bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A11: Identification of the premalignant cell of origin in human glioblastoma multiforme
Authors: Mitra Siddhartha S. , Gholamin Sharareh , Sinha Rahul , Morganti Rachel M. , Weissman Irving , Cheshier Samuel H. 
Published: May 2016

Abstract
One of the major difficulties in identifying the cell of origin for glioblastoma is the complex cellular composition of this disease. It is now hypothesized that the different subtypes of high-grade glioma may have different cell of origin and in mouse models it has been shown that the cell of origin resides within the progenitor populations. To identify the human cell of origin we delineated the stages of CNS stem cell differentiation in fetal and adult human brain. After a functional high throughput screen, we identified a panel of four antibodies (i.e CD15, Notch1, EGFR, and CD90) that in various combinations can separate long-term self-renewing multi-potent neural stem cells (NSCs) from multi-potent progenitors with limited self-renewal capacity (NPC) from non-neoplastic human fetal and adult Brain (sub-ventricular zone). FACS sorted cells were analyzed for single cell lineage multi-potentiality, lineage bias and self-renewal to trace and characterize their lineage relationships. In surgical human glioblastoma samples, however we observed in-vivo tumor initiating and in-vitro tumorsphere-forming frequency was predominant in the progenitor cells and not in the neural stem cells. Interestingly we did observe a small frequency of NSC cells forming distinct lesions in the brain, which on further analysis showed the presence of both the NSC and NPC, whereas the tumor initiating enriched population did not show the presence of the NSC but only tumor initiating NPCs. Taken together our data suggests the presence of “normal” or pre-malignant stem cells in glioblastoma, RNAseq and targeted sequencing of known mutations identified the genomic events which can distinguish these pre-malignant neural stem cells from the tumor initiating cancer stem cells. These pre-malignant cells could comprise a cellular reservoir that may need to be targeted to prevent tumor relapse.
Citation Format: Siddhartha S. Mitra, Sharareh Gholamin, Rahul Sinha, Rachel M. Morganti, Irving Weissman, Samuel H. Cheshier. Identification of the premalignant cell of origin in human glioblastoma multiforme. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A11.
Abstract B05: Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas
Authors: Eun Kim Ja , Cho Hye Rim , Xu Wen Jun , Kim Young-Hoon , Phi Ji Hoon , Choi Seung Hong , Park Sunghyouk , Park Chul-Kee 
Published: May 2016

Abstract
Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) and the discovery of IDH1 mutations are major recent advances in glioma management and research. However, the mechanism underlying the selective intracellular accumulation of the 5-ALA derivative protoporphyrinogen IX (PpIX) and the metabolic effect of IDH1 mutations in malignant glioma cells are still not fully understood. Based on clinical experience, we hypothesized an association between enhanced 5-ALA fluorescence and IDH1 mutations in WHO grade III gliomas. Using genetically engineered malignant glioma cells harboring wild type (U87MG-IDH1WT) or mutant (U87MG-IDH1R132H) versions of IDH1, we confirmed a lag in 5-ALA metabolism and a temporary accumulation of PpIX in U87MG-IDH1R132H cells. To investigate the metabolic aspects of the mechanism responsible, we used liquid chromatography–mass spectrometry (LC-MS) to screen for tricarboxylic acid (TCA) cycle-related metabolite changes resulting from 5-ALA exposure. We observed low baseline levels of NADPH, an essential cofactor for the rate-limiting step of heme degradation, in U87MG-IDH1R132H cells. Abundant levels of NADPH are required to metabolize excessive 5-ALA, giving a plausible reason for the temporary enhanced 5-ALA fluorescence in mutant IDH1 cells. This hypothesis was supported by the results of metabolic screening in human malignant glioma samples. We discovered a relationship between enhanced 5-ALA fluorescence and IDH1 mutations in malignant gliomas and investigated the metabolic aspects of the mechanism responsible, identifying significantly different levels of NADPH between wild type and mutant IDH1 malignant glioma cells.
Citation Format: Kim Ja Eun, Hye Rim Cho, Wen Jun Xu, Young-Hoon Kim, Ji Hoon Phi, Seung Hong Choi, Sunghyouk Park, Chul-Kee Park. Mechanism for enhanced 5-aminolevulinic acid fluorescence in isocitrate dehydrogenase 1 mutant malignant gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B05.
Abstract B10: Clinical validation of targeted next-generation sequencing for glioblastoma patients
Authors: Trépant Anne-Laure , Mercier Marie Le , Maris Calliope , Nève Nancy De , Blanchard Oriane , D'Haene Nicky , Salmon Isabelle 
Published: May 2016

