bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1904: Transforming growth factor-beta mediated epithelial to mesenchymal transition contributes to in vivo resistance to sorafenib in hepatocellular carcinoma
Authors: Lin Shiou-Der , Lin Tzu-Hsuan , Feng Wen-Chi , Shao Yu-Yun , Cheng Ann-Lii , Hsu Chih-Hung 
Published: August 2012

Abstract
Sorafenib, a multikinase inhibitor targeting Raf kinase and vascular endothelial growth factor receptor, is currently the only approved agent for hepatocellular carcinoma (HCC). However, the majority of HCC patients are inherently resistant to sorafenib treatment. To study molecular mechanisms underlying the resistance to sorafenib in vivo, we studied immunocompromised mice implanted with xenografts of human HCC cells subcutaneously, and identified tumors that showed primary resistance to sorafenib. Primary cultured cells were established from sorafenib-resistant xenografts, and verified for in vitro and in vivo sensitivity to sorafenib. The differentially expressed genes of the resistant cells versus control cells were analyzed by cDNA microarray. The expressions of candidate markers were confirmed by Western blotting, and their significances were verified by specific pathway inhibitors. A subline of Huh7 cells was established by primary culture from a sorafenib-resistant HCC-xenograft (designated as Huh7.1.SR). Compared to Huh7 cells primarily cultured from HCC-xenograft treated with vehicle alone (designated as Huh7.1.v), Huh7.1.SR had a moderate increase of resistance to sorafenib in vitro, with 50%-inhibitory concentration (IC50) increased from 5 to 10 μM. Subcutaneous xenograft studies confirmed that Huh7.1.SR retained the phenotype of in vivo resistance to sorafenib. The IPA (ingenuity pathway analysis) of differentially expressed genes of Huh7.1.SR versus Huh7.1.v cells revealed several pathway networks centering at transforming growth factor beta receptor (TGFBR), hepatocyte nuclear factors, NOTCH, pro-inflammatory cytokines, and nuclear factor kappa B. Huh7.1.SR had an increased expression of TGF-beta and p-Smad2, indicating that the TGF-beta pathway was activated. Huh7.1.SR cells expressed phenotypic features of epithelial to mesenchymal transition (EMT), including higher expression of vimentin, lower expression of E-cadherin, and increased cell migration. The expressions of Slug and Twist, two well-known transcriptional factors of inducing EMT, also increased in Huh7.1.SR cells. Treatment of SD-208, an inhibitor of TGF-beta receptor, partially reversed the phenotypic features of EMT in Huh7.1.SR cells. Moreover, concomitant treatment of SD-208 improved the sensitivity to sorafenib in Huh7.1.SR cells. Our data indicate that activation of TGF-beta signaling pathway is an important mechanism mediating the resistance to sorafenib in HCC in vivo. (The study was supported by the grant NSC 100-2325-B-002-043- from National Science Council of Taiwan)
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 1904. doi:1538-7445.AM2012-1904
Abstract 1909: Cytoprotective autophagy is involved in resistance towards MET inhibitors in human gastric adenocarcinoma cells
Authors: Humbert Magali , Medová Michaela , Aebersold Daniel M. , Tschan Mario P. , Zimmer Yitzhak 
Published: August 2012

