bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B43: A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy.
Authors: Zhang Lianhai , Yang Jie , Chen Yiyou , Cai Jie , Song Xiaoming , Huang Xuesong , Deng Jianyun , Chen Dawei , Yang Mengmeng , Li Shuangxi , Wu Aiwen , Li Ziyu , Li Zhongwu , Liu Yiqian , Wery Jean-Pierre , Li Henry , Ji Jiafu 
Published: August 2014

Abstract
Gastric carcinoma (GC) is a common cancer of high mortality and particularly prevalent in East Asia. There are only a few treatment options: surgery, chemotherapy, as well as Herceptin® for a small subset of patients with erbb2 amplification. Cetuximab has been approved for CRC (colorectal) and SCCHN, but not yet for gastric carcinoma. Cetuximab, combined with capecitabine/cisplatin, has recently been tested in Phase III clinical trial (EXPAND) in GC patients (1), but failed to demonstrate benefit over the existing chemotherapy (capecitabine/cisplatin). One of the reasons for the failure is only small subset of patients responding to cetuximab, which constitutes little effects on large trial populations, while the identity of the responders yet to be revealed. One of the keys to a successful search for effective treatment is the development of experimental model that truly mimics patient conditions. Patient derived xenograft (PDX or HuPrime®) is believed to best mimic human cancers (2). Recently, we have established a cohort of ∼70 GC xenograft (PDX) models from Asian and Caucasian patients. In the present study, we conducted a mouse clinical trial (MCT, or PDX trial) to test cetuximab in a cohort of GC-PDX, aiming at identifying those responsive to cetuximab. Interestingly, our trial result identified 4 of 20 (20%) GC-PDX responded to cetuximab. Genome-wide profiling and additional investigations revealed that high EGFR mRNA expression and immunohistochemistry score (3+) are associated with tumor growth inhibition. Furthermore, EGFR amplification were observed in 4/4 (50%) responders by DNAchip analysis or 2/4 confirmed with FISH analysis, with average copy number 5.8 and &gt;15 respectively. Our data suggest that a GC subtype with EGFR amplification and overexpression benefit from cetuximab treatment.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B43.
Citation Format: Lianhai Zhang, Jie Yang, Yiyou Chen, Jie Cai, Xiaoming Song, Xuesong Huang, Jianyun Deng, Dawei Chen, Mengmeng Yang, Shuangxi Li, Aiwen Wu, Ziyu Li, Zhongwu Li, Yiqian Liu, Jean-Pierre Wery, Henry Li, Jiafu Ji. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B43.
Abstract B54: Role and underlying mechanism of Runx3-Lgr5 in colon cancer cell lines.
Authors: Kim Bo Ram , Kang Myoung Hee , Kim Jun Suk , Oh Sang Cheul 
Published: August 2014

