tbuckley/cabot-search huggingface dataset:
Abstract 4099: Oligodendrocyte stimulates the invasion ability of glioblastoma cells
Authors: Toshiyuki Kawashima
Journal: Cancer Research (2016)

Abstract Background &amp; Aims: Glioblastoma (GBM, WHO Grade IV) is characterized by rapid cancer cell infiltration, and is one of the most lethal neoplasms among solid cancers. GBM might arise de novo, or following progression from lower grade gliomas. Recently, solid tumor progression has been recognized as the product of an evolving crosstalk between the cancer cells and its surrounding glial cells. The intensive invasion activity of GBM cells might be regulated by normal cells such as oligodendrocytes or fibroblasts. In this study, we evaluated the interaction between GBM cells and glial cells. Methods: Two GBM cell lines, T98G and U251, were used. Two oligodendrocyte cell lines, ODC1 and ODC2, were derived from surgical tissues of each patient with low-grade glioma (WHO Grade II). Two fibroblasts cell lines, GF1 and GF2, were derived from surgical tissues of each patient with GBM. The culture medium was composed of DMEM with 10% fetal calf serum. We examined the effects of glial cells on the invasion ability of GBM cells by wound-healing assay and invasion assay. Using IncuCyte invasion assay and matrigel invasion assay, the invasiveness of T98G and U251 cells was analyzed in the presence or absence of conditioned medium from oligodendrocyte cells or fibroblasts. The effect of the proliferation of T98G and U251 cells was examined by MTT assay or cell count. Results: ODC1 and ODC2 cells were positive for Olig2 staining but not for GFAP staining, suggesting that ODC1 and ODC2 were oligodendrocyte cells. GF1 and GF2 cells were spindle-shape and were negative for both Olig2 staining and GFAP staining, suggesting that GF1 and GF2 cells were fibroblasts. Oligodendrocyte cells, ODC1 and ODC2 cells, from grade II glioma significantly (p&amp;lt;0.01) increased the migration and invasion ability of GBM cells, T98G and U251 cells. In contrast, GF1 and GF2 fibroblasts from GBM did not affect on the migration and invasion ability of GBM cells. Both oligodendrocyte cells and fibroblasts did not stimulate the proliferation of T98G and U251 cells. Conclusion: Oligodendrocytes might up-regulate the invasiveness of malignant glioma cells. An invasion-stimulating factor(s) from oligodendrocyte cells might be partially associated with the progression from lowe-grade gliomas to GBM. Citation Format: Toshiyuki Kawashima. Oligodendrocyte stimulates the invasion ability of glioblastoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4099.
Abstract 4521: Substrate profiling for SETD8 reveals novel protein targets involved in DNA replication and DNA damage response
Authors: Fabio Pittella Silva, Gil Blum, Chamara Senevirathne, Minkui Luo
Journal: Cancer Research (2016)

Abstract Protein lysine methyltransferases utilize S-adenosyl-L-methionine (SAM) to catalyze the addition of methyl groups to specific lysine residues in both histones and non-histone proteins. Recent evidence indicates that their dysregulation is closely linked to the development and progression of cancer, making them potential therapeutic targets. SETD8 is the sole methyltransferase responsible for mono-methylation of histone H4 lysine 20 (H4K20me1). Its activity is essential for cell viability and has been associated with many essential cellular processes including transcriptional regulation, heterochromatin formation, genomic stability and cell-cycle progression. SETD8 is overexpressed in several types of cancer and may play important roles on malignancy through its trans-methylation activity or by direct interaction with its binding partners. It has been reported that the association between SETD8 and TWIST, a regulator of epithelial-mesenchymal transition, enhances the invasiveness of breast cancer cells. In addition, it was shown that SETD8-mediated methylation of p53 suppresses p53 dependent transcription activation in cancer cells. Despite the identification of a few non-histone proteins such as p53, PCNA and Numb as SETD8's substrates, a comprehensive investigation of new potential substrates is lacking to date. Here we used Bioorthogonal Profiling of Protein Methylation (BPPM) with engineered SETD8 and synthetic SAM analogues to profile novel substrates for SETD8. We identified SETD8 mutants amenable to accommodate non-native SAM analogues containing a terminal alkyne moiety for click chemistry. The engineered SETD8 can transfer this distinct chemical moiety into target proteins for subsequent pulldown and identification of the modified substrates. The BBPM technology applied here revealed previously known substrates of SETD8 as well as novel SETD8 targets. Among the main targets of our interest are those involved in DNA replication and DNA damage response. Our finding is expected to bring new perspectives on the biological importance of SETD8 as well as on its role in carcinogenesis. Citation Format: Fabio Pittella Silva, Gil Blum, Chamara Senevirathne, Minkui Luo. Substrate profiling for SETD8 reveals novel protein targets involved in DNA replication and DNA damage response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4521.