Abstract
MET, also known as hepatocyte growth factor receptor, is a receptor tyrosine kinase (RTK) that plays an important role both in normal cellular function as well as in oncogenesis. In many different cancer types, abnormal activation of MET is related to poor prognosis and various strategies to inhibit its function, including small molecule inhibitors, are currently in preclinical and clinical evaluation. Although promising results have been obtained with a variety of different MET RTK inhibitors, different resistance mechanisms were found. We hypothesized that autophagy, a self-digesting recycling mechanism for cellular organelles and macromolecules with cytoprotective functions, might be involved in resistance towards MET inhibitors. Autophagy induced upon MET inhibition might support cancer cell survival. We therefore aimed at investigating the involvement of autophagy upon MET inhibition in GTL-16 gastric adenocarcinoma cells. First, we treated GTL-16 cells with the MET inhibitor PHA665752. We observed a marked induction of autophagy in these cells upon MET inhibition as measured by LC3I/LC3II conversion and GFP-LC3 dot formation. Similar results were seen in another gastric adenocarcinoma cell line, namely MKN-45. Next, to investigate if MET inhibition-mediated induction of autophagy is a protective mechanism, we treated GTL-16 cells with PHA665752 in combination with compounds that influence autophagic activity. Interestingly, a combination treatment of MET and autophagy inhibitors (3-Methyladenine, 3-MA) significantly (MWU, p&lt;0.001) decreased cell viability as determined by an MTT assay. In contrast, using the autophagy activator lithium chloride in combination with MET inhibitors, cell viability was significantly increased (p&lt;0.01). All data were confirmed using a second MET-inhibitor. To exclude that 3-MA autophagy independent functions account for the increased cell death during treatment with PHA665752, we inhibited autophagy by knocking down the key autophagy gene ATG7 in GTL-16 cells using lentiviral vectors expression small hairpin (sh)RNA targeting ATG7. These “autophagy knockdown” GTL-16 cells displayed a significant increase in cell death upon MET inhibition as compared to GTL-16 control cells expressing a scrambled control shRNA. In conclusion, our results point to a cytoprotective function of autophagy in response to MET inhibition. The use of MET in combination with autophagy inhibitors may represent a novel therapeutic option for the treatment of gastric carcinoma with aberrant MET activity.
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 1909. doi:1538-7445.AM2012-1909
Abstract 1921: A novel FAK kinase inhibitor (PF-4554878) decreases growth and induces apoptosis in pancreatic neuroendocrine tumor cells
Authors: Francois Rony , Lu Shun , He Di-Hua , Zajac-Kaye Maria , Hochwald Steven N. 
Published: August 2012

Abstract
Introduction: Pancreatic neuroendocrine tumors (PNETs) are poorly understood and there are few effective therapies. Focal adhesion kinase (FAK) is an important tyrosine kinase implicated in cell survival signaling and found to be overexpressed in many malignancies. Our hypotheses are that 1) FAK expression is upregulated, 2) that FAK plays an important role in PNET cell survival, and 3) that a novel ATP competitive kinase inhibitor of FAK demonstrates anti-neoplastic efficacy in PNET cells. Methods: By Western blot, the expression of FAK was determined in frozen human PNETs compared to normal human pancreas. The compound, PF-4554878 (Pfizer), has been shown to be an ATP competitive kinase inhibitor of FAK. The in-vitro effects of this compound on cell signaling, viability and apoptosis in human pancreatic neuroendocrine cells (BON-1 and QGP-1) were evaluated. Statistical analysis was performed via t-test with significance defined as p&lt;0.05. Results: FAK was found to be overexpressed in PNETs compared to normal pancreas. PF-4554878 not only caused a decrease in PNET cell viability with an IC50 of 5 µM in human pancreatic neuroendocrine cell lines, but also caused a statistically significant dose-dependent increase in apoptosis by TUNEL staining and/or PARP cleavage. These effects were associated with a decrease in Y397 phosphorylation of FAK. Conclusions: A novel compound that inhibits the kinase activity of FAK results in decreased PNET proliferation and induction of apoptosis. These effects appear to be mediated through downregulation of p-FAK (Y397). This compound deserves further study as a novel treatment strategy in human PNETs.
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 1921. doi:1538-7445.AM2012-1921
Abstract 1931: A potential antitumor herb medicine, Corilagin, inhibits ovarian cancer cell growth by blockage of TGF-β/AKT/ERK signaling pathways
Authors: Jia Luoqi , Jin Hongyan , Zhou Jiayi , Chen Lianghua , Lu Yiling , Ming Yanling , Yu Yinhua 
Published: August 2012

