bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1899: Anti-skin tumor promoting effects of pentacyclic triterpenes found in Perilla frutescens
Authors: Cho Jiyoon , Rho Okkyung , Junco Jacob , Slaga Thomas J. , Camelio Andrew M. , Siegel Dionicio , DiGiovanni John 
Published: August 2015

Abstract
In this study, we conducted a comprehensive examination of a series of pentacyclic tritperpenes found in P. frutescens, including ursolic acid (UA) oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) for their effects on epidermal cell signaling, proliferation, and skin inflammation in relation to their ability to inhibit skin tumor promotion by TPA. For these experiments, female ICR mice (7-9 weeks of age) were treated with either acetone or 2 μmol of UA, OA, AA, CA, 3-epiCA, MA, or 3-epiMA 30 min prior to TPA (6.8 nmol) treatment The treatment protocol involved twice weekly treatments over a two week period. Mouse epidermis (6 hr time point) and whole skin (48 hr time point) were collected for Western blot analysis and histological analysis, respectively. Pretreatment with these compounds inhibited the activation of JNK1/2, Src, and Stat3 as well as the induction of Cox-2 protein. Pretreatment with the compounds also reversed the effect of TPA on PDCD4 and p27, and increased the activation of AMPK and LKB1. We also examined the effect of the compounds on TPA-induced epidermal hyperproliferation as assessed by epidermal thickness and epidermal labeling index (LI). All of the compounds examined significantly inhibited TPA-induced epidermal hyperproliferation (significant reductions in both epidermal thickness and LI). In addition, the effect of the triterpenes on TPA-induced infiltration of mast cells in dermis was evaluated. UA significantly inhibited the infiltration of dermal mast cells induced by TPA. Notably, OA, AA, CA, 3-epiCA, MA, and 3-epiMA produced a greater inhibitory effect than that seen with UA on the number of infiltrated mast cells. Thus, UA and a series of related triterpenes differentially inhibited multiple signaling pathways, epidermal hyperproliferation, and a marker of skin inflammation (infiltrated mast cells) induced by TPA. Several of the compounds including CA, 3-epiCA, MA, and 3-epiMA were particularly effective in these experiments. We are currently testing the ability of this group of compounds to inhibit skin tumor promotion by TPA in a two-stage skin carcinogenesis experiment. Collectively, the current data suggest that several pentacyclic triterpenes, in addition to UA, may have potent chemopreventive activity. Research supported by CA164159.
Citation Format: Jiyoon Cho, Okkyung Rho, Jacob Junco, Thomas J. Slaga, Andrew M. Camelio, Dionicio Siegel, John DiGiovanni. Anti-skin tumor promoting effects of pentacyclic triterpenes found in Perilla frutescens. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1899. doi:10.1158/1538-7445.AM2015-1899
Abstract 190: Modulation of MiR-21 signaling by MPS1 in human glioblastoma
Authors: Maachani Uday Bhanu , Tandle Anita , Shankavaram Uma , Kramp Tamalee , Camphausen Kevin A. 
Published: August 2015

Abstract
Monopolar spindle 1 (MPS1) is an essential spindle assembly checkpoint (SAC) kinase involved in determining spindle integrity. Beyond its mitotic functions, it has been implicated in several other signaling pathways. Its overexpression in cancer cells is known to contribute to genomic instability and tumorigenesis. Our earlier studies have elaborated on role of MPS1 in glioblastoma (GBM) radiosensitization. In this study using reverse phase protein arrays (RPPA), we assessed MPS1 mediated cell signaling pathways and demonstrated that inhibiting MPS1 could upregulate the expression of the tumor suppressor genes PDCD4 and MSH2 by downregulating micro RNA-21 (MiR-21). In GBMs MiR-21 expression is significantly elevated and is associated with chemo and radioresistance. Here, we show that MPS1 inhibition significantly repressed MiR-21 levels and elevated PDCD4 and MSH2 expression in GBM cells both in vitro and in vivo. Both MPS1 and MiR-21 depletion suppressed GBM cell proliferation, whereas, ectopic expression of MiR-21 rescued GBM cell growth from MPS1 inhibition. Further, we demonstrate that MPS1 mediates phosphorylation of SMAD3 but not SMAD2 in GBM cells; A possible mechanism behind MiR-21 modulation by MPS1. Collectively, our results shed light onto an important role of MPS1 in TGF-β/SMAD signaling via MiR-21 regulation. We also, evaluated the prognostic effect of MiR-21, PDCD4 and MSH2 expression on survival in GBM patients of different molecular subtypes from The Cancer Genome Atlas (TCGA) database, showing tumors with high MiR-21 expression and low PDCD4 and MSH2 expression were associated with significantly shorter survival times. To our knowledge this is the first report to demonstrate the role of MPS1 in MiR-21 modulation. This scenario in which MiR-21 is modulated by MPS1 inhibition may be exploited as a potential target for effective GBM therapy.
Citation Format: Uday Bhanu Maachani, Anita Tandle, Uma Shankavaram, Tamalee Kramp, Kevin A. Camphausen. Modulation of MiR-21 signaling by MPS1 in human glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 190. doi:10.1158/1538-7445.AM2015-190
Abstract 1933: Alteration of the protein tyrosine phosphatome in cancer
Authors: Moskal Damian , Tonks Nicholas K. , Lucito Robert 
Published: August 2015