Abstract
The cancer stem cells (CSCs) are thought to be responsible for recurrence and drug resistance after chemotherapy. CSCs markers are mostly studied in breast cancer and other cancers but study of CSCs marker is insufficient in GI cancers. LGR5 (Leucine-rich-repeat-containing G protein-coupled receptor5) is Wnt target gene that marks dividing stem cells such as hair follicle, intestine and stomach. Recently, the various evidences suggest LGR5 as cancer stem cell marker in colon cancer. However, its function and mechanism remain unclear. RUNX3(runt[[Unable to Display Character: &#8209;]]related transcription factor 3) is known as tumor suppressor gene in gastrointestinal epithelium. It is reported that loss of RUNX3 induces EMT, makes stem cell like subpopulation and reveals remarkable LGR5. But It is unclear whether upregulation of LGR5 influences tumorigenesis in colon CSC. Here we found that LGR5 is down-regulated when RUNX3 endogenously expressed whereas LGR5 is up-regulated when RUNX3 don't endogenously expressed in colon cancer. So, we confirm that overexpression of RUNX3 decrease proteinexpression of epithelial-mesenchymal transition(EMT) markers by western blotting and mRNA expression of LGR5, SOX2, OCT4, and NANOG by Real Time-PCR. We knockdown RUNX3 by siRNA in colon cancer cells that endogenously expressed RUNX3. The siRNA increases expression of LGR5. We performed colonosphere culture to measure size and number. Overexpression of RUNX3 decreases size, number and CSCs marker level whereas, knockdown of RUNX3 increases size, number and CSCs marker level in colonosphere formation.
These studies suggest that role of Lgr5 as colon cancer stem cell marker and Runx3 known as tumor suppressor gene and aim to identify the mechanism of the metastasis of colon cancer and recurrence with Lgr5 and RUNX3.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B54.
Citation Format: Bo Ram Kim, Myoung Hee Kang, Jun Suk Kim, Sang Cheul Oh. Role and underlying mechanism of Runx3-Lgr5 in colon cancer cell lines. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B54.
Abstract B60: FUCCI cell cycle imaging identifies drug-resistant quiescent cancer cells within tumors.
Authors: Yano Shuya , Tome Yasunori , Zhang Yong , Miwa Shinji , Suetsugu Atsushi , Kishimoto Hiroyuki , Tazawa Hiroshi , Bouvet Michael , Fujiwara Toshiyoshi , Hoffman Robert M. 
Published: August 2014

Abstract
Fluorescence ubiquitination cell cycle indicator (FUCCI) imaging was used to identify the cell cycle phase of cancer cells in small and large tumors. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor were in G0/G1 and 70% were in S/G2/M. In contrast in a large tumor, approximately 90% of cancer cells were in G0/G1 phase. Similarly, approximately 75% of cancer cells far from (&gt;100 µm) tumor blood vessels were in G0/G1. Longitudinal real-time imaging demonstrated that cytotoxic drugs used in the clinic killed only proliferating cancer cells at the surface of the tumors and, in contrast, had little effect on quiescent cancer cells that are the vast majority of an established tumor. These results demonstrate why solid tumors are usually drug resistant in the clinic. The results also suggest that drugs that target quiescent cancer cells are urgently needed.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B60.
Citation Format: Shuya Yano, Yasunori Tome, Yong Zhang, Shinji Miwa, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman. FUCCI cell cycle imaging identifies drug-resistant quiescent cancer cells within tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B60.
Abstract B71: DNA damage responses to cisplatin and dicycloplatin, a new platinum analog.
Authors: Yu Jing Jie , Yang Xuqing , Song Qinhua , Mueller Michael D. , Remick Scot C. 
Published: August 2014

Abstract
Background: Dicycloplatin (DCP), a new platinum compound approved by the Chinese FDA in March of 2012, shows better water solubility, greater stability, and lower toxicity, compared to cisplatin and carboplatin. Preclinical in vitro and in vivo studies and a Phase I clinical trial demonstrated that DCP possesses strong antitumor activity and lower adverse events than carboplatin. Phase II clinical trials using dicycloplatin plus paclitaxel in chemotherapy-naïve patients with advanced NSCLC found that efficacy and safety of DCP plus paclitaxel regimen were comparable to those of carboplatin plus paclitaxel regimen, with slightly better tolerance. Materials and Methods: Pharmacokinetic study of DCP characteristics was conducted using AP-4000TM LC-MS/MS System in patient blood samples. Molecular mechanism studies of dicycloplatin-induced gene-signature profiling were determined by Immunoblotting and compared to cisplatin profiling in human ovarian cancer cells. Results: Pharmacokinetic mass spectrometry shows different spectrums of dicycloplatin and of carboplatin in plasma. Two hours after administration, plasma concentration of dicycloplatin prototype is still high (17.1 μg/ml), following a peak concentration of 26.9 µg/ml at 0.5-h. Molecular mechanism investigation showed DCP-induced activation of several kinases including phosphorylations of Chk2 at threonine 68, p53 at serine 15 and BRCA1 at serine 1497. The increases in p-Chk2 and p-BRCA1 showed that the amount of DCP-induced phosphorylation doubled at 48-h and tripled for p-p53 at 24-h, compared to controls. Conclusion: Dicycloplatin appears to activate DNA damage-repair pathways through mechanisms similar to cisplatin.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B71.
Citation Format: Jing Jie Yu, Xuqing Yang, Qinhua Song, Michael D. Mueller, Scot C. Remick. DNA damage responses to cisplatin and dicycloplatin, a new platinum analog. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B71.
Abstract C105: Development and utilization of a cell morphology database, MorphoBase, for drug target identification.
Authors: Futamura Yushi , Kawatani Makoto , Muroi Makoto , Aono Harumi , Osada Hiroyuki 
Published: August 2014

