bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 352: The role of p62 (SQTSM1) in the transforming growth factor β signaling pathway
Authors: Ng Evelyn , Gunaratne Adrian , Guglielmo John Di 
Published: July 2017

Abstract
Transforming growth factor beta (TGFβ) is a cytokine that regulates many cellular processes, including cellular adhesion, proliferation and apoptosis. Its canonical downstream effectors include Smad2/3 proteins, which are phosphorylated and then translocate to the nucleus to alter gene transcriptional programs and promote processes such as epithelial-to-mesenchymal transition (EMT). Previous studies in our lab have shown that atypical Protein Kinase C (aPKC) isoforms associate with TGFβ receptors and modulate receptor trafficking and signal transduction. An aPKC-associated protein, p62 (SQSTM1) has been implicated in TGFβ-dependent EMT, however the mechanisms remain unclear.Here, we investigate the localization of p62 and its potential roles in modulating TGFβ signaling via knockdown and overexpression studies. Using antibody feeding and immunofluorescence microscopy, we support previous findings showing that p62 localizes to late endosomes. In addition, using a co-immunoprecipitation approach, we observed that p62 may associate with TGFβ type II receptor. To explore the functional role of p62 in TGFβ signaling, we conducted protein silencing using siRNA. We observed TGFβ-independent decreases in E-cadherin expression. However these changes were independent of the phosphorylation status or nuclear translocation of Smad2.P62 also plays an important role in autophagy by targeting proteins for degradation. Recently, prolonged TGFβ stimulation has been shown to induce cellular autophagy. Therefore, it is in our interest to characterize the relationship between TGFβ-dependent EMT and autophagy, and to determine whether p62 has a regulatory role between these two processes.
Citation Format: Evelyn Ng, Adrian Gunaratne, John Di Guglielmo. The role of p62 (SQTSM1) in the transforming growth factor β signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 352. doi:10.1158/1538-7445.AM2017-352
Abstract 3536: The role of Nuclear factor I transcription factors in glioma
Authors: Chen Kok Siong , Richards Linda J. , Bunt Jens 
Published: July 2017

Abstract
Gliomas are the most common brain tumors in adults. Among the malignant gliomas, grade IV glioma, or glioblastoma (GBM), is the most aggressive form. Despite harsh treatments such as surgery, radiotherapy and chemotherapy, the median survival of GBM patients remains at just 12-15 months. GBM tumors could originate from cells of the glial lineage that have escaped the normal glial differentiation mechanisms. Therefore, by applying knowledge about normal glial development, we might understand how pathways that normally drive differentiation are affected in these tumors. If reactivating these pathways induces the differentiation of proliferative tumor cells, we could use this as a novel target for therapy.
Our research is focused on the Nuclear factor I (NFI) transcription factors, one of the key factors to induce glial differentiation during normal development and is implicated in glioma. In insertional mutagenesis glioma mouse models, Nfi genes are consistently disrupted, suggesting a role for NFI in glioma initiation. Furthermore, loss of NFIB is common in human astrocytoma, while loss of NFIA is associated with oligodendroglioma. To determine whether loss of Nfi alters glioma initiation, progression or tumor histology, we have crossed inducible glioma mice with conditional Nfi deletion mice to follow tumor initiation and progression using fluorescence imaging and immunohistochemistry.
Based on analyses of glioma mRNA expression data sets, NFIB expression correlates inversely with tumor grade and survival. Using immunofluorescence, we determined that both NFIA and NFIB are mainly expressed within the non-proliferative cells in GBM tissue, suggesting that NFI may play a direct role in tumor cell differentiation. To establish whether NFI expression can indeed inhibit tumor proliferation and induce differentiation, U251 GBM cells were transfected with NFI. While overexpression of NFIA and NFIB reduced cell proliferation, an NFI dominant-negative protein enhanced proliferation. We are currently validating these finding in vivo by electroporating NFI expression constructs into patient-derived GBM xenografts in mice. Our preliminary data show NFIB electroporated cells are indeed differentiated and non-proliferative.
Our data suggests that NFI-mediated glial differentiation can be induced in glioma to inhibit tumor growth and may prevent recurrence. Hence, activation of NFI could be a potential target for a glial differentiation-based approach to treat glioma.
Citation Format: Kok Siong Chen, Linda J. Richards, Jens Bunt. The role of Nuclear factor I transcription factors in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3536. doi:10.1158/1538-7445.AM2017-3536
Abstract 3549: C-MYC sensitizes GBM with primitive features to glutamine metabolism disruption
Authors: Poore Brad Andrew , Taylor Isabella , Rubens Jeffrey , Hanaford Allison , Maxwell Micah , Eberhart Charles , Raabe Eric 
Published: July 2017

