bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-110: Establishment of a chordoma xenograft and in vivo testing of compounds identified by high-throughput screening
Authors: Trucco Matteo , Wilky Breelyn A. , Awad Ola , Shah Preeti , Gul Naheed , Xia Menghang , Huang Ruili , Loeb David M. 
Published: August 2012

Abstract
Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. Therapy primarily consists of surgical resection and radiation. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents for chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. We have established a chordoma xenograft growing in NOD/SCID/IL-2R gamma-null mice. The histology of the xenograft is consistent with a dedifferentiated chordoma. The xenograft expresses the chordoma marker T brachyury, which is aberrantly localized in the cytoplasm. SNP array shows loss of heterozygosity at the p16 locus, and gene expression profiling shows high expression of numerous cancer-related genes, such as ROS1 and CPA4 The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds. Two established chordoma cell lines, U-CH1 and UCH2B, were treated and cell viability measured by CellTiter-Glo assay. Cells were incubated for 48 hours with drug concentrations ranging from 0.5nM to 46uM. The screen yielded several compounds that showed activity and two were tested in the xenograft. Compared with mice treated with vehicle alone, both drugs showed a dramatic inhibition of tumor growth. In conclusion, we have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth.
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 LB-110. doi:1538-7445.AM2012-LB-110
Abstract LB-113: Non-invasive analysis of drug sensitivity in homo and-heterotypic multicellular tumor spheroids
Authors: Drewitz Maren , Salomon Michael , Thirion Christian , Oberdanner Christian , Kelm Jens M. 
Published: August 2012

Abstract
To gain full benefit of more organotypic tumor culture systems, appropriate assays which enable high-throughput analysis over time without destroying the tissues have to be adopted. Especially read outs for co-culture systems which allow the discrimination of a drug effect on the cancer cell and stroma environment will be of advantage to foster drug testing using more complex 3D models. Here we report the development of microtissue models harboring either fluorescent and/or Luciferase for non-invasive drug sensitivity testing of homotypic and heterotypic tumor spheroids. Microtissues were assayed in microtissue assay plate which allows for biochemical assays and quantitative fluorescence of single multicellular tumor spheroids. Both the fluorescent and secreted luciferase reporter can be measured over time without destroying the tissue allowing for additional end point analysis of interest. HCT116, a colon cancer cell line, was transduced with the reporter genes under the control of a constitutive promoter. To assess the dependency of the fluorescence intensity in accordance to microtissue growth, HCT116-GFP microtissues were assayed over time in a multiplate fluorescence reader. The size profile correlated closely to the increase in fluorescence intensity. For further assay validation the IC50 value were determined by intra-tissue lactate dehydrogenase (LDH) and fluorescence decrease after 72h compound incubation. Reference compounds such as Taxol, Staurosprin and Chlorambucil were tested. The IC50 values from both assays resulted in comparable IC50 values. For non-invasive drug sensitivity testing in heterogenic tumor microtissues HCT116 harboring a secreted Luciferase were combined with a red fluorescent mouse fibroblasts (NIH3T3). Assaying Luciferase on the one hand and red fluorescence intensity on the other allowed discriminating effects on cancer cells and the non-proliferative. Discrimination between specific effects of drug treatment on tumor cells and fibrobast matrix cells is also possible using a two color heterotypic cell model composed of GFP-expressing HTC116 and RFP expressing NIH3T3 cells. Cytotoxic agents targeting either the total cell population or only proliferative cells were tested on the model discriminating the biological response on the two cell populations. To enable the implementation of organotypic cell culture systems at an early time point in the drug development process non-invasive assays. Here, we demonstrate for the first time such a dual cell tumor microtissues system with integrated reporter functions which allows to distinguish effects on different cell populations.
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 LB-113. doi:1538-7445.AM2012-LB-113
Abstract LB-153: The helicase antigen (HAGE) promotes tumor cell proliferation via up-regulation of Ras protein signalling.
Authors: McArdle Stephanie E.B. , Linley Adam A.J , Mathieu Morgan M.G , Miles Amanda A.K , Regad Tarik , Rees Robert C. 
Published: August 2012