Abstract
Objective: Glioblastomas (GBMs) are the most common malignant primary brain tumours in adults. These tumours are resistant to conventional treatment approaches including surgical resection, radiotherapy and chemotherapy. International efforts to catalogue mutations for multiple forms of cancer coupled with the successes of targeted agents in patients with molecularly defined tumors and improvements in genomic technology have generated enthusiasm for incorporating genomic profiling into clinical cancer practice. The development of tyrosine kinase inhibitor treatments has made it important to test cancer patients for clinically significant gene mutations that influence the benefit of treatment. Therefore, the number of biomarkers that will need to be assessed is expected to increase rapidly. Recently, next generation sequencing (NGS) has begun to supplant other technologies for gene panel sequencing. However, few studies have validated the use of targeted NGS for GBM patients. In the present study we evaluate the clinical applicability of targeted NGS for patients with GBM.
Methods: DNA from 50 GBM samples (formalin-fixed paraffin-embedded tissue) was retrospectively subjected to targeted NGS with the Ampliseq Cancer Hotspot Panel, using the Ion Torrent Personal Genome Machine, which allowed us to analyze 2850 known cancer-related mutations in 50 genes. In addition, MGMT methylation status, EGFR amplification and 1p19q deletion were evaluated by Methylation Specific PCR (MSP), chromogenic in situ hybridisation (ISH) and fluorescence ISH, respectively.
Results: Preliminary results on 28 patients, all successfully sequenced, showed that the most frequent mutations were found in TP53 (25%) and EGFR (18%). Potentially actionable mutations were identified in 9 patients (32%), including 5 EGFR mutations, 2 PIK3CA mutations, 1 PTEN mutation, 1 PDGFRA mutation and 1 IDH1 mutation. The frequencies of these variants detected by NGS were consistent with frequencies reported in public databases. Moreover, PDGFRA and EGFR amplifications were detected by coverage analysis for 10 (36%) and 2 (7%) patients respectively.
Conclusions: Overall, the AmpliSeq Cancer Hotspot Panel can be applied in daily practice for GBM samples. Moreover, it can provide clinically relevant information for GBM patients.
Citation Format: Anne-Laure Trépant, Marie Le Mercier, Calliope Maris, Nancy De Nève, Oriane Blanchard, Nicky D'Haene, Isabelle Salmon. Clinical validation of targeted next-generation sequencing for glioblastoma patients. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B10.
Abstract B35: BMP regulation of cancer stem cell quiescence is responsible for chemotherapeutic resistance in glioblastoma
Authors: Wu Megan YiJun , Celebre Angela , Chan Jeffrey , Guan Jennifer , Dhand Karan , Loukides James , Karamchandani Jason , Das Sunit 
Published: May 2016