Abstract
Recently, we have identified that Corilagin is a major anti-tumor active component extracted from a well-known hepatoprotective and antiviral medicinal herb, Phyllanthus niruri L. Corilagin distinctly inhibited the growth of ovarian cancer cell lines SKOv3ip, Hey and HO-8910PM, with IC50s less than 20µg/ml, while displayed the low toxicity against normal ovarian surface epithelium (OSE), with IC50s around 100µg/ml. Corilagin induced cell cycle arrest at G2 stage and enhanced apoptosis in Hey cancer cells. To explore its anti-tumor activity in vivo, Corilagin was delivered intra-peritoneally to the mice bearing SKOv3ip xenograft. Although no statistical difference observed on mice weight between untreated and Corilagin treated groups, xenograft tumor growth was significantly restarted by 15µg/mL of Corilagin treated group comparing to untreated control group (p&lt;0.05). To understand the anti-tumor mechanisms of Corilagin, we performed reverse phase protein array (RPPA) analysis using untreated and Corilagen treated HO-8910PM cells, and the results were confirmed by Western blots. We have found that Corilagin blocked the activation of multiple signaling cascades, such as, pAKT and pERK. Particularly, Corilagin inhibits TGF-β secretion in the culture supernatant of all tested ovarian cancer cell lines and blocks the stabilization of Snail induced by TGF-β in HO-8910PM cells. In contrast, reduction of TGF-β secretion was not observed in cytotoxic drug Taxol-treated cancer cells, suggesting that Corilagin specifically targets TGF-β secretion. TGF-β signaling plays a critical role in epithelial-mesenchymal transition (EMT) and cancer metastasis. High concentration of TGF-β had been detected in ascites, blood and other body fluids of ovarian cancer patients. In addition, our recent studies identified that TGF-β being the most important inflammation factor in ovarian cancer, which stabilizes at the protein level of Snail, an inducer of EMT, and further enhanced Snail expression when combined with other inflammation factors. TGF-β is regulated by Smads, but could also be regulated by AKT/ERK signaling pathways. Our observations indicate that Corilagin extracted from Phyllanthus niruri L. acts as an effective natural targeted therapeutic agent against the growth of ovarian cancer cells via TGF-β/AKT/ERK signaling pathways.
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 1931. doi:1538-7445.AM2012-1931
Abstract 1934: Characterization of the anti-proliferative effect of 6-(3-aminopropyl)-9-methoxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione in cultured PC-3 cells
Authors: Park Eun-Jung , Morrell Andrew , Conda-Sheridan Martin , Cushman Mark , Pezzuto John M. 
Published: August 2012

Abstract
Previously, we reported interesting pharmacological responses mediated with indenoisoquinolines, including cytotoxic effects mediated by the topoisomerase I inhibitor 6-(3-aminopropyl)-9-methoxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (AM9-79). We currently describe further mechanistic evaluations performed with cultured PC-3 cells. AM9-79 strongly inhibited proliferation in a dose- and time-dependent manner (IC50 = 9.77 nM; 72 h incubation period). As indicated by Annexin V/7-AAD double staining, an elevated population of cells was undergoing apoptosis. Accordingly, cellular levels of pro-apoptotic proteins such as Bcl-2 were decreased, and the protein cleavage and enzymatic activities of several caspases, which play pivotal roles in apoptosis, were induced. Effects on gene expression were evaluated with a cDNA microarray, and it was found that AM9-79 significantly up-regulated the expression of BRCA2, CDKN1A, GADD45A, SERTAD1, and TP53. Consistent with these results, the protein level of CDKN1A (p21WAF1/CIP1), and phosphorylation/activation of ERK1/2, a signaling molecule positively correlated to the expression of BRCA2, were up-regulated. Further investigation of a potential upstream mechanism revealed treatment with AM9-79 decreased the protein level of EGFR and reduced nuclear translocation. This is relevant since current evidence indicates EGFR functions not only as a transmembrane receptor but also as a transcriptional factor. In accord with this response, decreased expression levels of downstream molecules (iNOS and cyclin D1) were observed. In sum, these data suggest AM9-79 can effectively function by novel mechanisms of relevance for the treatment or prevention of cancer. (Supported by P01 CA48112 awarded by the NCI)
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 1934. doi:1538-7445.AM2012-1934
Abstract 1945: A novel self assembled taxane nanoparticles for breast cancer chemotherapy
Authors: Kulkarni Ashish A. , Soh Hua Xiang , Sengupta Poulomi , Basu Sudipta , Sengupta Shiladitya 
Published: August 2012