Abstract
The discovery of cancer/testis (CT) antigens heralded a resurgence in interest in cancer immunotherapy. However, to date, therapy designed to target CT antigens in a variety of different tumours has had limited success and the function of these antigens remains for many still not completely understood. We believe that a better understanding of what possible processes CT antigens are involved in would help in the creation of additional treatment methods. The helicase antigen (HAGE) in a non-X-linked CT antigen shown to be expressed by a variety of tumours including melanoma, head and neck carcinoma and haematological cancers. It is classified as belonging to the DEAD-box family of RNA helicases, which are predicted to have roles in RNA metabolism including transcription, splicing, ribosome biogenesis and translation. These, along with tumour-restricted expression imply a definitive role in malignant cells. Here, we present data that strongly suggests a role for HAGE in promoting tumour cell line proliferation via increased Akt and Erk activation by increasing Ras protein expression. This work was funded by the John and Lucille van Geest Foundation.
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 LB-153. doi:1538-7445.AM2012-LB-153
Abstract LB-156: The role of AKR1B10 in early tumorigenesis depends on AMP-activated protein Kinase-α checkpoint
Authors: Ma Jun , Cao Deliang 
Published: August 2012

Abstract
The role of AKR1B10 in early tumorigenesis depends on AMP-activated protein Kinase-α checkpoint Jun Ma and Deliang Cao 1Department of Medical Microbiology, Immunology, & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine. 913 N. Rutledge Street, Springfield, IL 62794. Aldo-keto reductase 1B10 (AKR1B10) is upregulated in 71.4% ductal carcinoma in situ (DCIS) and 83.6% invasive breast cancer. Furthermore, AKR1B10 expression is correlated significantly with tumor size, node status and disease-related survival. In malignant cells, AKR1B10 promotes cell growth and survival via provoking cellular lipid synthesis and eliminating cytotoxic α, β-unsaturated carbonyl compounds. Therefore, AKR1B10 may play an oncogenic role in tumor growth and progression. This study is aimed to explore the role of AKR1B10 in early tumorigenesis. Interestingly, our data show that the expression of AKR1B10 in MCF10A cell, a normal breast epithelium cell line, led to elevation of p53 levels and premature senescence. However, in RAO-1 cells, an hTERT-immortalized breast epithelium cell line, AKR1B10 expression promoted glucose uptake, glycolysis and fatty acid synthesis, and subsequent cell growth instead. Further studies revealed that AMP-activated protein kinase-alpha (AMPKα), which is an important metabolic barrier during cell transformation, was activated upon AKR1B10 expression in both cell lines. On the other hand, down-regulation of AMPKα by shRNA rescued AKR1B10-induced senescence in MCF10A while partially abrogated pro-metabolism effect of AKR1B10 in RAO-1 cells and caused cell growth inhibition. In summary, the role of AKR1B10 in early tumorigenesis depended on AMPKα checkpoint. When this checkpoint is intact, AKR1B10 activates AMPKα and triggers p53 activation and consequential cellular senescence. On the contrary, when this checkpoint is dysfunctional, such as in cells with constitutive expression of telomerase, AKR1B10 activates AMPKα, enhances glucose and lipid metabolism and promotes cell proliferation.
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 LB-156. doi:1538-7445.AM2012-LB-156
Abstract LB-164: IDH mutations and tumorgenicity
Authors: Yen Kate , Wang Fang , Choe Sung , Schalm Stefanie , Hansen Erica , Straley Kimberly , Popovici-Muller Janeta , Travins Jeremy , Yang Hua , Silverman Lee , Kaelin William , Gross Stefan , Dang Lenny , Salituro Frank , Saunders Jeff , Schenkein David , Su Michael , Biller Scott 
Published: August 2012

Abstract
IDH mutations and tumorgenicity Kate Yen1, Fang Wang1, Sung Choe1, Stefanie Schalm1, Erica Hansen1, Kimberly Straley1, Janeta Popovici-Muller1, Jeremy Travins1, Hua Yang1, Lee Silverman1, William Kaelin2, Stefan Gross1, Lenny Dang1, Frank Salituro1, Jeff Saunders1, David Schenkein1, Michael Su1, Scott Biller1 Mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes are present in ∼16% of acute myeloid leukemia, and these mutations cause neomorphic enzyme activity that results in the production of 2-hydroxyglutarate (2HG). Mutational and epigenetic profiling of a large patient cohort of acute myeloid leukemia (AML) revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. To further investigate the intrinsic effect of 2HG on hematopoietic differentiation, we studied erythroleukemia cell lines transfected with IDH1 and IDH2 mutant alleles which overexpress the mutant enzyme, have high levels of 2HG, and exhibit GM-CSF independent growth. Further investigation showed that GATA1, a transcriptional factor known to direct myeloid differentiation, is also down-regulated by IDH2m in these cells along with its downstream direct target SLC4A1. These results demonstrate that the IDH2m can perturb the expression of transcription factors that could lead to alterations in myeloid differentiation. These data suggest that an inhibitor of IDH1/2 mutations could correct for the altered gene expression patterns seen in IDH1/2 mutant AML tumors leading to a profound effect on hematopoietic differentiation, proliferation and tumor growth. We are currently studying the global effects of IDH1/2 mutant overexpression on the methylation of histones and DNA to have a broader understanding of the biological consequence of the IDH1/2 gain of function mutations. Furthermore, treatment of these cell lines with compounds specific for either IDH1 or IDH2 mutant enzymes has a profound effect on their biology.
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 LB-164. doi:1538-7445.AM2012-LB-164
Abstract LB-17: NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma
Authors: Yamaguchi Tomoya , Yanagisawa Kiyoshi , Sugiyama Ryoji , Hosono Yasuyuki , Shimada Yukako , Arima Chinatsu , Kato Seiichi , Tomida Shuta , Suzuki Motoshi , Osada Hirotaka , Takahashi Takashi 
Published: August 2012

