantly inhibited BPDE-induced cell transformation, supporting a critical role for EGFR and Akt activation in BPDE-induced cell transformation. Interestingly, the BPDE-induced activation of EGFR and Akt was attenuated when MUC1 expression was knocked down. Suppression of EGFR or Akt significantly increased BPDE's cytotoxicity. Consistently, the MUC1-suppressed BEAS-2B cells were more sensitive to BPDE-induced death. Taken together, these results suggest that MUC1 plays an oncogenic role in the early stages of inflammation-associated lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR/Akt pathway that potentiates survival in immortalized bronchial epithelial cells.
This work is supported by 1R01ES017328.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1337. doi:10.1158/1538-7445.AM2011-1337
Abstract 1341: Insulin directly induces endometrial cell proliferation and carcinogenesis
Authors: Bishop Erin A. , Lightfoot Stan A. , Benbrook Doris M. 
Published: June 2012

Abstract
Introduction: Diabetes and insulin resistance are strong risk factors for type 1 endometrial cancer. The mitogenic actions of insulin are well described, but less is known about the role insulin may play in carcinogenesis. It is unknown if insulin plays direct role in the carcinogensis of endometrial cells or if insulin promotes carcinogenesis through its overall physiological effects. Key pathways within the insulin signaling cascade, such as Ras-MAPK and PI3-K-mTOR, are also involved in the formation and progression of many cancers. The goal of this study was to determine if insulin exerted direct effects on normal endometrial cell proliferation and carcinogenesis.
Methods: The effects of varying doses of insulin on endometrial cells collected from human menstrual blood from healthy volunteers were measured using a standard MTS cytotoxicity assay. These cells were also grown in 3-D organotypic culture for 2 weeks and exposed to a known carcinogen, 7, 12-dimethylbenz[α]anthracene (DMBA), insulin, and the combination of both agents. Effects of insulin were evaluated by histological evaluation and quantified with anchorage independent growth assays.
Results: Insulin increased proliferation of endometrial cells in a dose dependent fashion. In the organotypic model, insulin caused the development of malignant features such as nuclear pleomorphism, hyperchromasia, and mitosis as a single agent and enhanced these malignant features in the DMBA treated cultures. Consistent with these findings, soft agar colony forming assays demonstrated significantly greater numbers of anchorage-independent colonies in cultures treated with insulin plus DMBA in comparison to cultures treated with DMBA alone.
Conclusions: Insulin exerts direct effects on endometrial cells by increasing their proliferation and enhancing their susceptibility to carcinogenesis. Western immunoblotting is now being performed to characterize the effects of insulin on the AKT and MAPK signaling pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1341. doi:10.1158/1538-7445.AM2011-1341
Abstract 1346: Discovery of novel MSK1 inhibitors with hybrid virtual screening and structure-based drug design
Authors: Huang Zunnan , Liu Kangdong , Bode Ann M. , Dong Zigang 
Published: June 2012

Abstract
Mitogen- and stress-activated protein kinase 1 (MSK1) is a serine/threonine kinase that is involved in gene transcription regulation and pro-inflammatory cytokine stimulation. MSK1 is an attractive target for the treatment of chronic inflammatory diseases. Currently, no small molecule inhibitor has been identified that specifically targets MSK1 and only H-89 is a known inhibitor. In this study, we performed hybrid virtual screening (HVS) to identify novel small molecule inhibitors that target MSK1. For the screening, we used the active conformation of the C-terminal kinase domain of the dual kinase as the protein template. Computational screening of several well-known compound databases, including the FDA, Natural Product, ZINC all purchasable and PDB ligands databases, revealed 40 potential leads. We tested 11 lead compounds and found 5 that showed substantial in vitro inhibitory activity against MSK1. These results illustrated that our computational screening processes greatly enhanced the success rate of virtual screening. The high-performing HVS protocols were especially successful to retrieve thousands of promising new leads from millions of compounds in conjunction with structure-based drug design and then to further select true hits from the majority of high-scoring decoys.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1346. doi:10.1158/1538-7445.AM2011-1346
Abstract 1369: Synthesis of substituted N-[(3-(1H-pyrrol-1yl)methyl]-5,6-dihydropyridin-1(2H)-yl) benzamide/benzene sulfonamide as anticancer agents
Authors: Redda Kinfe Ken , Gangapuram Madhavi , Mochona Bereket , Mateeva Nelly , Ardley Tiffany 
Published: June 2012

