bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5158: Generation of a fully human Gas6 neutralizing antibody with anti-tumor activity in vivo.
Authors: Moody Gordon E. , Belmontes Brian , King Chadwick , Liu Shuying , Masterman Stephanie , Murawsky Chris , Tsuruda Trace , Wang Wei , Radinsky Robert , Beltran Pedro J. 
Published: August 2014

Abstract
Growth arrest specific 6 (Gas6) is a vitamin-K dependent protein that is involved in the regulation of a wide array of cellular activities, including adhesion, migration, immune evasion, and apoptosis. Gas6 as well as its receptors Axl, Mer, and Tyro3 are highly expressed in multiple malignancies suggesting that signaling through this axis may be tumor promoting in human disease. A strategy was devised to generate fully human neutralizing antibodies against Gas6 using XenoMouse technology. Hybridoma supernatants were first screened for their ability to bind Gas6, then for their ability to inhibit Gas6 binding to the Axl receptor and block Gas6-induced Axl phosphorylation in human cells. Two purified antibodies isolated from the screened hybridomas, 1D9.1 and 1G9.1, maintained potency in all 3 assays and also inhibited Gas6-induced cellular migration and proliferation. In the scratch wound migration assay, the antibodies inhibited both basal and Gas6-induced wound closure to a greater extent than the soluble extracellular domain of the receptor Axl (Axl- Fc). In the proliferation assay, the antibody 1D9.1 completely inhibited Gas6-induced proliferation with a half maximal effective concentration (EC50) of 0.15nM. In vivo characterization of one of the antibodies, 1D9.1, was conducted using a pharmacodynamic (PD) assay that measured the ability of the antibody to inhibit Gas6-induced Akt activation in the mouse spleen. Treatment of mice with a single dose (100-1000 μg) of 1D9.1 led to greater than 90% inhibition of Gas6-induced phosphorylated Akt (pAkt) for up to 72 hours. Based on the target coverage observed in the PD assay, we tested the efficacy of 1D9.1 against Panc-1 human pancreatic adenocarcinoma xenografts implanted in athymic nu/nu female mice. At doses of 50 and 150 μg, twice weekly, the Gas6 neutralizing antibody 1D9.1 was able to inhibit 55% and 76% of tumor growth, respectively. (p&lt;0.001 for both treatments vs. control Ig). When combined with gemcitabine, 1D9.1 was able to inhibit tumor growth to a greater extent than either agent alone (p&lt;0.001 vs. either monotherapy). Together, the data suggest that Gas6 neutralization should be further explored as a potential strategy for the treatment of pancreatic cancer.
Citation Format: Gordon E. Moody, Brian Belmontes, Chadwick King, Shuying Liu, Stephanie Masterman, Chris Murawsky, Trace Tsuruda, Wei Wang, Robert Radinsky, Pedro J. Beltran. Generation of a fully human Gas6 neutralizing antibody with anti-tumor activity in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5158. doi:10.1158/1538-7445.AM2013-5158
Abstract 516: VDR overexpression restores tamoxifen responsiveness.
Authors: Louie Maggie C. , Laim Johnny 
Published: August 2014

Abstract
Breast cancer is classified as either Estrogen Receptor (ER) positive or ER negative, depending on the presence or absence of the ERα. Approximately, 70% of breast cancers express ERα, with tamoxifen being the most commonly used treatment. However, prolonged treatment often results in the development of acquired resistance, which has presented a major challenge in development of more effective therapeutics for breast cancer. While many studies have focused on understanding the mechanisms behind the development of tamoxifen resistance, few have been successfully implemented into clinical practice. To mimic acquired resistance, we have established a tamoxifen-resistant cell line by treating MCF-7 cells with tamoxifen over prolong period of time in order to select for the resistant phenotype. Our lab has preliminary data that suggest that the Vitamin D receptor (VDR) is downregulated in tamoxifen-resistant breast cancer cells (MCF-7TamR) when compared to the parental MCF-7 cells. The role of VDR in tamoxifen resistance is unclear; however our preliminary data suggest that tamoxifen resistant cells transfected with a VDR overexpression plasmid displayed decrease cell proliferation when treated with tamoxifen in comparison to cells transfected with an empty vector, suggesting that restoring VDR expression may restore tamoxifen responsiveness. Data from this study will give us a better understanding about the role of VDR in the development of acquired resistance.