Intracoronary versus Intravenous Abciximab in ST-Elevation Myocardial Infarction: Results of the CICERO Trial in Patients Undergoing Primary Percutaneous Coronary Intervention With Thrombus Aspiration
Authors: Youlan L. Gu, Marthe A. Kampinga, Wouter G. Wieringa, Marieke L. Fokkema, Ad F. van den Heuvel, Eng-Shiong Tan, Gabija Pundziute, Rik van der Werf, Siyrous Hoseyni Guyomi, Felix Zijlstra, Bart J. de Smet
Journal: Circulation (2010)
Abstract 1852: Multiple PI3K pathway mutations predominate in low stage endometrial carcinomas
Authors: Dario R. Roque, Will R. Jeck, David N. Hayes, Arthur M. Dizon, Leslie Clark, Stuart Pierce, Weiya Z. Wysham, Tara Castellano, Paola A. Gehrig, Victoria Bae-Jump
Journal: Cancer Research (2016)

Abstract Objectives: Endometrial cancers (ECs) frequently harbor mutations in PI3K pathway genes. Our objective was to determine the mutation frequency of the PIK3 pathway in the tumors of EC patients prospectively enrolled on an IRB-approved institutional tumor sequencing initiative (UNCseq) and correlate these with clinical factors. Methods: Snap-frozen and FFPE tissue samples were collected from patients enrolled on UNCseq (NCT01457196). DNA was isolated using the Puregene DNA purification system, and Illumina libraries were prepared separately from tumor and a matched normal sample from each patient. Relevant targets, were enriched by a custom designed Agilent SureSelect hybrid capture enrichment library using standard protocols. Samples were sequenced on Illumina HiSeq machines in a variety of formats. Statistical analysis of clinical correlates was performed in R (v 3.1.1). Results: Data was collected from 109 EC patients. Thirty-six tumors (33.0%), 34 of which were endometrioid, had &amp;gt;2 mutations between PIK3CA and PIK3R1. 20 patients had multiple PIK3CA mutations (18.3%) and 11 had multiple PIK3R1 mutations (10.1%). In all but 5 cases, multiple mutations of PIK3R1 or PIK3CA were coincident with PTEN mutation (p = 0.018). There were strong correlations between PI3K pathway mutations and tumor grade and stage. High stage tumors (stage &amp;gt;2) were less likely (5/36) than stage 1 tumors (31/73) to have multiple PI3K mutations (p = 0.0056). Though not reaching significance, grade 3 tumors (8/37) were less likely than low-grade tumors (28/72) to demonstrate multiple PI3K mutations (p = 0.11). Of the 10 serous ECs, none exhibited multiple PI3K mutations. Conclusions: There is a strong relationship between mutated PIK3 pathway genes and clinically relevant tumor biology in ECs. Multiple mutations in the PIK3 pathway are common, suggesting that PI3K pathway inhibition in EC may need to be directed against PIK3CA and PIK3R1 simultaneously. These multiply mutated tumors are strongly linked to lower stage and grade tumors with concurrent PTEN mutations. We posit that initially PTEN mutant clones may give rise to subclonal populations with various PI3K mutations which may be relatively indolent until additional driver mutations are acquired such that one subpopulation predominates, resulting in higher grade and stage ECs. Citation Format: Dario R. Roque, Will R. Jeck, David N. Hayes, Arthur M. Dizon, Leslie Clark, Stuart Pierce, Weiya Z. Wysham, Tara Castellano, Paola A. Gehrig, Victoria Bae-Jump. Multiple PI3K pathway mutations predominate in low stage endometrial carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1852.