Abstract
Glioblastoma (GBM) is among the most lethal of known human cancers, with a median survival of less than 15 months. The highly infiltrative nature and genetic heterogeneity of GBM renders treatment difficult. Therefore, better and more targeted therapies are needed for patients with GBM. There is a new WHO subset of GBM that contains primitive neuronal components (GBM-PNC). These tumors can arise from a histologically classic GBM, and often the GBM-PNC portions of the tumor contain C-MYC or N-MYC amplifications. High MYC expression is known to alter cellular metabolism, increasing reliance on glutamine, which may create opportunities for therapeutic intervention. We hypothesized that depriving GBM-PNC cells of glutamine using metabolic inhibitors would suppress growth and tumorigenicity. To create genetically appropriate GBM-PNC models, we derived cortex (CTX) human neural stem cells and transformed them through lentiviral expression of mutant p53, constitutively-active AKT and hTERT. Transformed neurospheres were then lentivirally transduced with either C-MYC or BMI1. These models formed aggressive tumors in mice and recapitulated the histological features of GBM with expression of NESTIN, GFAP, and MAP2. When treated with the glutamine metabolic inhibitors DON or Acivicin, transformed neurospheres that expressed C-MYC had decreased cellular proliferation (BrdU incorporation, P&lt;0.05) and increased apoptosis (cleaved caspase-3 expression, P&lt;0.05) while neurospheres expressing BMI1 had no statistically significant changes. Additionally, cells overexpressing C-MYC had an increased expression of glutaminase, an essential enzyme for glutamine incorporation into the TCA cycle. We hypothesize that C-MYC expression sensitizes GBM-PNET cancer cell lines to DON or Acivicin inhibition through greater reliance upon glutamine for its TCA cycle intermediates. In addition C-MYC upregulates multiple glutamine transporters, which may also be used to transport DON and/or Acivicin inside the cell, conferring increased sensitivity. After further validating glutamine metabolic inhibitors in orthotopic xenografts and investigating the mechanism of action by metabolomics, we anticipate that metabolic inhibitors may have a therapeutic role in GBM-PNC.
Citation Format: Brad Andrew Poore, Isabella Taylor, Jeffrey Rubens, Allison Hanaford, Micah Maxwell, Charles Eberhart, Eric Raabe. C-MYC sensitizes GBM with primitive features to glutamine metabolism disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3549. doi:10.1158/1538-7445.AM2017-3549
Abstract 3553: Mutant KRas-mediated AKT2 activation supports lung cancer growth by activating complex II-driven mitochondrial metabolism
Authors: Park Kwan-Hee , Lee Ho-Young 
Published: July 2017