Abstract
Cancer has proven to be one of the most intractable human diseases, and as yet no anticancer agents that are highly effective and safe are available. Therefore, synthesis of novel, potent, selective and less toxic anticancer agents remains the most pressing goal of many investigators. Tetrahydropyridine (THP) ring moieties have attracted synthetic interests for being essential structures in many agrochemicals as well as medicinal agents. The anti-inflammatory and anticancer activities of compounds consisting of reduced pyridine ring systems were investigated in our laboratory. The pharmacological activities of the (THP) derivatives depended on the nature of the substituents on the THP ring moiety. In the current investigation, we synthesized many analogs maintaining the N-(3-[(1-H-pyrrol-1-yl)methyl]-5,6-dihydropyridin-1(2H)-yl) benzamide/benzene sulfonamides, at which the phenyl ring was substituted with groups having different electronic, steric and lipophilic properties.
Mesitylene sulfonyl chloride was added with stirring to a solution of ethylacetohydroxymate and triethylamine in dimethylformamide at 0o C. Hydrolysis of this compound with the mixture of p-dioxane-70% perchloric acid and allowing them to react for 45 min gave a white solid of O-mesitylene sulfonyl hydroxylamine (MSH). MSH was used to prepare the N-amino salt since it served as an aminating agent. 3-[(1H-pyrrol-1-yl)methyl]pyridine was reacted with MSH in dichloromethane to produce 3-[(1H-pyrrol-1-yl)methyl]-1-aminopyridinium mesitylenesulfonate, the N-amino salt. Reaction of the amino salt with substituted benzoyl chloride/benzenesulfonyl chloride in anhydrous tetrahydrofuran containing triethylamine gave stable benzoyl/benzene sulfonyl imino ylides. This was followed by reduction with sodium borohydride in absolute ethanol, which furnished the target compounds substituted N-(3-[(1H-pyrrol-1-yl)methyl]-5,6-dihydropyridin-1(2H)-yl) benzamide/benzene sulfonamides. These compounds were evaluated for their cytotoxic effects on MCF-7 estrogen receptor positive breast cancer cells, MDA-MB-231 estrogen receptor negative breast cancer cell line, and Ishikawa cells, using the CellTiter-Glo (CTG) luminescent cell viability assay. N-(3-[(1H-pyrrol-1-yl)methyl]-5,6-dihydropyridin-1(2H)-yl)-4-methoxybenzene- sulfonamide showed the most potent cytotoxicity with an IC50 values of 47, 28, and 44 µM on MCF-7, Ishikawa and MDA-MB-231 cell lines, respectively.
This research was supported by NIH/ RCMI Grant # G12 RR 03020 and Pharmaceutical Research Center NIH/NCRR Grant 1 C06 RR12512-01.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1369. doi:10.1158/1538-7445.AM2011-1369
Abstract 1375: A homogeneous high-throughput screening assay for inhibitors of the interaction of MLL-AF4 and AF9 in pediatric leukemia
Authors: Drake Katherine , Napper Andrew D. 
Published: June 2012