Abstract
Introduction: Cancer stem cells (CSCs) represent a distinct cellular population that has been implicated in tumor recurrence following chemotherapy. Accumulating evidence indicates that BMP signaling plays an important role in the regulation of CSCs, and may be involved in the resistance of CSCs to cytotoxic drugs. The role of BMP pathway regulation of the CSC phenotype responsible for treatment resistance in glioblastoma (GBM) has not been explored.
Methods: Paraffin-embedded (FFPE) samples from GBM patients were used to evaluate the expression of markers for BMP signaling (pSMAD1/5/8), proliferation (PCNA), and stemness (SOX2) by immunostaining. We tested the self-renewal capacity of primary patient-derived glioma stem cell (GSC) lines using a sphere formation assay. Expression of stemness markers SOX2 and Bmi-1 in BMP4 treated and untreated GSCs, was analyzed by Western blotting. We also performed xenograft transplantation, whereby GSCs were injected intracranially into immunedeficient mice. When tumor formation was confirmed post-injection, mice were administrated EdU and sacrificed at successive time points thereafter. The frequency of all EdU positive cells as well as ID-1positive/ EdU positive cells was quantified from the primary tumor sections throughout the labeling and chase. To study chemoresistance in glioblastoma, GSC lines were treated with graded concentrations of temozolomide (TMZ).
Results: We found that pSMAD1/5/8 positive cells in primary patient tumors were largely PCNA-negative. BMP4 treatment inhibited GSC proliferation and self-renewal (sphere-formation), but did not abolish expression of markers of stemness, such as Sox2 and Bmi-1, or tumorigenicity. In our in vivo model, we found ID-1 positive cells retain EdU following a long-term chase. Taken together, these results demonstrate that BMP4-enriched cells possess the characteristics of a quiescent stem cell population. BMP4 treatment protects GSCs against TMZ-induced growth inhibition. Furthermore, pSMAD1/5/8-expressing cells do not possess the DNA damage marker gamma-H2AX following TMZ treatment, suggesting that activation of the BMP pathway protects GSCs against TMZ-induced DNA damage.
Conclusion: This study establishes that the BMP signaling pathway is involved in the maintenance of GSC quiescence and may play a role in glioblastoma chemoresistance.
Citation Format: Megan YiJun Wu, Angela Celebre, Jeffrey Chan, Jennifer Guan, Karan Dhand, James Loukides, Jason Karamchandani, Sunit Das. BMP regulation of cancer stem cell quiescence is responsible for chemotherapeutic resistance in glioblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B35.
Abstract B36: NF-kappaB-dependent and -independent roles for NIK in regulating GBM cell invasion
Authors: Duran Camille L. , Lechuga Linda Herrera de , Lee Dong W. , Bayless Kayla J. , Sitcheran Raquel 
Published: May 2016

Abstract
The aggressive invasion of GBM cells into healthy brain tissue is a major factor contributing to the therapy resistance and poor prognosis of this malignancy. Our recent results demonstrated that the alternative, or noncanonical, NF-kappaB signaling pathway, predominates in the aggressive mesenchymal subtype of GBM. Additionally, NF-kappaB-inducing kinase (NIK), a key upstream activator of noncanonical NF-kappaB signaling, robustly promotes GBM cell invasion and pathogenesis. We demonstrate that expression of NIK is increased in response to exposure to collagen, a major extracellular matrix (ECM) protein present in GBM tumors, with NIK protein levels continuing to increase during invasion in 3D collagen matrices. Interestingly, NIK expression levels correlates with induction of membrane type-1 matrix metalloproteinase (MT1-MMP), a critical enzyme in many invasive tumors, functioning to degrade the basement membrane and ECM during cell migration and invasion. We provide evidence that NIK promotes MT1-MMP activation through increased phosphorylation at membrane protrusions and elevated enzymatic activity. Notably, the activation of MT1-MMP and the pro-invasive effects of NIK persist in the absence of the downstream NF-kappaB transcription factors RelA/p65 and RelB. Together, these data demonstrate a novel ability of NIK to promote GBM cell migration and invasion that is independent of NF-kappaB transcriptional activation functions. The results underscore the therapeutic potential of targeting noncanonical NF-kappaB signaling in these highly invasive tumors.
Citation Format: Camille L. Duran, Linda Herrera de Lechuga, Dong W. Lee, Kayla J. Bayless, Raquel Sitcheran. NF-kappaB-dependent and -independent roles for NIK in regulating GBM cell invasion. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B36.
Abstract IA12: Investigating the functional consequences of ATRX deficiency in glioma
Authors: Huse Jason T. 
Published: May 2016

