bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5408: RNA fusion detection in thyroid nodules with a targeted RNA sequencing panel
Authors: Tian Song , Baird Michelle , Reinecke Frank , Deng Jixin , Ranjbar Mohammad Nezami , Samara Raed , Lader Eric 
Published: July 2017

Abstract
Thyroid nodules are quite common and detected in as high as 67% of the population. Only a small portion of thyroid nodules are malignant thyroid cancers. Advances in understanding the molecular pathology of thyroid cancer are leading to the development of better biomarkers and novel targeted therapies. The tumorigenic role of RNA fusions has been reported in many forms of cancer. Fusions can result from structural rearrangements like translocations and deletions, transcription read-through of neighboring genes, or the trans- and cis-splicing of pre-mRNAs. Many fusions act as key drivers for cancer development. Detection of fusion RNA is a challenge with traditional technologies like FISH and qPCR, as they are laborious, low throughput, and do not provide detailed information about the fusion. Here we explored the possible use of a tumor fusion-targeted RNA-based panel (QIAseq targeted RNAscan panel, which is targeting 223 fusion gene pairs, 576 unique fusions) as a tool to study fusions in thyroid nodules. The presence of these fusions were surveyed in RNA samples from 10 thyroid cancer (PTC and FVPTC) samples and 19 non-cancer control samples (NH and FA) using this oncology targeted panel and sequenced on the Illumina NextSeq. PAX8-PPARG, a fusion gene with a well-established link to thyroid cancer, was found in the cancer group. In addition, we observed a universal expression of a recurrent read-through transcript, HALC1-COQL, in all thyroid nodules. Our results suggest that a targeted RNA-based panel provided a useful tool for fusion gene study in thyroid cancer. The role of the expected rearrangement and the unexpected read-through fusion in thyroid nodules needs to be further evaluated, as it could provide useful information for thyroid nodule differentiation.
Citation Format: Song Tian, Michelle Baird, Frank Reinecke, Jixin Deng, Mohammad Nezami Ranjbar, Raed Samara, Eric Lader. RNA fusion detection in thyroid nodules with a targeted RNA sequencing panel [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 5408. doi:10.1158/1538-7445.AM2017-5408
Abstract 5417: The tumor suppressor klotho: A master regulator of metabolism in breast cancer
Authors: Rubinek Tami , Wolf Ido 
Published: July 2017

Abstract
One of the hallmarks of cancer is reprogramming of energy metabolism, characterized by a shift to aerobic glycolysis (Warburg effect). A major regulator of this phenomenon is the IGF-1/Pi3K/AKT pathway. Klotho is a transmembrane protein, which can be cleaved, shed and act as a circulating hormone. Klotho-deficient mice manifest a syndrome resembling accelerated aging, while klotho overexpression extends life span. Klotho is a potent tumor suppressor in BC. As klotho is a potent inhibitor of the IGF-1/Pi3K/AKT pathway in BC, we hypothesized that it may revert the metabolic switch in BC cells. We first analyzed the effect of klotho on the energy sensor enzyme AMP-activated kinase (AMPK) and its down-stream effector acetyl CoA carboxylase (ACC). Overexpression of klotho, or treatment with the soluble protein, elevated AMPK and ACC phosphorylation in three BC cell lines. AMPK is activated by the tumor suppressor liver kinase B1 (LKB1) and elevated AMP/ATP ratio. Expression of a dominant negative LKB1 prevented activation of AMPK by klotho and decreased the ability of klotho to inhibit cell growth and migration, implying that klotho tumor suppressor activities are LKB1 dependent. We next analyzed the effects of klotho on critical components of glucose metabolism. Treatment with soluble klotho reduced expression of the glucose transporter GLUT1 and the key glycolytic enzymes hexokinase2 (HK2), phosphofructokinase1 (PFK1), pyruvate kinase M2 (PKM2) and pyruvate dehydrogenase kinase 1(PDK1). Using the Seahorse analyzer we noted reduced oxidative mitochondrial metabolism and glycolysis following klotho treatment. Energy is obtained essentially in the mitochondria with the transfer of protons across the inner membrane that produces ATP. We, therefore, analyzed klotho effect on the mitochondria membrane potential and noted reduction in the mitochondria potential following treatment with klotho. Finally, we examined the effects of klotho on specific metabolites and also conducted an NMR-based metabolic profiling. In accordance with the alterations in signaling pathways and levels of glycolytic enzymes, klotho reduced glucose uptake and inhibited lactate, pyruvate and 3-hydroxy-butyrate production. Furthermore, klotho also inhibited ATP production. Taken together, our data indicate klotho as a regulator of metabolic activity in BC and suggest that reversal of the metabolic switch is a key mechanism of klotho-mediated tumor suppressor activities.