Abstract
Chromosomal translocations of the mixed lineage leukemia (MLL) gene occur in 5-10% of pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), including up to 80% of infant ALL and most treatment-related secondary AML. These MLL rearrangements result in a portion of the MLL protein being fused to one of a number of transcription factors. The prognosis for MLL-rearranged (MLL-R) leukemia is much poorer than for leukemia devoid of MLL fusions; five-year survival of &lt;40% in the case of infant ALL. MLL fusions are potent inducers of leukemia, through recruitment of a protein complex that activates transcription of the HOX (homeobox) oncogene HOXA9, which in turn blocks normal differentiation of progenitor cells and confers a stem cell-like phenotype. The transcription factor AF4 is the most common MLL fusion partner, and MLL-AF4 is associated with a particularly poor prognosis. Direct interaction of MLL-AF4 with the transcription factor AF9 has been shown to be critical to leukemic transformation. Here we describe the development of a homogeneous high-throughput screening (HTS) assay for small-molecule inhibitors of the binding of MLL-AF4 to AF9 and the validation of this assay in pilot HTS. A recent study showed that peptides containing as few as 10 amino acids derived from the AF9 binding site in AF4 bind to AF9 with low nanomolar potency and selectively kill MLL-AF4-containing leukemia cell lines. We have developed an assay that measures binding of an AF4-derived peptide to AF9 protein using AlphaScreen technology, a homogeneous proximity-based method well suited to HTS in 384- and 1536-well plates. Laser excitation of donor beads results in the generation of singlet oxygen, which encounters acceptor beads brought into close proximity by the binding of AF4 peptide to AF9, giving an amplified luminescent signal. Inhibitors are identified by reduction of the luminescent signal. We have validated the assay by demonstrating low nanomolar inhibition by several AF4-derived peptides and by screening a library of 2000 drugs and natural products. The next step is transfer of the assay to the Broad Institute (Cambridge, MA) for HTS against the 400,000-compound NIH library. The ultimate goal is the optimization of lead compounds as novel therapies targeted to pediatric leukemia harboring MLL-AF4, both as stand-alone agents and as synergistic potentiators of existing chemotherapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1375. doi:10.1158/1538-7445.AM2011-1375
Abstract 1380: Engineered toxin bodies with specific activity against EGFR and HER2 expressing cells
Authors: Grant Kari , Higley John , Higgins Jack , Robinson Lee , Null Bill , Zhu Keng , Kim Jason , Cunningham Casey , Poma Eric 
Published: June 2012

Abstract
Antibody approaches that abrogate signaling from the HER2 or EGFR receptors have been proven effective in patients with breast or colorectal cancer, respectively. These antibodies do not have an effect however in colorectal patients with KRAS mutations or breast cancer patients that lack HER2 gene amplification as signal interruption is not sufficient to induce cell death. Here we identify several novel compounds that specifically recognize and kill HER2 and EGFR expressing cells irrespective of receptor signaling. These compounds were identified from a screen of a novel biologic library derived from a de-immunogenized Shiga-like toxin 1 A subunit (SLT1A); SLT1A has no intrinsic binding ability of its own but can drive internalization, retrograde transport to the cytosol, and enzymatic inhibition of ribosome activity. This modified library of engineered toxin bodies (ETBs) was created through the insertion of random amino acids near the C-terminus of the SLT1A scaffold to confer binding ability to SLT1A while preserving the therapeutic PK and ADME profile of the scaffold. HER2 and EGFR specific ETBs have been identified that exhibit potent cell-kill activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1380. doi:10.1158/1538-7445.AM2011-1380
Abstract 139: MicroRNA-375 and microRNA-221: Potential noncoding RNAs associated with antiproliferative activity of benzyl isothiocyanate in pancreatic cancer
Authors: Basu Aruna , Alder Hansjuerg , Khiyami Amer , Leahy Patrick , Croce Carlo M. , Haldar Subrata 
Published: June 2012