Citation Format: Maggie C. Louie, Johnny Laim. VDR overexpression restores tamoxifen responsiveness. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 516. doi:10.1158/1538-7445.AM2013-516
Abstract 517: Ectopic expression of an obscurin signaling cassette decreases migration and invasion of metastatic breast cancer cells.
Authors: Perry Nicole A. , Kontrogianni-Konstantopoulos Aikaterini 
Published: August 2014

Abstract
The obscurins (∼70-820 kDa) are a family of proteins expressed from the 150 kb OBSCN gene, located on human chromosome 1. Sequencing analysis of breast and colorectal cancers, as well as melanoma and glioblastoma, revealed that obscurins are mutated at a substantial frequency and these mutations may be driving tumor formation. Our work has recently demonstrated that obscurins are present in normal breast, skin, and colon cells, but absent in their cancerous counterparts. Downregulation of obscurins’ expression is sufficient to allow non-tumorigenic breast epithelial cells to evade apoptosis induced by etoposide. Furthermore, absence of obscurins allows increased migration and invasion of breast epithelial cells. Remarkably though, we observed that ectopic expression of a fragment of obscurin composed of tandem src homology 3-Rho guanine exchange factor-pleckstrin homology (SH3-RhoGEF-PH) motifs was sufficient to decrease monolayer migration and invasion of metastatic breast cancer MDA-MB-231 cells, which are naturally deficient in obscurins, by &gt;20% and &gt;70%, respectively. Based on our observations that 1) absence of obscurins allows increased migration and invasion of breast cells, and 2) expression of an obscurin cassette mitigates this migratory and invasive behavior of metastatic breast cancer cells, we postulate that obscurins may act as metastasis suppressors in breast epithelium. We have therefore begun to investigate how the tripartite obscurin fragment, SH3-RhoGEF-PH, can influence the behavior of the cytoskeleton and therefore affect migration and invasion. We have found that the RhoGEF domain directly induces guanine nucleotide exchange in RhoA, but not Rac1 or Cdc42. This activity may be allosterically regulated by the adjacent SH3 domain, which interacts with the RhoGEF domain in a yeast two-hybrid assay. Furthermore, the PH domain binds to 3’-phosphorylated inositol lipid headgroups, providing a mechanism for the obscurins to respond to signals generated at the plasma membrane. Together, this evidence suggests that the tripartite signaling cassette can recapitulate the full-length obscurins’ metastasis-suppressing activity, and may merit development as a therapy for advanced breast cancer.
Citation Format: Nicole A. Perry, Aikaterini Kontrogianni-Konstantopoulos. Ectopic expression of an obscurin signaling cassette decreases migration and invasion of metastatic breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 517. doi:10.1158/1538-7445.AM2013-517
Abstract 5173: The circadian factor period 2 modulates p53 stability and function in downstream signaling.
Authors: Finkielstein Carla V. , Gotoh Tetsuya , Vila-Caballer Marian , santos carlo , liu jingjing , yang jianhua 
Published: August 2014

Abstract
The human Period 2 (hPer2) factor is a transcriptional regulator placed at the core of the circadian clock mechanism responsible for generating the negative feedback loop that sustains the clock. Its relevance to human diseases is underlined by alterations in its function that impacts many biochemical and physiological processes and, when absent, results in the development of various cancers. The tumor suppressor role of Per2 is speculated to involve transcriptional activation of p53, altered expression of cell cycle components, and regulation of the DNA-damage response pathway. However, it is entirely unclear how Per2 operates mechanistically. First, we identified hPer2 binds the C-terminus half of human p53 (hp53) and forms a stable trimeric complex with hp53’s negative regulator, the oncogenic protein Mdm2. Second, we determined that hPer2 binding to hp53 prevents Mdm2 from ubiquitinating and targeting hp53 by the proteasome. Accordingly, downregulation of hPer2 expression directly impacts hp53 levels whereas its overexpression influences both hp53 protein stability and transcription. Furthermore, we spatially define the distribution of the trimeric complex and determine the site for processing to be located in the nucleus. Third, we establish that hp53-mediated gene transcription is influenced by the presence of hPer2. Target genes such as 14-3-3σ, hp21WAF1/CIP1, and gadd45α show a synergistic increase in expression when hPer2 and hp53 are co-expressed in a hp53-deficient background. This result is the direct consequence of hPer2 dissociation of hp53 as result of checkpoint activation as shown by studies performed using a constitutively bound form of the hPer2/hp53 complex. Overall, our findings directly place hPer2 at the heart of the hp53-mediated response by modulating its stability and controlling its function.