Abstract
While the importance of receptor tyrosine kinase pathways in cancer has and continues to be carefully studied there are more than 100 tyrosine phosphatases, either receptor or non receptor, that also play an important role in cancer development. However there has been no comprehensive study of all PTPs or the protein tyrosine phosphatome (PTPome), to identify which have a role in cancer. We as a cancer community are fortunate to have access to a wide array of data types from a number of data sources such as TCGA, where we can determine if the PTPs are mis regulated in more than 20 types of cancers, totaling close to 4,000 samples. We utilized TCGA data for all tumor types with mature data sub setting the data to analyze the PTPome for all data types including expression, methylation, copy number and sequence data where available. Our intention was to use the genomic data to identify PTPs that were important to specific cancers as well as to understand which PTPs play an important role in multiple tumor types. Presently we have studied copy number variations, expression and methylation changes in 20 different tumor types. Thus far, copy number variations, as could be expected were extremely useful to determine the primary mutations in specific tumor types as well as PTPs that are found recurrently in multiple tumor types but not as useful to identify a number of PTPs that are co-altered or altered in the same individual tumors. We were surprised to find that the methylation data was not very useful to identify alterations but could use the methylation data to corroborate other alterations found. Presently we are also using the methylation data to determine if it can be used to identify possible clinical correlations. The expression data has been very useful to identify co-altered PTPs. Interestingly we found several PTPs that are altered together (for example, PTPN6, PTPN7, PTPN18, PTPN22, PTPRC, DUSP2 and DUSP22 with an overall pvalue of 0.02 and much lower if measured between any two PTPs in this list). In addition we have found PTPs that are co-altered in a specific tumor type but possibly more interesting PTPs that are co-altered in a number of tumor types. We are now studying if our results can be used to determine if these PTPs represent multiple specific pathways that are advantageously altered in carcinogenesis.
Citation Format: Damian Moskal, Nicholas K. Tonks, Robert Lucito. Alteration of the protein tyrosine phosphatome in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1933. doi:10.1158/1538-7445.AM2015-1933
Abstract 1935: Gene expression analysis reveals distinct pathways of resistance to antiangiogenic therapy in ovarian cancer
Authors: Devapatla Bharat Kumar , Jaiprasart Pharavee , Woo Sukyung 
Published: August 2015

Abstract
Purpose: The rapid development of resistance after an initial response phase is a major challenge of antiangiogenic therapies. The molecular mechanisms underlying clinical resistance to antiangiogenic therapies are not yet well understood. We aimed to identify potential mediators of resistance to antiangiogenic therapy, with a view toward eventually developing therapeutic approaches to improve antiangiogenic therapies.
Methods: We developed preclinical in vivo phenotypic resistance models of antiangiogenic therapy using human ovarian carcinoma cells. We used two representative anti-VEGF agents to block VEGF (bevacizumab, 10 mg/kg BIW, IP) or its receptor (sorafenib, 30 mg/kg daily, PO). The treatment was given until tumors showed a long-term trend toward continued progression after an initial response (resistant tumor). Whereas treatment-sensitive tumors were defined by a long-term trend toward stable disease or regression. We conducted next generation sequencing to compare changes in the gene expression in resistant and sensitive tumors, distinguishing their origin (tumor vs stroma cells). To get a more detailed perspective of the overall changes in gene expression, Gene Set Enrichment Analysis (GSEA) was performed by pair-wise comparison according to treatment outcome (resistant vs sensitive) with respect to bevacizumab and sorafenib, of which the entire MSigDB collections were compared to. Further, significantly enriched pathways were validated with clinical gene expression profiling studies of various tumor types deposited in GEO and ArrayExpress.
Results: Our GSEA analysis revealed significant differences (FDR&lt;0.25) in enrichment of various pathways between sensitive and resistant tumors. We observed ERK, P38 MAPK, ATP dependent helicase activity, and phosphatidylinositide 3-kinases pathways are differentially enriched between sensitive and resistant phenotypes of bevacizumab-treated group. In sorafenib-resistant group, six pathways were enriched including E2F1, KRAS and PDGF regulated pathways.
Conclusions: Here, we report distinct pathways of response to bevacizumab and sorafenib in preclinical ovarian cancer models, which may provide critical insights into ovarian tumor's adaption during anti-VEGF blockade. These pathways may also provide important clues for identifying synergistic therapeutic strategies to overcome or delay resistance to antiangiogenic agents.
Citation Format: Bharat Kumar Devapatla, Pharavee Jaiprasart, Sukyung Woo. Gene expression analysis reveals distinct pathways of resistance to antiangiogenic therapy in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1935. doi:10.1158/1538-7445.AM2015-1935
Abstract 1936: CoMEt: A statistical approach to identify combinations of mutually exclusive alterations in cancer
Authors: Wu Hsin-Ta , Leiserson Mark D.M. , Vandin Fabio , Raphael Benjamin J. 
Published: August 2015