Abstract
Background: Tumor cells often dynamically and specifically change shape depending on the mode of action of a drug. It prompted us to accumulate information on morphological changes induced by various compounds with known mechanisms and construct a database linking morphology to drug function, termed “MorphoBase,” which may be helpful in the target identification of a drug and the discovery of unique bioactive compounds.
Material and Methods: We designed a high-content imaging algorithm to segment the cells and quantify the effects of various authentic compounds on morphological changes in 2 cancer cell lines, srcts-NRK and HeLa cells, against 12 morphological parameters. We also developed a data analysis program that incorporated multivariate statistical tools to analyze the similarities in morphological changes; principal component analysis (PCA) was applied to visualize phenotypic responses, and the similarities in morphological changes were ranked by 2 statistical computations: “Similarity ranking” determined by Euclidean distances and “Probability scores.”
Results: A test set of 208 authentic compounds was created and their multiparametric phenotype responses were analyzed. As a result, inhibitors with a common mode of action formed clusters in PCA and were mutually ranked in their top 20 nearest neighbors, suggesting that MorphoBase can be used to successfully profile phenotypes by drug function. The importance of this database was verified by establishing the molecular targets of three antimitotic drugs and a new cytotoxic fungal metabolite pyrrolizilactone. When compared the similarity in induction of each morphologic feature with those in the dataset, their molecular targets were predicted to be tubulin and proteasome, respectively. We thus demonstrated that these compounds actually inhibit plausible targets in vitro and in a cell-based system.
Conclusions: As an alternative to current high-content approaches, we developed a phenotype profiling system, based on MorphoBase. Our new system classifies the compounds by mode of action and predicts the molecular target of compounds with unknown mechanisms. This sensitive and convenient profiling tool has the potential to significantly cut the time it takes to establish on- and off-target effects of novel anticancer drugs, and will facilitate the discovery of bioactive compounds with unique mechanisms of action as well.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C105.
Citation Format: Yushi Futamura, Makoto Kawatani, Makoto Muroi, Harumi Aono, Hiroyuki Osada. Development and utilization of a cell morphology database, MorphoBase, for drug target identification. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C105.
Abstract C107: Isolation and characterization of human breast epithelial cells.
Authors: Hoynowski Steven 
Published: August 2014