Abstract
Emerging evidence, though currently sparse, suggests that “lineage-specific transcription factors” with developmental roles in normal progenitor cells of particular lineages may also confer dependency for survival to certain types of cancer cells. Accumulated evidence indicates that NKX2-1, a lineage-specific transcription factor also known as TITF1 and TTF-1, which is expressed in a major fraction of lung adenocarcinomas, plays essential roles in peripheral lung development. We previously identified NKX2-1 as a lineage-survival oncogene in lung adenocarcinoma, while other investigators reached similar conclusions through genome-wide searches for focal genomic aberrations. Previous findings including ours thus clearly indicate the requirement of sustained NKX2-1 expression for lung adenocarcinoma survival, while it remains elusive how NKX2-1 mediates survival signals. In the present study, we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and proapoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation. Interestingly, ROR1 was also identified as a receptor tyrosine kinase with a “sustainer role” for the interaction of EGFR-ERBB3 and ERBB3 phosphorylation in a ROR1 kinase-independent manner, consequentially leading to PI3K activation. It was also of note that ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Secondary EGFR mutation, MET amplification, and HGF overexpression may arise in lung adenocarcinomas in patients undergoing EGFR-TKI treatment, leading to treatment resistance. The existence of such diverse mechanisms makes it difficult to predict which should be targeted to prevent expansion of resistant clones. From a clinical point of view, it is thus of particular interest that ROR1 inhibition appears to be effective for treatment of gefitinib-resistant lung adenocarcinomas with various resistance mechanisms. Taken together, the present findings identify ROR1 as an “Achilles’ heel” in lung adenocarcinomas. Future development of novel therapeutic means including ROR1-specific antibodies and small molecules that inhibit both or either of the two distinct prosurvival signal-sustaining functions is greatly anticipated for attempts to reduce the intolerable death toll from currently “hard-to-cure” lung adenocarcinomas.
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 LB-17. doi:1538-7445.AM2012-LB-17
Abstract LB-173: Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model
Authors: Ochoa-Callejero Laura , Pérez-Martínez Laura , Rubio-Mediavilla Susana , Oteo José A. , Martínez Alfredo , Blanco José R. 
Published: August 2012

Abstract
Chronic liver disease caused by infections or dietary toxins may result in liver fibrosis, cirrhosis and, eventually, hepatocellular carcinoma (HCC). The only curative treatments for patients with advanced liver disease are partial surgical resection and liver transplantation. However, organ shortage as well as an increasing organ demand call for early treatment of liver disease and prevention of fibrosis on high risk individuals. Stellate cells of the liver seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. This diet was deficient in choline and was supplemented with ethionine in the drinking water (CDE diet). Animals receiving the CDE diet presented higher mortality, higher levels of markers for liver injury such as transaminases, alkaline phosphatase, and bilirubin, developed severe hepatic fibrosis, and were affected by numerous tumors by week 16, when compared with control mice receiving a regular diet. In addition, many cytokines, chemokines, and other matrix components including CCL2, CCL3, CCL4, CCL5, CCR5, CXCL10, IL-12, TGF-b1, or MMP9, were elevated by the CDE diet. Animals which received the CDE diet but were simultaneously treated with MVC presented significantly higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. Animals treated with MVC on top of a normal control diet did not show any evidence of toxicity or any morphological change when compared with non-treated mice. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing 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 LB-173. doi:1538-7445.AM2012-LB-173
Abstract LB-182: Effects of methyl donor status on intestinal tumorigenesis in ApcMin/+ mice
Authors: Kadaveru Krishna , Protiva Petr , Greenspan Emily J. , Kim Young-In , Rosenberg Daniel W. 
Published: August 2012