Abstract
Identifying driver mutations in cancer genomes is a significant challenge due to the mutational heterogeneity of tumors: different combinations of somatic mutations drive different tumors, even those of the same cancer type. This mutational heterogeneity arises because driver mutations target genes in signaling and regulatory pathways, each of which can be perturbed in numerous ways.
We introduce CoMEt, an algorithm to identify combinations of candidate driver mutations de novo, without any prior biological knowledge (e.g. pathways or protein interactions). CoMEt searches for combinations of mutations that exhibit mutual exclusivity, a pattern expected for mutations in pathways. CoMEt uses an exact statistical test for mutual exclusivity that is less biased toward high frequency alterations than previous approaches and more sensitive in detecting combinations of lower frequency alterations. We compute the exact test using a novel tail enumeration procedure and also derive a binomial approximation. CoMEt simultaneously identifies collections of one or more combinations of mutually exclusive alterations, consistent with the observation of multiple hallmarks of cancer, and also performs simultaneous analysis of subtype-specific mutations. Finally, CoMEt uses an MCMC algorithm to sample from collections in proportion to their significance, summarizing the distribution in a marginal probability graph. We show that CoMEt outperforms other mutual exclusivity approaches on simulated and real data.
We apply CoMEt to hundreds of samples from four different TCGA cancer types: gastric cancer (STAD), glioblastoma (GBM) and acute myeloid leukemia (AML), and breast cancer (BRCA). We identify multiple mutually exclusive sets within each cancer type. These include the RTK/RAS pathway in gastric cancer, the Rb and p53 signaling pathways in glioblastoma, and a collection containing multiple kinases, including FLT3, as well as the RAS genes in AML. In addition, we analyze subtype-specific mutations using CoMEt by encoding the subtype of each sample and computing exclusivity between and within subtypes. We apply this approach using four gene expression subtypes of breast cancer and identify several pathways that are enriched for mutations in specific subtypes including the PI(3)K/AKT signaling pathway in the Luminal A subtype. Many of these overlap known pathways, but others reveal novel putative cancer genes. These findings provide testable hypotheses for experimental validation.
Citation Format: Hsin-Ta Wu, Mark D.M. Leiserson, Fabio Vandin, Benjamin J. Raphael. CoMEt: A statistical approach to identify combinations of mutually exclusive alterations in cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1936. doi:10.1158/1538-7445.AM2015-1936
Abstract 1937: In-depth genomic analysis reveals complex functional consequence of driver mutations in breast cancers
Authors: Xu Yaomin , Guo Xingyi , Zhao Shilin , Torstenson Eric , Edwards Todd , Shyr Yu 
Published: August 2015

Abstract
Understanding the extensive functional consequences of molecular drivers of a cancer is challenging. We developed an in-depth genomic analytical framework to identify the gene and pathway targets dysregulated by somatic driver mutations. Using The Cancer Genome Atlas (TCGA) breast cancer data, we systemically analyzed all high frequent mutation events including amplification, deletion and point mutation across tumor tissues. Those include the known molecular driver genes such as PIK3CA, GATA3, PTEN and TP53. Utilizing bagging with distance-based regression for differential gene expression analysis, we identified several thousands gene targets associated with the somatic mutations. Integrating gene co-expression regulatory network and the association dependence structure among the somatic mutations, we explored a complex association network of molecular pathway modules or sub-modules that are specific to a mutational event or common to a set of events. Interestingly, we found those modules commonly associated with sets of mutation events were significantly enriched in well-known breast cancer related pathways such as ERBB2, PI3AK and TGFB1. Combined with the publicly available data of a genome-wide RNA-mediated interference screen in breast cancer, we further demonstrated that those modules enriched with cell proliferation essential genes. Our analysis strategy provides a novel view of complex functional mechanism driven by the driver mutation events and it has high potential to provide novel insights to the understanding of the tumorigenesis or the development of therapeutic targets.
Citation Format: Yaomin Xu, Xingyi Guo, Shilin Zhao, Eric Torstenson, Todd Edwards, Yu Shyr. In-depth genomic analysis reveals complex functional consequence of driver mutations in breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1937. doi:10.1158/1538-7445.AM2015-1937
Abstract 1942: Regulation of GRNMB transcription and cellular effects by chondroitin 4-sulfation
Authors: Tobacman Joanne Kramer , Feferman Leo , Bhattacharyya Sumit 
Published: August 2015