Citation Format: Tami Rubinek, Ido Wolf. The tumor suppressor klotho: A master regulator of metabolism in breast cancer [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 5417. doi:10.1158/1538-7445.AM2017-5417
Abstract 542: Genomic and clonal characterization of immunogenic epitope landscape across The Cancer Genome Atlas
Authors: Lee HoJoon , Greer Stephanie , Grimes Susan M. , Cheong Jae-Ho , Ji Hanlee P. 
Published: July 2017

Abstract
Recent advances in cancer immunotherapy and genomic sequencing technologies have created promising opportunities for precision cancer medicine. Somatic mutation in coding regions of cancer genomes may lead to amino acid alterations that generate immunogenic peptides, called neoantigens. These novel peptides are tumor-specific. An individual’s own MHC genotypes restricts the presentation of these tumor-specific peptides and thus there are a limited number of candidate epitopes for immune cellular recognition. Current studies have not comprehensively studied how MHC-restricted neoantigens are present across tens of thousands of cancer. Nor have these studies determined how somatic mutations and their associated neoantigens are represented among different subclonal populations existing within individual tumors. To address these limitations, we have mapped the complex immunogenomic topology of neoantigen epitopes across 8,000 tumors representing 18 different cancer types. This neoantigen landscape accounts for how neoepitope candidates are distributed among the various clonal subpopulations existing within any given tumor.Our study utilized genomic data from the Cancer Genome Atlas (TCGA). Our automated pipeline provides results from 8,000 samples from 18 cancer types that have somatic variant calls, copy number variation, whole exome sequence, and RNA-Seq data. Identification of somatic mutations that lead to highly immunogenic antigens involved five different steps; i) in-silico translation of identified mutations, ii) expression as measured per RNA-Seq, iii) patient’s own major histocompatibility complex genotype, iv) binding affinity specific to the MHC alleles for any given patient and v) occurrence of clonal subpopulations as demonstrated by intratumoral genetic heterogeneity. We mapped the neoantigen landscape with quantitative representation of the genetic clonal diversity existing within individual tumors. In average, 2% of missense mutations from a patient are detected in RNA-Seq, with binding affinity to own HLA genotypes, and from the dominant clonal subpopulation.In summary, our study demonstrates the various relationships among the number of optimal antigens, the number of clonal subpopulations, the number of mutations, and clinical phenotypes such as tumor stage. Our automated bioinformatics process facilitates the use of exome and RNA-Seq as potential diagnostic analytic process for precision immunotherapy.
Citation Format: HoJoon Lee, Stephanie Greer, Susan M. Grimes, Jae-Ho Cheong, Hanlee P. Ji. Genomic and clonal characterization of immunogenic epitope landscape across The Cancer Genome Atlas [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 542. doi:10.1158/1538-7445.AM2017-542
Abstract 5423: ZAP70 alters metabolism in chronic lymphocytic leukemic cells
Authors: Das Subhadip , Dielschneider RF , Henson Elizabeth S. , Gibson Spencer B. 