Abstract
Breast cancer is the most frequently diagnosed form of cancer and a second leading cause of cancer deaths among women in the United States, with an estimated 207,090 new cases and 39,840 deaths since the beginning of 2010. Taxane-based chemotherapeutic agents are extensively used as a treatment for breast cancer and have shown important clinical benefits in both adjuvant and metastatic settings. However, the therapeutic efficacy of these drugs is hampered by limitations such as poor water solubility, narrow therapeutic indices and significant off-target toxicities which limit its dose escalations and treatment frequency. Also, current drug delivery strategies often suffer from constraints such as lower potency, low loading, non-biocompatibility/ non-biodegradability and uncontrolled release of the drug. Clearly, there is an urgent need for a paradigm shift in the strategies for the development of drug delivery vehicles for breast cancer management. We propose a novel approach in the design of nanomedicine where an active molecule can self-assemble into a nanoparticle resulting in increased loading, improved antitumor outcome and reduced off-target side effects. Different taxane analogs were attached to cholesterol using an acid labile linker. The self assembly of taxane-cholesterol conjugate was facilitated by phosphatidylcholine and DSPE-PEG to form well defined nano-sized particles. The loading of 10-15 μg/μL of drugs was obtained and sustained release of drugs was observed at pH 5.5 over 48h. In a preliminary cell viability studies, the taxane nanoparticles showed comparable efficacy to drug alone. Next, in order to achieve tumor specific homing of the nanoparticles, we plan to incorporate multiple copies of iRGD peptide on the nanoparticle surface that will bind to αvβ3 integrins overexpressed on the endothelium of tumor vessels and help in effective internalization of nanoparticles. The optimum density of peptides on the nanoparticle surface will be achieved by conjugating the peptide to DSPE-PEG. We believe that this study will not only uncover a novel and most effective nanotechnology-based approach for breast cancer treatment but will also eventually lead to an improvement in the quality of life of patients at minimum cost.
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 1945. doi:1538-7445.AM2012-1945
Abstract 195: The tumor cell compartment holds the unfavorable prognostic value of miR-21 in gliomas
Authors: Hermansen Simon K. , Dahlrot Rikke H. , Nielsen Boye S. , Hansen Steinbjørn , Kristensen Bjarne W. 
Published: August 2012

Abstract
High-grade gliomas are some of the most lethal forms of human cancer and new clinical biomarkers and therapeutic targets are highly needed. MicroRNAs (miRNAs), a group of short noncoding RNAs, hold great potential as new biomarkers and targets as they are commonly deregulated in a variety of diseases including gliomas. MicroRNA-21 (miR-21) is the most consistently over-expressed miRNA in several cancers including gliomas and is therefore very promising as a useful clinical biomarker and therapeutic target. To better understand the role of miR-21 in gliomas, paraffin embedded glioma tissue samples from 193 patients with grade I, II, III and IV tumors were analyzed by in situ hybridization (ISH) using LNA-DNA chimeric probes. We found miR-21 expression in tumor cells and tumor-associated blood vessels, whereas no expression was seen in adjacent normal brain parenchyma. Using advanced image analysis we obtained quantitative estimates reflecting the miR-21 expression levels. The miR-21 levels correlated significantly with grade (p = 0.027, rs = 0.161, 95% CI, 0.015 to 0.301) with the highest levels measured in grade IV gliomas. Furthermore, quantitative estimates obtained for the tumor cells alone were significantly associated with poor prognosis in all tumors (p = 0.012) and grade III and IV tumors alone (p = 0.005). This was independent of known clinical parameters (age, grade and sex). In conclusion, we have shown that miR-21 is constricted to tumor cells and tumor blood vessels and that tumor cell miR-21 represent a valuable prognostic biomarker for the disease.
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 195. doi:1538-7445.AM2012-195
Abstract 1964: Development of a nanovaccine for cancer therapy
Authors: Bright Vanessa R. , Gilchuk Pavlo , Gordy Laura , Flyak Andrew , Joyce Sebastian , Yankeelov Thomas , Pham Wellington 
Published: August 2012