Abstract
Increased expression of glycoprotein (transmembrane) NMB (GPNMB; osteoactivin) has been identified in triple negative breast cancer, melanoma, glioma, and hepatocellular carcinoma, and followed decline in expression of the enzyme arylsulfatase B (ARSB; N-acetylgalactosamine 4-sulfatase). The expression and regulation of GPNMB was evaluated in HepG2 cells and in ARSB-deficient and control C57BL/6J mouse hepatic tissue. Increased expression of GPNMB was attributable to promoter activation by phospho(Ser)MITF (microphthalmia-associated transcription factor), the phosphorylation of which was activated by phospho(Ser)-p38 MAPK. When ARSB was reduced, nuclear phospho-MITF increased and GPNMB promoter activity increased, as detected by Renilla reniformis luciferase assay. Chromatin immunoprecipitation assay confirmed that phospho-MITF bound to a specific motif in the GPNMB promoter, and binding increased when ARSB was silenced. Up-regulation of promoter activity increased the expression of GPNMB message and the synthesis of GPNMB protein in the HepG2 cells and ARSB-null mouse liver. The tyrosine phosphatase SHP2 bound more tightly to C4S when ARSB was reduced, leading to inhibition of SHP2 activity and reduced removal of phosphate from Tyr182 of phospho-p38 MAPK. The increase in C4S stimulated phospho(Ser)-p38 MAPK by activation of RhoA, leading to MITF phosphorylation and increased GPNMB expression. Silencing GPNMB by siRNA reduced phosphorylation of ERK and expression of matrix metalloproteinase (MMP)-9, consistent with effects on hepatic cell invasiveness. These findings indicate that ARSB-induced changes in chondroitin 4-sulfation impact on critical phosphorylations mediated by SHP2 and p38 MAPK, leading to activation of MITF and increased expression of GPNMB. The interaction between chondroitin 4-sulfation and phosphorylations may regulate vital cell processes, including transcriptional events and cell-matrix interactions.
Citation Format: Joanne Kramer Tobacman, Leo Feferman, Sumit Bhattacharyya. Regulation of GRNMB transcription and cellular effects by chondroitin 4-sulfation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1942. doi:10.1158/1538-7445.AM2015-1942
Abstract 1950: Emerging role of CITED2 in hypoxia and TGF-beta mediated proliferation and invasion in lung cancer
Authors: Kuo Ming-Han , Hsieh Cheng-Han , Wang Yuan-Hung , Wu Cheng-Wen , Chou Yu-Ting 
Published: August 2015

Abstract
Lung cancer remains the leading cause of cancer mortality in the world. Metastatic property is one of the major reasons for treatment failure in lung cancer patients. Tumor microenvironment plays a key role in shaping tumor progression. In solid tumors, a decreased oxygen and nutrient supply creates a hypoxic microenvironment in the central region, which elicits a set of genes to endow cancer cells with increased survival or proliferation abilities. On the other hand, TGF-beta, which is often released by tumor stroma cells, attenuates cell proliferation but induces invasion of lung cancer. How cancer cells are shaped by tumor microenvironment with elevated proliferation and invasion abilities are elusive. Here, we report that CITED2, a MYC interacting transcriptional modulator, responds to hypoxia induction and TGF-beta suppression to orchestrate cellular proliferation and invasion, respectively. We observed that hypoxia induced CITED2 expression in a group of lung cancer cells, the proliferation and survival of which were dependent on CITED2 signaling. TGF-beta stimulation inhibited CITED2 expression, causing decreased cell proliferation. Nonetheless, hypoxia potentiated TGF-beta mediated invasion and rendered cell resistant to TGF-beta induced cell growth arrest by elevating CITED2 dependent signaling. Our findings provide that CITED2 functions as an oncogeneic switch for hypoxia and TGF-beta mediated proliferation and invasion in lung cancer, deserving additional evaluation as a biomarker for lung cancer progression.
Citation Format: Ming-Han Kuo, Cheng-Han Hsieh, Yuan-Hung Wang, Cheng-Wen Wu, Yu-Ting Chou. Emerging role of CITED2 in hypoxia and TGF-beta mediated proliferation and invasion in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1950. doi:10.1158/1538-7445.AM2015-1950
Abstract 1953: Group I Paks as therapeutic targets in NF2-deficient meningioma
Authors: Chow Hoi Yee 
Published: August 2015

Abstract
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.
Citation Format: Hoi Yee Chow. Group I Paks as therapeutic targets in NF2-deficient meningioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1953. doi:10.1158/1538-7445.AM2015-1953