Published: July 2017

Abstract
Chronic lymphocytic leukemia (CLL) has the highest incidence among adults in western countries. Prognosis of CLL is highly variable but one of the biomarker zeta-chain-associated protein 70 (ZAP70) over expression is associated with aggressive disease with time to treatment being 2.6 years for ZAP70 expressing (ZAP70+) patients and 8 years for ZAP70 deficient (ZAP70-) patients. Thus ZAP70 may play a role in CLL progression. Metabolic reprograming plays a central role in cancer progression and is altered in CLL cells. However, the role of ZAP70 in metabolism in CLL cells is remains unclear. We found that ZAP70 binds to pyruvate kinase M2 (PKM2). PKM2 is key isoform of pyruvate kinase which is rate limiting enzyme of the glycolytic pathway and provides a metabolic advantage to tumour cells allowing for increased growth. Our results also indicated the PKM2 is expressed in CLL cells and binding to ZAP70 is not affected by glucose starvation or treatment with kinase inhibitors. Furthermore immunofluorescence microscopy revealed that ZAP-70 and PKM2 colocalize in CLL cells in the cytoplasm. In addition, we found ZAP70+ cells have increased rate of oxygen consumption from basal level determined by addition of inhibitor (Oligomycin A) and mitochondrial uncoupler (FCCP). Simultaneously ZAP70+ cells also have higher extracellular acidification rates. This indicates ZAP70+ CLL cells have increased mitochondrial respiratory capacity with high glycolytic rate. In addition, fluorometric analysis indicates ZAP70+ CLL cells have high glucose consumption rate towards production of lactate compared to ZAP70- CLL cells. Collectively, our data reveals a new function for ZAP70, which is to regulate the Warburg effect and may play a role in CLL progression and may identify new therapeutic targets.
Note: This abstract was not presented at the meeting.
Citation Format: Subhadip Das, RF Dielschneider, Elizabeth S. Henson, Spencer B. Gibson. ZAP70 alters metabolism in chronic lymphocytic leukemic 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 5423. doi:10.1158/1538-7445.AM2017-5423
Abstract 5427: Distinctions between the metabolic changes in glioblastoma cells and glioma stem-like cells following irradiation
Authors: Spehalski Elizabeth I. , Peters Cord , Tofilon Philip , Camphausen Kevin 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and, even with aggressive treatment that includes surgical resection, radiation, and temozolomide administration, prognosis is poor due to tumor recurrence. There is evidence that within GBMs a small number of glioma stem- like cells (GSCs) exist, which are thought to be radiation resistant and may be capable of repopulating a tumor after treatment. Like most cancers, GBMs largely employ aerobic glycolysis to create ATP, a phenomenon known as the Warburg effect. Experiments have shown that the cellular metabolism of GSCs differs from that of differentiated cells, making them an attractive target for novel therapeutic approaches. Much work has been done to analyze the metabolic profiles of GSCs with the goal of identifying potential therapeutic targets, but little data exists linking metabolic changes to radiation resistance. The purpose of this study is to characterize the metabolic differences between glioma stem- like cells and traditional GBM tumor cells with and without radiation treatment (IR).
To this end, we compared the metabolism of a human derived GSC line with two commonly used GBM cell lines before and after IR. At baseline, we find that glioma stem-like cells are more quiescent than GBM cells, which have higher levels of both glycolysis and oxidative phosphorylation. GBM lines show higher levels of both basal and maximal respiration, as well as basal glycolysis and glycolytic capacity than GSCs. They also express higher levels of energy, glycolysis, and TCA cycle metabolites than GSCs. Inversely, GSCs demonstrate metabolic signs of quiescence such as decreased NEAA synthesis.
After IR, the radiation- sensitive GBM tumor cell line (U251) exhibits increases in all metabolic pathways, whereas the levels of glycolytic and oxidative metabolites in the GSCs remain unchanged. All cell lines show an increase of ATP and NAD production following IR. These findings indicate that the metabolism of GSCs undergoes different alterations than that of GBM tumor cells after IR, making them an attractive target for novel therapeutic approaches in conjunction with radiation therapy. Additionally, differences in metabolic signatures between GSC lines could be useful for non-invasive diagnostic modalities such as 13C MR spectroscopy.