Abstract
Breast cancer is one of the most common cancers among women in the United States and it is the second leading cause of cancer deaths in this population. Roughly 232,000 women in the U.S. were diagnosed with malignant breast cancer in 2013 and approximately 40,000 of these patients will die. The majority of breast cancers originate in the lobular or ductal cells of the milk-producing glands. In these structures, there are two main cell types: the inner luminal cells, which are surrounded by basal myoepithelium. These cells are structurally distinct and are the precursors to variable forms of breast cancer. As such, it is important to study them not only separately but also together. Current methods for culturing human mammary epithelial cells select for those of a basal phenotype. Isolation of pure basal and luminal cell populations was accomplished by using antibody-linked magnetic beads to isolate essentially pure populations of both basal (CALLA/CD10) and luminal mammary (MUC1/CD227) epithelial cells from organoid explant cultures. Organoids were isolated and plated on collagen I coated flasks in either DFCI (basal) or MBCM (luminal) media and cultured at 37°C in 5% CO2 to induce cell migration. The media was replenished every 2 - 3 days until the cells reached confluence. Cultured cells were harvested and immunopurified using a CALLA/CD10 or MUC1/CD227 antibody and magnetic beads. Positively selected cells were seeded in tissue culture treated flasks and propagated with medium exchange every 2 - 3 days. Each cell population was analyzed using flow cytometry to determine their purity. The DFCI/CD10 cells were over 98% CD10 positive with very little MUC1 reactivity, suggesting that they are an essentially pure basal epithelial cell population. The cells isolated using MBCM/MUC1 appear to be a mixed population with 86% MUC1 positive luminal cells and the remainder being CD10 positive basal cells. A second round of immunopurification resulted in an isolated cell population that was greater than 95% MUC1 positive, suggesting a pure luminal epithelial cell population. This procedure has been used on several organoid preparations and has generated high cell yields in addition to high cell purity. These isolated cell types can now be tested individually for drug sensitivity.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C107.
Citation Format: Steven Hoynowski. Isolation and characterization of human breast epithelial cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C107.
Abstract C12: Beta-catenin enhances synovial sarcomagenesis and provides a therapeutic target.
Authors: Jones Kevin B. , Illum Benjamin , Jin Huifeng , Zhu Mu Julie , Monument Michael , Grossmann Allie , Capecchi Mario R. 
Published: August 2014

Abstract
β-catenin is a master regulator in the cellular biology of development and neoplasia. Its dysregulation is implicated as a driver of colorectal carcinogenesis and the epithelial-mesenchymal transition in other cancers. Nuclear β-catenin is known to be a poor prognostic sign in synovial sarcoma, the most common soft-tissue sarcoma in adolescents and young adults. Beyond this prognostic correlation, the biology of β-catenin's role in synovial sarcoma has not been explored. We show through genetic experiments in mice demonstrate that loss of β-catenin hampers SS18-SSX2-driven synovial sarcomagenesis. Expression of a stabilized form of β-catenin greatly enhances synovial sarcomagenesis. Stabilization of β-catenin specifically enables transformation under the influence of the SS18-SSX2 fusion oncogene by blocking differentiation and apoptosis. As part of the mechanism of this impact, β-catenin recruits BRG1-containing SWI/SNF chromatin remodeling complexes to activated target genes. Compounds disrupting the transcriptional activity of β-catenin are toxic to human and mouse synovial sarcoma cell lines.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C12.
Citation Format: Kevin B. Jones, Benjamin Illum, Huifeng Jin, Julie Zhu Mu, Michael Monument, Allie Grossmann, Mario R. Capecchi. Beta-catenin enhances synovial sarcomagenesis and provides a therapeutic target. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C12.
Abstract C123: Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability.
Authors: An Changhyeok , Kim Min Sung , Lee Jae Im , Yoo Nam Jin , Lee Sug Hyung 
Published: August 2014