Abstract
Comprehensive genomic profiling in cancer continues to reveal frequent alterations in epigenetic regulators, firmly implicating chromatin biology in the oncogenic process. We and others recently found that inactivating mutations in the SWI/SNF family member ATRX represent defining molecular alterations in diffusely infiltrating gliomas, where they invariably pair with mutations in TP53 and IDH1/2. ATRX normally regulates the composition of histone monomers at a variety of sites across the genome, and may also affect the distribution of specific histone modifying complexes. A number of studies have linked ATRX deficiency to a wide spectrum of physiological dysfunction, including aberrant gene regulation, abnormal telomere maintenance, genomic instability, and aneuploidy. Nevertheless, the precise mechanisms by which ATRX deficiency promotes oncogenesis remain unknown.
To investigate the effects of ATRX deficiency on chromatin structure, gene expression, and transformation, we inactivated Atrx in murine neuroepithelial progenitor cells (NPCs) also lacking Tp53. We found that, in this context, Atrx deficiency induced widespread alterations in chromatin accessibility and organization, which in turn led to dramatic shifts in gene expression. Among the altered transcriptional networks were pathways implicated in cellular motility and invasion, an established feature of diffusely infiltrating gliomas. Intriguingly, Atrx-deficient NPCs also exhibited significantly increased transwell migration. Our findings demonstrate that ATRX deficiency promotes disease-relevant biological behavior by modulating chromatin accessibility and influencing gene expression. We are now performing detailed epigenetic and biochemical studies to identify the precise transcriptional events mediating these effects. We are also investigating how IDH mutations influence the genomic distribution of ATRX, thereby modulating its function and the consequences of its deficiency.
Citation Format: Jason T. Huse. Investigating the functional consequences of ATRX deficiency in glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA12.
Abstract A32: The role of microRNA in the regulation of DUSP16 gene and JNK family in hepatocellular carcinoma patients
Authors: Tantawy Marwa , Hassan Nagwa , Kobaisi Mohamed , Wahab Abdel Hady Abdel 
Published: May 2016

Abstract
Introduction: Human hepatocellular carcinoma (HCC) is consider one of the most common and lethal tumors worldwide, HCC is currently the fifth most common solid tumor worldwide and the fourth important cause of cancer-related death. Eighty percent of new cases found in developing countries as Egypt, but the incidence is increasing in economically developed regions, including Japan, Western Europe, and the United States.
It has shown that expression level of different miRNAs was correlated with cellular liver processes such as inflammation, hepatocyte regeneration and apoptosis which indicate their important role in many liver diseases including hepatocellular carcinoma. The main objective of the present study is to correlate between the expression levels of liver specific miRNAs with different mitogen activated protein kinase (MAPK) pathway in primary HCC patients.
Patients and Methods: The expression level of miRNA targeting MAPK pathway, Dual-Specificity Phosphatase 16 (DUSP16), c-Jun N-terminal kinases (JNK) family (JNK1, JNK2 and JNK3) were detected in tissue biopsy of 38 primary HCC patients as well as 6 healthy controls using qRT-PCR technique. Detection of the protein levels for DUSP16, JNK1 and JNK2 was done using immunohistochemistry (IHC) assay.
Results: The correlation between different expressions was done using (statistical method). Significant correlation was observed between 10 miRNAs with mRNA for DUSP16, JNK1, JNK2 and JNK3 (miR-18b; miR-30c; miR-30e; miR-99a; miR-126; miR-194; miR-198; miR-215; miR-455 and miR-455-3p). Highly significant down regulation was detected in JNK2 and JNK3 gene expression in HCC patients as compared to controls with (P value = 0.016, 0.000) respectively. Using IHC assay, 34% (13 out 38) showed DUSP16 (P value &lt;0.0001), 82% (31 out 38) for JNK1 (P value &lt;0.0001) and 71% (27 out 38) for JNK2. All control samples didn't show any protein expression of genes analyzed.
Conclusion: Understanding the role of miRNA in MAPK pathway may open new avenue for development novel treatment strategy in primary hepatocellular carcinoma.
Citation Format: Marwa Tantawy, Nagwa Hassan, Mohamed Kobaisi, Abdel Hady Abdel Wahab. The role of microRNA in the regulation of DUSP16 gene and JNK family in hepatocellular carcinoma patients. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr A32.
Abstract B1-01: Whole genome expression based drug repurposing
Authors: Geeleher Paul , Bhutra Steven , Wang Jacqueline , Huang R. Stephanie 
Published: May 2016