Abstract
Large high-throughput studies in patients with pancreatic cancer revealed that oncogenic miR-221 is commonly upregulated microRNA whereas putative tumor suppressor miR-375 is generally down modulated when compared to adjacent benign pancreatic tissue or normal pancreas. In our laboratory, we observed that deregulated expression of miR-375 and miR-221 (as noted in pancreatic cancer patients) can be recapitulated in PDX1-Cre+; KRasG12D+ pancreatic cancer mouse model. Coherent data obtained from pancreatic cancer patient samples to preneoplastic lesions developed in preclinical mouse model tempted us to postulate that aberrant expression of these miRNAs (−375 and-221) might play significant role for the development of pancreatic cancer. Interestingly, ablation of miR-221 by ectopic expression of antagomir-221 in pancreatic ductal carcinoma cells can significantly exert antiproliferative effect with increased expression of p27kip1, a target of miR-221. To the other end, premiR-375 overexpression diminished cell proliferation with downmodulation of Insulin like growth factor binding protein 5 (IGFBP5) and Caveolin-1 (CAV-1 gene), which are of particular interest because of their potential link with pancreatic cancer cell growth and diagnosis. It is quite intriguing that the levels of both CAV-1 and IGFBP5 expression were elevated when miR-375 expression wanes in KRASG12D driven PanIN lesion in compound mutant mice.
Previous studies in our laboratory demonstrate that benzyl isothiocyanate (BITC), a prototypical member of the isothiocyanate (ITC) family, inhibits proliferation of human pancreatic cancer cells by causing cell cycle arrest and inducing apoptosis. Interestingly, real time qRT-PCR analysis indicates that anticancer agent BITC can diminish oncogenic miR-221 expression and elevate the level of tumor suppressor miR-375 in pancreatic cancer cells. Besides, genetic manipulation studies revealed that enforced silencing of miR-221 or overexpression of miR-375 enhances the antiproliferative effect of BITC in pancreatic ductal carcinoma cells. Next we explored the efficacy of BITC to interfere with the development of mouse PanIN lesions. Results indicate that pancreata of BITC administered compound mutant mice exhibit reduced level of IGFBP5 protein. Histopathological analysis of the extent of PanINs as well as studies on the magnitude of expression of miR-221/miR-375 and other molecular mediators in these pancreata are in progress. Explicitly, our investigation might provide new insight into nonconventional microRNA replacement therapy against pancreatic cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 139. doi:10.1158/1538-7445.AM2011-139
Abstract 1425: Significance of Dickkopf-3 overexpression in the pathogenesis of esophageal adenocarcinoma
Authors: Wang Zhuwen , Thomas Dafydd G. , Orringer Mark B. , Beer David G. , Lin Jules 
Published: June 2012

Abstract
Ninety percent of those diagnosed with esophageal adenocarcinoma ultimately die of their disease highlighting the need for novel therapeutic targets. In order to identify significant molecular changes and potential pathways involved in the progression to esophageal adenocarcinoma, 46 esophagectomy samples, including Barrett's metaplasia, low- and high-grade dysplasia, and esophageal adenocarcinoma, were evaluated using oligonucleotide microarrays. Dickkopf-3 (Dkk-3), a divergent member of the Wnt inhibitor family, was overexpressed in 33.3% (5 of 15) of esophageal adenocarcinoma samples relative to Barrett's metaplasia. The goal of this study was to define the functional significance of Dkk-3 overexpression in esophageal adenocarcinoma. Dkk-3 protein was present at moderate to high levels in 46.8% (29 of 62) of esophageal adenocarcinoma on a tissue microarray. Stable transfection of Dkk-3 into the esophageal adenocarcinoma cell line OE33 lead to significantly increased proliferation 1.6 times vector controls (p &lt; .005). In addition, OE33 cells stably transfected with Dkk-3 showed significantly greater invasion on matrigel assay than native OE33 cells (p &lt; .005). There was no significant decrease in Wnt pathway activation by TOPFLASH assay after transfection of Dkk-3 when compared to OE33 native and vector controls suggesting that overexpression of Dkk-3 acts through a Wnt-independent pathway in esophageal adenocarcinoma. Levels of SMAD4, a key downstream mediator of the TGF-ß pathway, were increased on Western blot after treatment with activin, a member of the TGF-ß superfamily, in OE33 cells stably transfected with Dkk-3 when compared to native and vector controls. These findings suggest that Dkk-3 may be important in mediating proliferation and invasion of esophageal adenocarcinoma through the TGF-β pathway and that Dkk-3 could be a novel therapeutic target in the treatment or prevention of metastatic disease in a cancer with otherwise limited therapeutic options.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1425. doi:10.1158/1538-7445.AM2011-1425