Abstract
Background: Cohesin is a protein complex that regulates chromatid cohesion and plays roles in preventing aneuploidy and maintaining chromosomal stability. SGOL1 encodes a cohesin protector and PDS5B encodes a regulatory cohesion factor. Both SGOL1 and PDS5B are considered putative tumor suppressor genes.
Purpose: Aim of this study was to explore whether SGOL1 and PDS5B genes are mutated and expressionally altered in gastric (GC) and colorectal cancers (CRC).
Method: In a database, we found that both genes possessed mononucleotide repeats in coding sequences that could be mutation targets in cancers with microsatellite instability (MSI). We analyzed mutations in them in 91 GC and 100 CRC with high MSI (MSI-H) or stable MSI/low MSI (MSS/MSI-L) by single-strand conformation polymorphism analysis and DNA sequencing. We also analyzed SGOL1 and PDS5B expressions in the GC and CRC by immunohistochemistry.
Results: Overall, we found 21 SGOL1 frameshift mutations in 21 cancers and 18 PDS5B frameshift mutations in 16 cancers. SGOL1 and PDS5B frameshift mutation were detected in 26.6% and 20.3% of MSI-H respectively, but not in MSS/MSI-L (0/112). In immunohistochemistry, losses of SGOL1 and PDS5B were identified in 19 - 47% of the GC and CRC irrespective of MSI status. The losses were more common in those with the frameshift mutations or MSI-H than those without the mutations or MSI-H.
Conclusion: The data indicate that frameshift mutations of SGOL1 and PDS5B, and their losses may be a feature of GC and CRC with MSI-H. Also, the data suggest that these alterations might contribute to cancer pathogenesis by deregulating cohesin-related functions.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C123.
Citation Format: Changhyeok An, Min Sung Kim, Jae Im Lee, Nam Jin Yoo, Sug Hyung Lee. Frameshift mutations of chromosome cohesion-related genes SGOL1 and PDS5B in gastric and colorectal cancers with high microsatellite instability. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C123.
Abstract C131: HSP27 is necessary in cells showing oncogene hyper-activation.
Authors: Konda Johndavid , Olivero Martina , Musiani Daniele , Lamba Simona , Bardelli Alberto , Di Nicolantonio Federica , Di Renzo Maria Flavia 
Published: August 2014

Abstract
The small heat shock protein of 27 KDa (HSP27) encoded by the HSPB1 gene, is a molecular chaperone with anti-aggregation property, it participates in sequestering damaged proteins, and is involved in the proteasomal degradation of certain proteins under stress conditions. Besides its role in stressed condition, HSP27 plays crucial roles within the cell under unstressed conditions and it provides cytoskeletal structural stability and exerts important anti-apoptotic function by binding apoptotic proteins. Clinically, Hsp27 is highly expressed in many cancers including breast, ovarian and prostate carcinomas and is associated with aggressive tumor behaviour, metastasis, poor prognosis and resistance to chemotherapeutics. Using LV driven expression of HSP27 specific shRNA, HSP27 suppression in three gastric cancer cell lines (GTL-16, MKN-45 and EBC-1) showing addiction to MET because of MET gene amplification was able to induce cell death. Moreover, HSP27 silencing synergized in inducing apoptosis with the MET inhibitor JNJ-38877605, which alone was only able to induce cell cycle blockade. Similarly, (H3255) lung carcinoma and (DiFi) colorectal carcinoma cell lines which carry EGFR amplification and are susceptible to EGFR inhibition were exquisitely susceptible to HSP27 silencing, that induced cell death. HSP27 silenced in twenty human colorectal (CRC) cell lines with either wt KRAS or harbouring KRAS mutations (SW620, LS513, LS1034) or BRAF mutations (OXCO-1, COLO741, COLO-201, COLO-205), Among them the LS513 and LS1034 cells and the COLO-201 and COLO-205, addicted to KRAS and BRAF, respectively, came out to be also addicted to HSP27, as they undergo apoptosis by HSP27 silencing. Taken together, these data suggest that cells addicted to oncogene over-activation require HSP27 for survival and that HSP27 interferes with the effectiveness of targeted agents. Due to its involvement in cancer development, the inhibition of HSP27 has been proposed as a potential cancer treatment strategy. Antisense and peptide aptamer strategies have shown that targeting HSP27 increases cancer cell death in vitro and in vivo in preclinical models. More important, an antisense drug inhibiting HSP27 is available for human therapy and is ongoing Phase II clinical trials. Therefore, HSP27 knockdown in combination with targeted therapies can be envisaged as a viable therapeutic approach for clinical application.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C131.
Citation Format: Johndavid Konda, Martina Olivero, Daniele Musiani, Simona Lamba, Alberto Bardelli, Federica Di Nicolantonio, Maria Flavia Di Renzo. HSP27 is necessary in cells showing oncogene hyper-activation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C131.