Abstract
Non-small cell lung cancer (NSCLC), the most common type of lung cancer (comprising 80-85 %), is a leading cause of cancer-related death worldwide. KRAS mutation is s major driver oncogene in NSCLC. Constitutive activation of K-Ras via oncogenic mutations plays a key role in development and progression of NSCLC, and is an important target for drug development. Indeed, drugs that target RAF-MAPK and PI3K, the well-established downstream pathways of K-Ras, are being evaluated in the clinic. However, to date, no effective treatments specifically targeting K-Ras have reached the clinic. A new direction for anti-Ras therapies targeting Ras-mediated altered cellular metabolism is implied by recent studies. Hence, as an attempt to investigate novel therapeutic targets to suppress KRAS-driven NSCLC, we assessed metabolic changes in NSCLC cell line and mouse model systems with oncogenic K-Ras mutations. We show that activation of Ras causes metabolic alterations, leading to aerobic glycolysis. Interestingly, despite the changes in the glycolytic pathway, NSCLC cell line and mouse models carrying K-Ras mutation revealed an elevated mitochondrial membrane potential, superoxide production as well as maximal oxygen consumption rate. Moreover, blockade of mitochondrial respiration effectively reduced mutant KRas-driven neoplastic phenotypes in NSCLC cell lines vitro and lung tumor formation in vivo. In contrast, blockade of glycolysis was not effective in the mutant KRas-driven tumorigenic activities. Mechanistically, mutant KRas-mediated activation of Akt2 led to increased expression of succinate dehydrogenase subunit A (SDHA) through increased protein stability by blocking proteasome-mediated degradation, resulting in mitochondrial complex II-dependent respiration. Our study suggests that induction of mitochondrial complex II-dependent respiration is an important mechanism by which oncogenic mutant KRas induces metabolic changes and ROS stress in NSCLC cells, contributing to lung carcinogenesis. Our findings elucidate potential metabolic targets that may provide novel therapeutic strategy for treating NSCLC with oncogenic KRAS mutations.
Citation Format: Kwan-Hee Park, Ho-Young Lee. Mutant KRas-mediated AKT2 activation supports lung cancer growth by activating complex II-driven mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3553. doi:10.1158/1538-7445.AM2017-3553
Abstract 3555: Lipid droplets, a novel metabolic target in glioblastoma
Authors: Geng Feng , Guo Jeffrey , Cheng Xiang , Wu Xiaoning , Cheng Chunming , Chakravarti Arnab , Guo Deliang 
Published: July 2017

Abstract
Lipid metabolism reprogramming is a novel feature of malignancies. Identifying the vulnerability of lipid alteration in tumor cells provides a new window to treat cancer. Here, we unraveled that glioblastoma (GBM) patients containing high levels of lipid droplets (LDs), special organelles storing cholesterol esters and triglycerides in cells, presented poor survival. We found that LDs largely formed in tumor tissues from GBM patients, but rarely in low grade of gliomas and normal brain tissues, demonstrating that LDs might serve as a novel diagnostic biomarker and prognostic marker for GBM. We further revealed that sterol O-acyltransferase 1 (SOAT1), the key enzyme controlling cholesterol esterification and LD formation, is highly expressed and correlated with LD prevalence in tumor tissues from GBM patients. Genetic or pharmacologic inhibition SOAT1 using avasimibe, a phase III clinical trial drug in human atherosclerosis patients, significantly suppressed GBM growth and prolongs survival in xenograft models. Moreover, we found that inhibiting SOAT1 suppressed sterol regulatory element-binding protein-1 (SREBP-1), a key transcription factor playing a central role in lipid synthesis, underlying the molecular mechanism of targeting SOAT1-mediated GBM growth suppression. In summary, our data demonstrate that LDs/cholesterol esters uniquely formed in tumor tissues provides an ideal target to specifically inhibit GBM cells whereas sparing normal brain tissues, and reveal that blocking cholesterol storage via targeting SOAT1 represents a promising strategy for GBM treatment.
Citation Format: Feng Geng, Jeffrey Guo, Xiang Cheng, Xiaoning Wu, Chunming Cheng, Arnab Chakravarti, Deliang Guo. Lipid droplets, a novel metabolic target in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3555. doi:10.1158/1538-7445.AM2017-3555
Abstract 3567: Sequencing the human TCRβ repertoire on the Ion S5™ System
Authors: Topacio-Hall Denise S. , Looney Tim , Sun Yongming , Miller Lauren , Linch Elizabeth , Lowman Geoffrey , Lin Lifeng , Andersen Mark , Hyland Fiona , Mongan Ann 
Published: July 2017