Abstract 5036: Elucidating an oncogenic role of an extracellular matrix protein, Agrin, in hepatocellular carcinoma
Authors: Sayan Chakraborty, Wanjin Hong
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is one of the most fatal cancers worldwide. Despite offering poor survival advantage, broad spectrum receptor tyrosine kinase inhibitors are the sole chemotherapeutic treatments for advanced stages of HCC. Hence, there is a pressing clinical need to broaden the scope of HCC treatments through the systematic identification of suitable candidate(s) overexpressed in liver cancer. Therefore, we performed a SILAC based quantitative proteomics of cell surface proteins in HCC lines and identified proteoglycan Agrin to be overexpressed and secreted in HCC. Our systematic cell biological analysis indicated a role of Agrin in maintaining focal adhesion integrity through stimulation of focal adhesion kinase (FAK). We showed that Agrin functions in cellular migration, invasion and tumor growth. However, the exact mechanisms by which Agrin's mediates liver tumorigenesis remain unknown. The present study dissects how Agrin mediated signals from the extracellular matrix are sensed by tumor cells. Our evidences reveal that Agrin binds to its co-receptor(s) Lrp4 and subsequently activates MuSK to mediate oncogenic effects through activating focal adhesions. Additionally, integrins and focal adhesions collaborate closely with Agrin in communicating ECM signals to intracellular components in multiple HCC cell lines, thereby stimulating their invasive, migratory and growth capabilities. More importantly, Lrp4-MuSK as well as integrin-FAK pathways are crucial downstream signaling axes of Agrin's functions in liver tumorigenesis. The signal transduction network initiated by Agrin activates the oncogenic program in liver by negatively regulating tumor suppressor pathways. These novel insights will have profound impact on the possibility of targeting Agrin mediated oncogenesis in HCC. Citation Format: Sayan Chakraborty, Wanjin Hong. Elucidating an oncogenic role of an extracellular matrix protein, Agrin, in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5036.
Abstract 967: Vemurafenib regulates miRNA-211 expression in melanoma - effects on extracellular vesicle RNA cargo and function
Authors: Taral R. Lunavat, Lesley Cheng, Berglind Einarsdottir, Cecilia Lässer, Jonas A. Nilsson, Andrew F. Hill, Jan Lötvall
Journal: Cancer Research (2016)

Abstract In melanoma, more than 50% of the patients harbor BRAF somatic missense mutations, most affecting the V600 region. Vemurafenib, a potent BRAF inhibitor used for the treatment of late stage melanoma, has shown promising results by causing programmed cell death in melanoma cells. Recently, extracellular vesicles including apoptotic bodies, microvesicles and exosomes has been shown to contain genetic information especially RNA with distinct repertoire of RNA, which could be transferred from one cell to another. Here we investigate the effects of Vemurafenib on melanoma cells and the RNA content in their subsets of extracellular vesicles. Upon vemurafenib treatment, we found that the melanoma cells harboring the BRAF mutation significantly increases the RNA and protein cargo in the different subsets of extracellular vesicles. The RNA profile also changes substantially in apoptotic bodies and microvesicles with significant changes in the ribosomal RNA ratio. Further, using small RNA sequencing, we found that extracellular vesicles from treated cells harbor unique miRNAs. The significantly different miRNA detected with sequencing analysis was validated in vitro with PCR and confirmed that miR-211 is upregulated in cells as well as subsets of extracellular vesicles after treatment. Furthermore, miR-211 was validated to be significantly upregulated in tumors tissues harvested from patient derived xenograft (PDX) as well as cell line derived xenograft and its vesicular subsets. This shows that vemurafenib induces miR-211 upregulation in BRAF mutant cells and PDX especially in the subsets of extracellular vesicles. miR-211 induction upon oncogene treatment could be potentially used as a biomarker in melanoma patients with BRAF mutation. Citation Format: Taral R. Lunavat, Lesley Cheng, Berglind Einarsdottir, Cecilia Lässer, Jonas A. Nilsson, Andrew F. Hill, Jan Lötvall. Vemurafenib regulates miRNA-211 expression in melanoma - effects on extracellular vesicle RNA cargo and function. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 967.