Abstract
Currently, personalizing cancer chemotherapy relies on pathology and more recently molecular biomarker-based approaches. However, as the driving biology is normally not fully understood, the majority of existing biomarkers do not capture a substantial proportion of variability in drug response. This partly explains the commonly observed lack of reproducibility of findings (e.g. from many conventional gene expression signatures) when these markers are applied to new datasets. We developed an approach to predict in vivo drug sensitivity that leverages whole-genome gene expression microarray data and allows the expression of every gene to influence the prediction by a small amount. Our approach builds statistical models from gene expression and drug sensitivity data in a very large panel of cell lines, then applies these models to gene expression data from primary tumor biopsies. In this study, we applied this approach to tumor samples collected in The Cancer Genome Atlas (TCGA). We derived predicted sensitivity for over one hundred drugs in each of the tumor samples. As a proof-of-concept, we demonstrated that a targeting agent (lapatinib) designed against a specific tumor marker (HER2 positive) is indeed predicted to be more sensitive in HER2 positive breast cancers when compared to the other type of cancers. Meanwhile, we identified other agents that exhibit similar or superior sensitivity when compared to commonly prescribed agents in different disease settings. These findings warrant further evaluation of these agents to be repurposed for possible new indications. Interestingly, some of our derived drug sensitivity predictive estimates are correlated with observed survival outcomes in certain cancer patients. When screening all tumor types based on their molecular profiles, we defined several classes of drugs that maybe differentially effective based on tumor molecular profiles. In conclusion, a genome-wide expression drug sensitivity model built in cell lines can be a powerful approach in repurposing drug in cancer treatment.
Citation Format: Paul Geeleher, Steven Bhutra, Jacqueline Wang, R. Stephanie Huang. Whole genome expression based drug repurposing. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-01.
Abstract B1-13: Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma
Authors: Vu Ha Linh , Davies Michael A. , Aplin Andrew E. 
Published: May 2016

Abstract
Melanoma is a devastating form of skin cancer with limited therapeutic options. Fifteen to twenty percent of melanoma patients have an activating mutation in NRAS, a small GTPase. NRAS has several downstream effectors, the most well-characterized is RAF leading to activation of MEK/ERK. While there are no FDA-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. Phase I to III studies of MEK inhibitors in mutant NRAS melanomas have shown disappointing clinical efficacy, the reasons for which are unclear. In 3D systems that mimic the dermal microenvironment, we found a heterogeneous response in our panel of mutant NRAS melanoma cells to the allosteric MEK inhibitor, trametinib. To explore the underlying basis of this heterogeneity, we utilized a high-throughput reverse-phase protein array (RPPA) platform to identify compensatory signaling alterations. The RPPA analysis of phospho-proteomic changes in NRAS mutant melanoma in response to trametinib indicated a compensatory increase in AKT signaling. Interestingly, we detected a decrease in mitogen inducible gene 6 (MIG6), a negative regulator of ERBB receptors. The overexpression of MIG6 led to a negative regulation of EGFR (ERBB1) and ERBB2, and subsequent decrease in AKT activation. Conversely, the depletion of MIG6 increased EGFR and ERBB2 signaling. Either depletion of MIG6 or addition of EGF increased migration of NRAS mutant cells treated with trametinib, an invasive phenotype that may mitigate the negative effects of trametinib on cell growth. Our results indicate a potential role for the combined inhibition of EGF/ERBB receptors and MEK in NRAS mutant melanoma patients.
Citation Format: Ha Linh Vu, Michael A. Davies, Andrew E. Aplin. Phospho-proteomic analysis of MEK inhibition in mutant NRAS melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-13.