Citation Format: Elizabeth I. Spehalski, Cord Peters, Philip Tofilon, Kevin Camphausen. Distinctions between the metabolic changes in glioblastoma cells and glioma stem-like cells following irradiation [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 5427. doi:10.1158/1538-7445.AM2017-5427
Abstract 544: Hypoxia response signaling is linked to TACE resistance in hepatocellular carcinoma (HCC) patients
Authors: Fako Valerie , Lee Joyce , Cheung Tan-To , Ng Irene O. , Wang Xin W. 
Published: July 2017

Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and outcome is dismal, due to tumor heterogeneity and lack of effective treatment options for patients with later stage disease. Transcatheter arterial chemoembolization (TACE) is the gold standard of therapy for patients with intermediate to locally advanced tumors. TACE delivers a high dose of chemotherapy directly to the tumor via the hepatic artery, followed by an embolizing agent to restrict tumor blood supply. However, tumor hypoxia is linked to alterations in metabolism, such as increased glycolysis (the Warburg effect), and can lead to enhanced cell survival. Several randomized control trials (RCTs) showed a survival benefit with TACE, but only with strict patient selection criteria. In Asia, TACE is also commonly used as adjuvant therapy after surgical resection, yet RCTs evaluating adjuvant TACE have shown conflicting results, likely due to patient selection and stratification. We hypothesize that tumor gene expression is predictive of response following TACE, and that differential cellular metabolism resembling a hypoxic phenotype prior to treatment is responsible for TACE resistance. We retrospectively analyzed gene expression data in treatment-naive tumor tissue from a cohort of Chinese patients who received TACE. Using hierarchical clustering, followed by class comparison and survival risk prediction, we identified a 14-gene signature that is predictive of response vs. non-response to TACE, as measured by overall survival, independent of other clinical variables. We found that hypoxia- and glycolysis-related genes are enriched among differentially expressed genes in TACE Responders vs. Non-Responders, and that hypoxia master regulator HIF-1α and hypoxia target gene VEGF are significantly up-regulated in Non-Responders. We determined that a key glycolysis gene is up-regulated in Non-Responders, and conversely, two rate-limiting genes involved in gluconeogenesis, the pathway opposing glycolysis, are up-regulated in Responders. We also examined metabolomic data from the TACE cohort, and found an enrichment of glycolysis-related metabolites in Non-Responders, and gluconeogenesis-related metabolites in Responders. Further investigation will be required to connect altered glucose metabolism to TACE resistance and to determine driver genes linking hypoxia and metabolism, which, together with our 14-gene signature, may serve as a stratification tool to guide personalized treatment modalities for HCC patients.
Citation Format: Valerie Fako, Joyce Lee, Tan-To Cheung, Irene O. Ng, Xin W. Wang. Hypoxia response signaling is linked to TACE resistance in hepatocellular carcinoma (HCC) patients [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 544. doi:10.1158/1538-7445.AM2017-544
Abstract 5440: miRNAs as novel therapeutic adjuvants for improving the efficacy of vincristine and radiation therapy in treating medulloblastoma
Authors: Abdelfattah Nourhan , Rajamanickam Subapriya , Subbarayalu Panneerdoss , Timilsina Santosh , Onyeagucha Benjamin , Chen Yidong , Rao Manjeet 
Published: July 2017

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite recent improvements in the overall survival, only a modest percentage of patients survive Myc-driven high-risk MB. The quality of life for surviving patients is substantially reduced due to the devastating and often irreversible side effects of radiation and chemotherapy. Recently, in a large unbiased genomic screen, we uncovered a group of microRNAs (miRNAs) capable of meditating drug sensitivity in c-myc amplified high-risk MB. Our functional screen of ~1900 miRNAs identified miR-584-5p as a potent candidate that uniquely sensitizes high-risk MB to radiation as well as vincristine (VCR) (20 to 25-fold dose reduction), an anti-mitotic agent routinely administered alongside radiation and in combination with other chemotherapeutic drugs to treat medulloblastoma patients. Our studies revealed that miR-584 might act as a potent tumor suppressor as it inhibited MB growth in vivo as well as migration and invasion of c-myc amplified MB. We show that miR-584 overexpression results in defective mitosis leading to mitotic catastrophe, apoptosis, DNA damage and G2-M cell-cycle arrest in high-risk MB cells without affecting normal neural stem cell growth. Notably, we discovered that miR-584 directly regulates the expression and activity of genes including histone deacetylase 1 (HDAC1), and eukaryotic translation initiation factor 4e family member 3 (EIF4E3) that are known to play important roles in microtubule dynamics, metaphase-anaphase transition and radio-resistance. Moreover, silencing either of these two target genes resulted in significant inhibition of MB growth and enhanced sensitivity to VCR and ionizing radiation. Overexpressing miR-584 or silencing either HDAC1 or EIF4E3 also inhibited the MB stem cell proliferation and self-renewal. We report that while miR-584-5p is predominantly expressed in normal brain and cerebellum, its expression is significantly reduced in MB patient derived xenografts (PDXs). In contrast to miR-584, EIF4E3 and HDAC1 were found to be overexpressed in medulloblastoma patients. These findings are highly significant, unexpected and innovative as this miRNA and its target genes are the first to be shown to affect the therapeutic efficacy of VCR and radiation in c-myc amplified high-risk medulloblastoma.