Abstract 1513: Pan-cancer analysis of alternative splicing patterns and association to genomic aberrations
Authors: Sergei Häyrynen, Matti Nykter
Journal: Cancer Research (2016)

Abstract Alternative splicing of pre-messenger RNA is responsible for the diversity of transcriptome and proteome, with the majority of multi exon genes producing multiple transcripts. Aberrations in regulative factors of alternative splicing are known to produce transcript isoforms associated with cancer progression and prognosis. Both mutations in the proximity of spliced regions and mutations in and regulation of previously identified splicing factor genes are known to alter splicing patterns. In this study, we utilized publicly available TCGA data to study association patterns between alternative splicing and its regulatory elements across multiple cancer tissue types. We collected evidence of splicing patterns of annotated isoforms in addition to novel patterns identified using our previously developed tools using RNA-seq data. We mined for associations between somatic mutations and changes of splicing patterns as well as genome and transcriptome level changes in splicing factors. Selective transcriptome assembly was done in loci with differentially expressed patterns and novel patterns with sufficient evidence to identify transcript isoforms and quantify isoform specific expression. In our study we compiled a catalogue of splicing patterns and their changes across multiple cancer types. Integration of this comprehensive set of quantified splicing patterns with data on proximal mutations and aberrations in splicing factors resulted in statistically relevant associations with clinical phenotypes. Our analysis enables identification of mechanisms behind splicing aberrations common to all cancers and cancer specific splicing patterns. Citation Format: Sergei Häyrynen, Matti Nykter. Pan-cancer analysis of alternative splicing patterns and association to genomic aberrations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1513.
Ureteroenteric Fistula Revealed by 99mTc-DTPA Renal Scan
Authors: Xiaoyan Hou, Weifang Zhang, Yanyan Zhang
Journal: Clinical Nuclear Medicine (2016)

A 55-year-old woman with a history of cervical carcinoma, status post hysterectomy and radiation therapy 8 years prior, presented worsening back pain for 9 months. The patient underwent a Tc-DTPA renal scan, which showed that a vertically linear tracer distribution was seen alongside the right ureter. Ureteroenteric fistula was confirmed and repaired by surgery.
Abstract 1720: Role of SENP1 in HBx-induced cell migration and stemness-related properties in hepatocellular carcinoma
Authors: Te Sheng Chang, Yen-Hua Huang
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is the sixth most common cancer, and the third leading cause of cancer mortality worldwide. Surgical resection can be curative for early stage HCC, but the risk of tumor recurrence remains high. Tumor stemness properties have been linked to early recurrence of HBV-related HCC (HBV-HCC), which continues to be a great challenge in clinical practice. However, the progress in the strategy of individualized therapy against HBV-HCC is slow and disappointed. Here we demonstrate that HBx regulates the cell migration and cancer stemness properties of HCC cells through Sentrin-specific protease 1 (SENP1) modification. By a large cohort of HCC patients receiving curative heptectomy, we found that SENP1 expression level is highly associated with the gene expression levels of cell migration-related gene SNAIL/TWIST and pluripotency-related gene OCT4 particularly in HBV-HCC. Furthermore, SENP1 expression level is significantly associated with tumor metastasis as well as the early recurrence of HCC using Kaplan-Meier analysis. Further experiments using cell line model, we demonstrated that HBx overexpression not only increases the protein levels of SENP1 and pluripotent transcription factor OCT4, but also enhances cell migration in HepG2 cells. Inhibition of SENP1 significantly suppressed the HBx-induced cell migration and cancer stemness in vitro and in vivo. In summary, in this work, we demonstrate that SENP1 plays a critical role in HBx-induced cell migration- and cancer stemness-related properties in HBV-HCC. Findings in this study will facilitate the potential strategy targeting on SENP1 for individualized adjuvant therapy against HBV-HCC. Citation Format: Te Sheng Chang, Yen-Hua Huang. Role of SENP1 in HBx-induced cell migration and stemness-related properties in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1720.