Citation Format: Carla V. Finkielstein, Tetsuya Gotoh, Marian Vila-Caballer, carlo santos, jingjing liu, jianhua yang. The circadian factor period 2 modulates p53 stability and function in downstream signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5173. doi:10.1158/1538-7445.AM2013-5173
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5178: Smad7 is integrated mediator for the proteolysis of Myc.
Authors: Kang Jin-Muk , Hyun Ja-Shil , Lee Bona , Kim Ja-Kyung , Lee Ji-Hee , Kim Seong-Jin , Kim Tae-Aug 
Published: August 2014

Abstract
Myc, a pleiotropic transcription factor, plays a prominent role in human cancer progression. The regulation of Myc stability, therefore, is critical to understand the molecular mechanism of tumorigenesis in various cancers. Myc stability is tightly regulated by the activity of ubiqutin ligases, Skp2 and Fbw7. However, a key mediator of this process has not been addressed yet. Here, we have identified Smad7 as an intermediary regulating Myc stability by recruiting F-box protein, Skp2. Microarray analysis using the cell lines stably expressed Smad7, indicates that Smad7 markedly inhibits transcription of, c-myc-target genes including Id1, Id2, and Id3 without affecting c-myc gene expression. The expression of Myc protein, however, is down-regulated by induction of Smad7 in vitro, and in vivo, Smad7 transgene inducible system in primary epidermal keratinocyte. Conversely, the loss of Smad7 is implicated in the increase of endogenous Myc and Id2 expression, indicating that Smad7 is involved in post-translational regulation of Myc. Indeed, Smad7 ubiquitylates Myc through Smad7 PY motif, showing that mutation or deletion on PY motif diminishes the ubiquitylation of Myc. Treatment of proteasome inhibitor abates Smad7-mediated Myc degradation in HaCaT cell line that conditionally express level of human c-myc. Mapping of Smad7 interactions with Myc and Skp2 indicates that c-terminus, MH2 domain, of Smad7 binds to 3LRR/7LRR domain (aa142-390) of Skp2, and also interacts with Fbw7. Furthermore, intermediate domain (aa 162-236) of Myc has been identified to interact with c-terminus of Smad7. In the presence of Skp2 and Fbw7, Smad7 facilitated the degradation of Myc, thus impairing Myc stability. Smad7 also markedly represses Myc-mediated transcriptional activity and its target gene expression. These findings provide a new insight of Smad7 functions as a key mediator for the proteolysis of Myc proto-oncoprotein.
Citation Format: Jin-Muk Kang, Ja-Shil Hyun, Bona Lee, Ja-Kyung Kim, Ji-Hee Lee, Seong-Jin Kim, Tae-Aug Kim. Smad7 is integrated mediator for the proteolysis of Myc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5178. doi:10.1158/1538-7445.AM2013-5178
Abstract 5186: PPME1 is a potential novel molecular target in gastric and lung cancer.
Authors: Li Jing , Han Sufang , Qian Ziliang , Su Xinying , Fan Shuqiong , Fu Jiangang , Liu Charles , Yin Lucy , Gao Zeren , Zhu Guanshan , Zhang Jingchuan , Yu De-Hua , Ji Qunsheng 
Published: August 2014

Abstract
Protein phosphatase 2A (PP2A) is a human tumor suppressor, and it accounts for the majority of serine/threonine phosphatase activity which is tightly regulated via the methylation of carboxy-terminal of PP2A. Methylation at the carboxyterminal Leu 309 residue by S-adenosylmethionine-dependent leucine carboxyl methytransferase-1 (LCMT1) leads to the activation of PP2A, whilst demethylation of Leu 309 by specific protein phosphatase methylesterase-1 (PPME1) suppresses the PP2A activity. Recent evidence showed that PPME1 is up-regulated in glioblastoma patients and associated with a poor prognosis. In this study we profiled 131 Chinese gastric cancer (GC) samples and 124 Chinese non-small cell lung carcinoma (NSCLC) samples by Affy and aCGH to identify potential drug targets, and found PPME1 gene amplification in 3.8% of the GC samples and 3.1% of the NSCLC samples. The PPME1amplification correlated with its mRNA expression. In addition, we confirmed that PPME1 protein expressions were also elevated in the PPME1-amplified tumor samples indicated by immunohistochemistry as compared with corresponding adjacent non-tumor samples. To further investigate the role of PPME1 amplification in tumor growth, we utilized siRNA-mediated gene silencing approaches to specifically knock down PPME1 expression in the PPME1 amplified human cancer cell lines SNU668 (GC) and Oka-C1 (NSCLC). We found that suppression of the PPME1 expression resulted in significant inhibition of cell proliferation and induction of cell death in those cells. In contrast, little effects were observed on the cell growth and survival of non PPME1-amplified human cancer cells, MKN1 (GC) and HCC95 (NSCLC). Moreover, we showed that the PPME-1 knock-down also resulted in a decrease of PP2A demethylation at Leu309, which correlated with down-regulation of phosphorylation of MAPK and AKT in the cells. Taken together, our data indicate that PPME-1 could be an attractive therapeutic target for subsets of gastric and lung cancers.