Abstract
The goal of the present study is to determine the effects of folate deficiency on intestinal tumorigenesis in ApcMin/+ mice, a widely used animal model for human familial adenomatous polyposis (FAP). Since folate plays an important role in maintaining methyl donor status, dietary folate levels were reduced in combination with a panel of methyl donors, including choline, methionine and vitamin B12. Although the impact of folate on colorectal cancer (CRC) has been studied extensively, its role in cancer chemoprevention remains controversial. For example, folate supplementation has been widely discussed as a strategy for lowering cancer incidence. However, excess folate has also been associated with increased cancer risk. The following studies were designed to evaluate the effects of folate deficiency on intestinal tumorigenesis in ApcMin/+ mice. In Study 1, methyl donor sufficient diet (MDS) and methyl donor deficient diet (MDD) were fed to mice, beginning at either 5 or 10 weeks of age. Intestinal tumors were evaluated at 16 weeks of age. MDD diet suppressed intestinal tumor formation in ApcMin/+ mice by ∼80% when started at 5 weeks of age. Importantly, the protective effect was lost when the MDD diet was started at 10 weeks of age, indicating an important time-dependency on cancer suppression. Gene expression profiling of normal colonic mucosa after 11 weeks on MDD diet identified the most significantly down-regulated genes related to immune response and inflammation, data that are consistent with a recently published human colon expression profiling study (Protiva et al., 2011). The cancer suppression, however, was associated with reduced food intake and lowered body weight gain (up to 40%) throughout the experimental period. To control for this effect, Study 2 was performed in which ApcMin/+ mice were pair-fed with either methyl donor sufficient (MDS) or methyl donor deficient (MDD) diet, beginning at 5 weeks of age for a total of 11 weeks. A third group received MDS ad libitum. At 16 weeks of age, intestinal tumor formation was significantly reduced (54%, p&lt;0.001) in the caloric-restricted MDS group. In the MDD group, however, tumor suppression was almost complete (∼96%, p&lt;0.001). Associated with tumor protection were increased numbers of apoptotic cells within the villous epithelium of the small intestine, with a concomitant reduction in cell proliferation assessed by Ki-67 and Phospho-histone H3 (pHH3). While cancer protection by methyl donor deficiency is partially dependent on reduced caloric intake, additional mechanisms dependent on altered cell turnover must be invoked to explain these results.
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 LB-182. doi:1538-7445.AM2012-LB-182
Abstract LB-183: Identification of anti-cancer activity in structural components of ancestral wheat
Authors: Matthews Shawna B. , Santra Meenakshi , Jiang Weiqin , Zhu Zongjian , Thompson Henry J. 
Published: August 2012

Abstract
In 2009 the average American consumed 134.9 lbs of wheat, making this staple crop a primary source of calories, fiber, and nutrients in the human diet; however little is known about the anti-cancer activity of small molecules present in wheat. In this study, more than 75 wild and less domesticated wheat varieties were extracted using a modified Bligh Dyer technique for in vitro screening. Dried extracts were dissolved in DMSO, diluted with cell culture medium, and evaluated for anticancer activity against MDA-MB-468 (ER- & PR-) and T47D (ER+ & PR+) human breast cancer cell lines in 96-well plate format as assessed by crystal violet staining. The results showed that diploid species of Middle Eastern origin, where human cultivation of wheat began 9000 years ago, have a remarkable ability to inhibit the proliferation of breast cancer cells compared to the domesticated species of tetraploid and hexaploid wheat, which have little or no effect. Furthermore, this anti-cancer activity resides exclusively in the straw-like fibrous hull surrounding the wheat seed, which is not consumed by humans. Principal components analysis of wheat metabolites, analyzed via UPLC-TOF-MS, demonstrated that wheat varieties capable of inhibiting the growth of human breast cancer cells in vitro are chemically distinct from the varieties that do not have inhibitory capability, suggesting that small molecules may be associated with the inhibitory effect. Taken together, these data suggest that ancestral diploid wheat, which is now rarely grown and even more rarely consumed, may possess significant anti-cancer potential in the hulls, and that this anti-cancer potential is an opportunity for advancement of breast cancer prevention through identification of bioactive components and wheat varieties. This work was supported by a grant from the Colorado Wheat Research Foundation.
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 LB-183. doi:1538-7445.AM2012-LB-183