Abstract 1177: The role of nischarin in the breast tumor microenvironment
Authors: Mazvita Maziveyi, Shengli Dong, Suresh K. Alahari
Journal: Cancer Research (2016)

Abstract Women with denser breasts, have a higher risk of developing breast cancer. Breast density reflects the amount of connective tissue and collagen present. During metastasis, tumor cells move through tracks of extracellular matrix (ECM). A stiff and ordered tissue microenvironment is necessary for tumor cell invasiveness. Matrix stiffness is mediated by ECM fiber organization and cell-matrix adhesions. Our lab is investigating a tumor suppressor that contributes to ECM organization. The protein Nischarin interacts with a number of signaling proteins such as integrin α5, PAK1, LIMK1, LKB1, MLCK, ERK and Rac1 to prevent cancer cell migration. Our data shows that spontaneous breast tumors from wild-type (WT) animals have reduced ECM fiber expression and organization compared to those from homozygous Nischarin Null mice. Furthermore, we have found Nischarin to alter integrin and focal adhesion signaling, therefore affecting cell-matrix adhesions. We hypothesize that the absence of Nischarin in the breast tumor leads to increased matrix stiffness, through increased fiber organization, and altered cell-matrix adhesions. Since no breast tumor suppressors have been linked to collagen and fibronectin ECM remodeling, we present a novel role for Nischarin in organizing the ECM. By integrating cell signaling with optical and computational instrumentation, we will assess the role of Nischarin in the bidirectional cellular/matrix crosstalk, which will add to our understanding of the metastatic process in breast cancer. Citation Format: Mazvita Maziveyi, Shengli Dong, Suresh K. Alahari. The role of nischarin in the breast tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1177.
Abstract 1139: Translational control of MYC protein stability as a target of small molecules
Authors: Naohiko Ikegaki, Luqman Baloch, Christopher Chu, Joshua Lomahan, Jamie Harris, Bill Chiu
Journal: Cancer Research (2016)

Abstract It is well established that MYC family proteins drive tumor growth and sustain the malignant phenotype. However, MYC family proteins have gained the reputation of being “un-druggable” by small molecule inhibitors. This is because MYC proteins lack intrinsic enzymatic activities or appropriate molecular grooves to which small molecules may bind and inhibit their function. Nonetheless, previous studies suggest that MYC family proteins (MYC, MYCN, MYCL) can be “targetable” indirectly by accelerating their turnover rate at different biochemical pathways that regulate the steady state level of the proteins. These include transcriptional-inhibition of the corresponding genes and acceleration of their proteasome-dependent degradation. The goal of this study is to gain a better understanding of how the MYC family protein turnover is regulated, which in turn might help develop future new drugs against “MYC family-driven” cancers. We have used neuroblastoma, a childhood cancer, as a disease model and identified several small molecules that rapidly destabilize MYC and MYCN proteins in MYC-driven neuroblastoma cells. The small molecules include FCCP, OSU-03012 and Salinomycin. Preliminary data suggest that the common target of these compounds is mitochondria. Recently, we have also found Halofuginone, an FDA approved orphan drug for Scleroderma treatment exhibits a similar MYC-destabilizing activity. At submicromolar concentrations and less than one hour of drug-treatment, Halofuginone rapidly causes significant down-regulation of MYC proteins in neuroblastoma cells. Halofuginone is known to activate the eIF2α pathway, which controls translation. Activation of the eIF2α pathway is initiated by the activation of eIF2a kinases (GCN2, HRI, PERK, PKR) via autophosphorylation by various stress-related stimuli such as reactive oxygen species and misfolded proteins. The activated eIF2α kinases then inactivates eIF2α by phosphorylation, which subsequently halts translation globally. Interestingly, FCCP, OSU-03012 and Salinomycin treatments also caused eIF2α phosphorylation. These observations suggest that activation of the eIF2α pathway results in translational block of the MYC family protein expression in tumor cells. Because half-lives of MYC family proteins are very short, a sudden attenuation in protein translation can cause rapid down-regulation of the proteins. Hence, activation of the eIF2α pathway by small molecules may prove effective for rapid down-regulation of MYC family proteins in MYC-driven cancer cells. Citation Format: Naohiko Ikegaki, Luqman Baloch, Christopher Chu, Joshua Lomahan, Jamie Harris, Bill Chiu. Translational control of MYC protein stability as a target of small molecules. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1139.