Abstract
Next-generation Sequencing (NGS) is proving an important tool in increasing understanding of the human immune system, and thereby cancer immunology. αβ-T cells are the primary constituents of human cell-mediated adaptive immunity. The antigen specificity of each αβ-T cell is encoded in the 500-600 bp transcript encompassing the variable portion of the rearranged TCRα and TCRβ subunits, which can be read via NGS in a process termed repertoire sequencing. Until now, the main challenge the field faces is the lack of a technology that can provide a contiguous read of 600 bp to minimize the complexity of designing bias-prone primers and informatics challenges of stitching short reads. Here we leverage the long read capability of Ion 530™ chip to comprehensively sequence all three CDR domains of the TCRβ chain. The Ion 530™ chip offers greater than 15 M productive reads, allowing a multiplex of 2-4 samples with sufficient coverage for most repertoire profiling studies. Initial testing with Leukocyte total RNA demonstrates that this multiplex PCR assay produced repertoires that were much more similar to data derived from 5’RACE protocol than the commonly used BIOMED2 primer set. This result suggested that the use of long reads minimizes bias by allowing targeting of less variable regions. To further assess the performance of the assay, we designed a model system of 30 plasmid controls containing common human T-cell CDR3 sequences. Each plasmid was amplified individually and sequenced to confirm the detection of a single clonal population. Analytical sensitivity of the assay and accuracy of the accompanied analysis solution were further evaluated by spiking in plasmid concentrations from 10 pg to 0.0001 pg (5 million to 50 copies) in a background of 100 ng cDNA reverse transcribed from leukocyte total RNA. Results showed the assay offers linearity over 5 orders of magnitude of decreasing input concentration. In summary, we have demonstrated a NGS workflow for TCRβ sequencing that offers multiplex flexibility on Ion S5 with sample to answer in less than 48 hours. For Research Use Only. Not for use in diagnostic procedures.
Citation Format: Denise S. Topacio-Hall, Tim Looney, Yongming Sun, Lauren Miller, Elizabeth Linch, Geoffrey Lowman, Lifeng Lin, Mark Andersen, Fiona Hyland, Ann Mongan. Sequencing the human TCRβ repertoire on the Ion S5™ System [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3567. doi:10.1158/1538-7445.AM2017-3567
Abstract 357: NKX2-1 regulates SMAD and non-SMAD pathways in thyroid stem cells
Authors: Iwadate Manabu , Takizawa Yoshinori , Kimura Shioko 
Published: July 2017

Abstract
NKX2-1 plays a critical role in thyroid differentiation. Recently, we established Side Population cells-derived Thyroid cell line (SPTL) from mouse thyroid Side Population cells. In SPTL cells, NKX2-1, PAX8 and E-cadherin were not expressed when examined by western blotting. Immunocytochemistry revealed that only 1% of SPTL cells were NKX2-1 positive. When GFP-SPTL cells were directly injected into mouse thyroid, a few GFP-SPTL cells with weak expression of NKX2-1 were found in part of thyroid follicle, suggesting that SPTL cells have potential of thyroid stem cells. Comprehensive gene expression analysis indicated that TGF-beta signaling pathway is critical for SPTL cells. TGF-beta signaling and NKX2-1 appear to play an important role in thyroid stem cells and thyroid differentiation. Here we show that NKX2-1 regulates both SMAD and non-SMAD pathways in SPTL cells. To examine the role of NKX2-1 in SPTL cells, we produced SPTL cells having doxycycline-inducible Nkx2-1 expression (named SPTL(Nkx2-1on)). In SPTL(Nkx2-1on) cells, doxycycline induced NKX2-1 as expected, while PAX8 and E-cadherin expression was not. Upon overexpression of NKX2-1 in SPTL(Nkx2-1on) cells, TGF-beta-induced phospho-SMAD3 expression was inhibited. Additionally, NKX2-1 enhanced the expression of phospho-AKT. In GFP-myrAKT(constitutively active AKT)-overexpressing SPTL cells, AKT was found localized in their cytoplasm. TGF-beta did not induce phospho-SMAD3 in these cells. The data indicate that NKX2-1 inhibits SMAD pathway through AKT activation. Ourwork demonstrates that TGF-beta signaling is controlled by NKX2-1 in thyroid stem cells.
Citation Format: Manabu Iwadate, Yoshinori Takizawa, Shioko Kimura. NKX2-1 regulates SMAD and non-SMAD pathways in thyroid stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 357. doi:10.1158/1538-7445.AM2017-357
Abstract 3574: A survey of mutations in biomedical literature using a machine based approach
Authors: Koyama Takahiko , Rhrissorrakrai Kahn , Parida Laxmi 
Published: July 2017