Citation Format: Nourhan Abdelfattah, Subapriya Rajamanickam, Panneerdoss Subbarayalu, Santosh Timilsina, Benjamin Onyeagucha, Yidong Chen, Manjeet Rao. miRNAs as novel therapeutic adjuvants for improving the efficacy of vincristine and radiation therapy in treating medulloblastoma [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 5440. doi:10.1158/1538-7445.AM2017-5440
Abstract 5456: Avoiding chemotherapy resistance in squamous cell carcinomas: anticancer activities of terpenoids and their impact on the regulation of microRNAs
Authors: Hernandes Camila , Silva Bruna da , Klingbeil Maria de Fatima Guarrido , Mathor Monica Beatriz , Pereira Ana Maria Soares , Severino Patricia 
Published: July 2017

Abstract
MicroRNAs are small noncoding RNAs that play important roles in cellular biology. They have been implicated in pharmacogenomics by down-regulating genes that are essential for drug function. In this work we verified the potential anticancer activity of the quinone methide triterpenes maytenin and 22-β-hydroxymaytenin, as well as of a quinone methide triterpene-rich extract obtained from cultivated Maytenus ilicifolia root cells, and evaluated the associated microRNA expression following half maximal inhibitory concentration (IC50) treatment. Standard selectivity index (SI) for the isolated compounds and the root cell extract was determined by the logarithmic shift in effective concentration (IC50) between cancer cell lines and oral keratinocytes. Both isolated molecules as well as the root cell extract presented pronounced antiproliferative and pro-apoptotic activities in four cell lines derived from head and neck squamous cell carcinomas, including a metastasis-derived cell line. A positive SI, with an average 2-fold increase in potency, was detected for single agents and for the extract. MicroRNA expression profiles were assessed at 24h, 48h and 72h following treatment and an average of 100 molecules presented consistent marked variation in expression levels. Considering associations of microRNAs, genes they regulate, and the drugs effects dependent on these genes, the down-regulation of miR-193a-3p and miR-21 in treated cells is of particular interest. Both microRNAs have been involved in 5-fluorouracil and cisplatin resistance, current agents of standard chemoradiotherapy for locally advanced head and neck cancer. Squamous cell carcinoma of the head and neck is one of the most common cancer types worldwide whereas treatment options based on conventional therapies or targeted therapies under development have limited efficacy. Plant-derived products are valuable sources for the development of new therapeutic options for cancer treatment or as synergistic agents in existing regular care.
Citation Format: Camila Hernandes, Bruna da Silva, Maria de Fatima Guarrido Klingbeil, Monica Beatriz Mathor, Ana Maria Soares Pereira, Patricia Severino. Avoiding chemotherapy resistance in squamous cell carcinomas: anticancer activities of terpenoids and their impact on the regulation of microRNAs [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 5456. doi:10.1158/1538-7445.AM2017-5456