Citation Format: Jing Li, Sufang Han, Ziliang Qian, Xinying Su, Shuqiong Fan, Jiangang Fu, Charles Liu, Lucy Yin, Zeren Gao, Guanshan Zhu, Jingchuan Zhang, De-Hua Yu, Qunsheng Ji. PPME1 is a potential novel molecular target in gastric and lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5186. doi:10.1158/1538-7445.AM2013-5186
Abstract 5197: RIN1 suppresses apoptosis in melanoma cells and is a potential therapeutic target.
Authors: Ting Pamela Y. , Colicelli John 
Published: August 2014

Abstract
The RAS effector RIN1 is frequently overexpressed in melanoma tumor samples. This aberrant overexpression is associated with tumor thickness, lymph node metastasis and poor prognosis. RIN1 is a multifunctional protein that has been shown to regulate growth factor receptor signaling and endocytosis, as well as the activity of the non-receptor tyrosine kinase ABL, which functions in actin remodeling and the DNA damage response.
Here, we identify RIN1 as a suppressor of apoptosis in melanoma. shRNA-mediated knockdown of RIN1 in the melanoma cell line A375 suppressed proliferation and induced apoptosis. We found RIN1 to be commonly overexpressed in melanomas, with elevated levels of the protein detected in 10 of 13 melanoma cell lines tested in comparison with human neonatal melanocytes. Additionally, depletion of RIN1 in several primary cell types does not affect cell viability. This supports the hypothesis that some melanoma cells are addicted to RIN1 and suggests its potential as a therapeutic target.
To examine the role of RIN1 in melanoma cell survival, point mutations were made to disrupt several known functions. These include receptor tyrosine kinase binding, ABL binding, Rab5 GEF activity and RAS association. The mutants have been stably transduced into melanoma cells under the control of a tetracycline-responsive promoter and they will be used to elucidate the contribution of different RIN1-dependent pathways to oncogenic activity. Overall, our goal is to determine the molecular mechanisms governing oncogenic addiction to RIN1 as well as points of vulnerability that could be therapeutically targeted.
Citation Format: Pamela Y. Ting, John Colicelli. RIN1 suppresses apoptosis in melanoma cells and is a potential therapeutic target. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5197. doi:10.1158/1538-7445.AM2013-5197
Abstract 5200: Genome-wide integrative analysis for the determination of the consequence of AT-rich interacting domain 2 (ARID2) depletion in hepatocellular carcinoma.
Authors: Furuta Mayuko , Nguyen Ha H. , Fujimoto Akihiro , Shiraishi Yuichi , Miyano Satoru , Tsunoda Tatsuhiko , Nakagawa Hidewaki 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We previously reported the genomic aberrations obtained by the whole genome sequencing of 27 HCCs derived from Japanese patients (Nature Genetics 44, 760, 2012). The statistical and functional analyses yielded frequently and recurrently mutated genes involved in chromatin regulation, including ARID1A, ARID1B, ARID2, MLL and MLL3. Among the chromatin regulators mutated in HCCs, we here focused on ARID2, a component of Polybromo-associated BRG1-associated factor (PBAF) complex, which is one of the SNI/SNF chromatin remodeling complex involved in ligand-dependent transcriptional activation by nuclear receptors. Most of the somatic mutations in ARID2 detected in HCCs by our sequencing studies indicated its loss-of-function, suggesting their role as a tumor-suppressor. Although its somatic mutation in HCC and other types of cancer have been recently reported, its detailed function and role in tumorigenesis is poorly understood. To determine its role in hepatocarcionogenesis, we first analyzed their activity on cell growth using HCC cell lines. Knockdown (KD) of ARID2 in ARID2-intact HCC cell lines, JHH4 and JHH5, promoted cell growth, while overexpression of ARID2 in ARID2-null HuH28 suppressed cell growth compared with controls. These findings are consistent with its role as a tumor-suppressor in HCC. We also performed RNA-Seq using the ARID2-KD RNA samples from ARID2-intact cell lines to predict its down-stream target genes, which might be affected by ARID2 depletion in HCCs. Pathway analysis of genes up- or down-regulated by ARID2-KD revealed that a large number of cancer-related genes showed their expression changes. In addition, some cytokines and kinases involved in carcinogenesis significantly appeared to be activated on the basis of down-stream target gene expression profile. These results indicate that somatic loss-of-function mutations in a component of chromatin regulator such as ARID2 could lead the genome-wide gene expression change appeared in HCCs.