Abstract
Purpose: Despite significant advancements in dendritic cell (DC)-based cancer immunotherapy, the approach remains challenging, especially with regard to developing a simple yet robust method for activating the immune system against cancer in the context of using tumor antigen-activated DCs. To improve the feasibility of this immunotherapy approach, we sought to develop a robust vaccine that utilizes nanotechnology to activate endogenous DCs in the host. Method: Using a superparamagnetic iron oxide (SPIO) nanoparticle as the carrier for this therapy, two immune system activating molecules were conjugated to the nanoparticle. The dextran-coated SPIO nanoparticles were reacted with an epoxyamine linker to produce amine groups on the surface of the nanoparticle. Next, a potent Natural Killer T (NKT) cell activating glycolipid, was conjugated to the SPIO nanoparticle via a disulfide-containing crosslinker. For in vivo studies, an MUC-1 derived antigenic peptide was conjugated as well to the same nanoparticles. Here, adult MUC-1 transgenic C57BL/6 mice were implanted with MUC-1 transfected C57G tumors. The protein and adjuvant conjugated nanoparticle was delivered to mice via subcutaneous injection. Tumor growth in the treated and untreated groups of mice was measured by ultrasound over a 5-week period. Results: Using a mouse model, the effectiveness of a nanovaccine was determined. The nanoparticle conjugated with the NKT cell agonist induced robust IFN-γ and IL-4 response in wild-type mice while no response was elicited in NKT cell- or DC-deficient mice probed with the same nanovaccine. In a different mouse model group, treatment of tumor-bearing MUC-1 animals with the nanovaccine resulted in markedly diminished tumor growth compared to the untreated group. Conclusion: The results indicate that the nanoparticle delivery vehicle can induce a robust immune response in mice. Beyond this vehicular capability, the SPIO nanoparticles can be used as contrast agents for magnetic resonance imaging. As a result, this multimodal and multivalent nanovaccine, achieved through nanotechnology, has the potential to provide microanatomical and functional imaging feedback of the DC-targeted anti-cancer immunotherapy, thus leading to longitudinal treatment and monitoring.
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 1964. doi:1538-7445.AM2012-1964
Abstract 1965: Evaluating the use of Fe3O4@TiO2 nanoparticles and nanoconjugates with a HPV 18 E2 peptide as a potential therapy for HPV containing cancer cells
Authors: Doty Caroline B. , Yuan Ye , Wu Aiguo , Paunesku Tatjana , Woloschak Gayle E. 
Published: August 2012

Abstract
Over half a million women world wide are affected by cervical cancer each year. HPV, human papillomavirus, is currently seen as the causative agent of this form of cancer. There are multiple mechanisms by which HPV can cause cervical cancer, the primary mechanisms being the integration of HPV viral DNA into human DNA and the production of the viral oncoproteins E6 and E7. The mechanism of action of these oncoproteins lies in the deregulation of tumor suppressor proteins p53 and Rb. Current cervical cancer therapies, such as radiation, surgical removal, and chemotherapy target the cancerous cells but not the causative agent, HPV. The purpose of this investigation is to find the optimal formulation for, and evaluate the ability of, titanium dioxide (TiO2) shell - iron oxide (Fe3O4) core nanoconjugates (Fe3O4@TiO2) to target HPV genome as a method of therapy. Fe3O4@TiO2, which act the same as pure TiO2 nanoparticles, produce reactive oxygen species (ROS) in solution and have the ability to cleave DNA upon the induction of photon energies above 3.2 eV (e.g. white light), as was shown as a part of these studies. In this study, 6nm Fe3O4@TiO2 nanoconjugates were covalently linked, via a dopamine linker, to a truncated HPV 18 E2 peptide. The peptide linked to the nanoparticle is a 22 amino acid sequence that contains a nuclear localization sequence as well as a DNA binding motif. We hypothesized that (1) the Fe3O4@TiO2-PNA nanoconjugates would localize to the nucleus of cells; (2) presence of nanoconjugates in cells would lead to the production of reactive oxygen species (ROS) upon induction with white light; (3) presence of light activated nanoconjugates in cells would lead to double strand breaks in DNA. The nanoconjugate was tested in HeLa cells which contain multiple copies of HPV genome. To evaluate the effectiveness of this nanoconjugate therapy, we have used DCFDA staining to determine levels of ROS in cells upon the induction of light. As a method to determine double strand DNA damage, we have used immunofluorescence techniques to reveal changes in 53BP1 foci. Upon the introduction and induction of Fe3O4@TiO2-HPV 18 E2 peptide nanoconjugates in HeLa cells we have found increases in ROS levels and increases 53BP1 foci suggesting the presence of double strand DNA damage.
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 1965. doi:1538-7445.AM2012-1965