Abstract
Introduction:
Being able to characterize mutations for both pathogenicity and drug response is indispensable to the analysis of tumor genomics and the development of therapeutic options. While a great deal of data has been deposited in various structured, genomic databases, a large portion of insights are primarily and often times solely found in biomedical literature. Medline contains about 26 million literature citations; a number that is unrealistic for a human to read. Thus machine based approaches are needed to comprehensively capture the landscape of reported mutations.
Method:
An automated pattern matching method is utilized to extract mutations from Medline abstracts as presented in Human Genome Variation Society (HGVS) format and RefSNPs (rs) number. A typical HGVS protein mutation is described as [reference amino acid][position][new amino acid], as in p.His1047Arg, His1047Arg, or simply H1047R in HGVS format. This method identifies and consolidates all mentioned protein mutations and their alternate formulations.
Result:
Over 300,000 unique abstract-mutation pairs were identified including 90,000 unique mutations. Well known cancer mutations such as BRAF V600E, JAK2 V617F and EGFR L858R are among the most frequent appearing in oncology literature. At the other end, 51,000 mutations are mentioned in just a single abstract, 16,000 mutations in two abstracts, 7,600 in three abstracts, and so forth.
Conclusion:
The number of mutations appearing in Medline abstracts represents just a small portion of the 2 million unique coding mutations contained in the COSMIC database. While we expect the actual coverage of mutations by literature to be more comprehensive if this approach is extended to the full text body, the number would likely remain small compared with the total reported COSMIC mutations. One of the great challenges in oncology is characterizing variants of unknown significance (VUS), and by first extracting all reported mutations, even those mentioned in only one article, and their specific biological context, we can begin to identify broader patterns in mutations’ pathogenicity and their impact on drug response.
Citation Format: Takahiko Koyama, Kahn Rhrissorrakrai, Laxmi Parida. A survey of mutations in biomedical literature using a machine based approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3574. doi:10.1158/1538-7445.AM2017-3574
Abstract 3588: Computational method to identify non-coding cancer drivers
Authors: Liu Eric Minwei , Dhingra Priyanka , Fundichely Alexander M. , Khurana Ekta 
Published: July 2017

Abstract
Cancer is caused by mutations in driver genes - yet ~25% patients do not show any mutations in known drivers. ~99% somatic mutations obtained from whole-genome sequencing localize to regions that do not code for proteins and many of these non-coding mutations regulate gene expression. Although variants in protein-coding regions have received the majority of attention, numerous studies have now noted the importance of non-coding variants in cancer - for example, mutations in the promoter of the TERT gene. Identification of functional non-coding variants that drive tumor growth remains a challenge and a bottleneck for the use of whole-genome sequencing in the clinic. Cancer drivers are generally identified by the high frequency at which their mutations occur across patients. However, mutation rate is highly heterogeneous across the genome and many non-driver elements show higher mutation frequency than others, such as regions bound by transcription factors (TFs) in melanoma or regions replicating late during cell division in colon cancer. We have developed a novel computational approach to predict non-coding cancer drivers that differentiates between regions highly mutated due to positive selection (true drivers) vs those due to mutation rate heterogeneity (false positives). This method integrates the signals of high functional impact of variants with the recurrence of variants across multiple tumor samples to identify the elements that show more and higher functional impact mutations than expected randomly. Our method controls for multiple covariates of mutation rates, such as replication timing, histone modification marks and open chromatin regions to identify the non-coding cancer drivers. The functional impact is predicted using the FunSeq scheme that uses the properties of ENCODE elements (including conservation, TF motif disruption and network properties) within a weighted scoring scheme to predict deleteriousness of non-coding variants. I will present the details of this method and discuss the ongoing efforts to analyze ~2,900 tumor whole-genomes in the ‘Pan-Cancer Analysis of Whole Genomes, PCAWG’ consortium.
Citation Format: Eric Minwei Liu, Priyanka Dhingra, Alexander M. Fundichely, Ekta Khurana. Computational method to identify non-coding cancer drivers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3588. doi:10.1158/1538-7445.AM2017-3588