Citation Format: Mayuko Furuta, Ha H. Nguyen, Akihiro Fujimoto, Yuichi Shiraishi, Satoru Miyano, Tatsuhiko Tsunoda, Hidewaki Nakagawa. Genome-wide integrative analysis for the determination of the consequence of AT-rich interacting domain 2 (ARID2) depletion in hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5200. doi:10.1158/1538-7445.AM2013-5200
Abstract 5205: Galectin-3 and AP-1 mediate transcriptional effect of Arylsulfatase B (N-acetylgalactosamine-4-sulfatase) on versican in prostatic cells.
Authors: Bhattacharyya Sumit , Feferman Leonid , Tobacman Joanne Kramer 
Published: August 2014

Abstract
N-acetylgalactosamine-4-sulfatase (Arylsulfatase B; ARSB) modifies the glycosaminoglycans (GAGs) chondroitin-4-sulfate (C4S) and dermatan sulfate by removing 4-sulfate groups from the non-reducing end and thereby regulating GAG degradation. Previous studies demonstrated that ARSB was reduced in malignant human colonic, mammary, and prostatic tissue and suggested that ARSB acts as a tumor suppressor. In this report, ARSB was silenced by siRNA in the WPMY-1 human prostate stromal myofibroblast cell line (ATCC), and effects on C4S, total sulfated glycosaminoglycans (GAGs), ErbB2, total EGFR, phospho-ERK, versican, and AP-1 were determined. Total sulfated GAGs were measured by Blyscan assay (Biocolor), and C4S was determined by Blyscan assay following immunoprecipitation by C4S antibody. Phospho(T202/Y204 for ERK1 or T185/Y187 for ERK2)-ERK, ErbB2, and total EGFR were measured by ELISA. Versican, an extracellular matrix chondroitin sulfate proteoglycan with EGF-like repeats at its C-terminus, was measured by ELISA and QPCR. ARSB and galectin-3 were silenced by siRNA (Qiagen). ARSB activity declined from 140.4 ± 8.4 to 21.4 ± 0.9 nmol/mg protein/hr following silencing. Total sulfated GAGs increased from 17.9 ± 0.7 μg/mg protein in control cells to 28.6 ± 1.4 μg/mg protein following ARSB silencing, and C4S increased from 7.4 ± 0.6 μg/mg protein to 15.5 ± 0.8 μg/mg protein following ARSB silencing. Total EGFR increased to 2.65 times baseline, and ErbB2 increased to over six-fold times baseline. Phospho-ERK increased to more than three times baseline, from 5.0 ± 0.5 ng/mg protein to 15.2 ± 0.8 ng/mg protein following silencing. Versican protein increased from 122.1 ± 5.3 ng/mg protein in control to 295.2 ± 11.2 ng/mg protein and mRNA increased more than two-fold. ARSB-silencing induced increases in versican mRNA and in activation of c-Jun and c-Fos, and these increases were inhibited when galectin-3 was also silenced. [All findings are highly significant (p&lt;0.001, one-way ANOVA with Tukey-Kramer post-test)]. Previously, we have shown reduced binding of galectin-3 to C4S following ARSB silencing. Since there is an AP-1 binding site in the versican promoter, study data demonstrate that transcriptional effects of ARSB silencing on versican are mediated by galectin-3 and AP-1. The profound effects of ARSB silencing on versican and phospho-ERK in the prostatic myofibroblasts provide further evidence that ARSB acts as a tumor suppressor.
Citation Format: Sumit Bhattacharyya, Leonid Feferman, Joanne Kramer Tobacman. Galectin-3 and AP-1 mediate transcriptional effect of Arylsulfatase B (N-acetylgalactosamine-4-sulfatase) on versican in prostatic cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5205. doi:10.1158/1538-7445.AM2013-5205