tbuckley/cabot-search huggingface dataset:
DDIS-07. MSC-DERIVED EXOSOMES AND microRNA IN GLIOMA THERAPY
Authors: Irtiza Hasan, Eric Momin, Joy Gumin, Satoshi Adachi, Brittany Kerrigan, Anwar Hossain, Frederick Lang
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), the most common and deadly adult brain tumor, is notoriously resistant to therapy, not only because of the presence of Glioma Stem-like Cells (GSCs) but also because of the formidable delivery challenges imposed by the blood-brain barrier. Consequently, there is an urgent need to identify effective therapeutics and to elucidate successful strategies for delivering these new agents to GBMs. A promising new therapeutic approach is treatment with microRNAs (miRs), which are small, noncoding RNA that are powerful regulators of gene expression. We have shown that restoration of tumor suppressor miRs that are down-regulated in GBMs is capable of inhibiting the growth of GSCs. Despite the therapeutic potential of miRs, however, it is currently unknown which miRs will be most effective against GBMs and how these miRs will be delivered. To define miRs that are most effective against GBMs, we undertook a “candidate approach” based on a literature review and tested miR-124 & miR-128 as potential anti-glioma miRs. These initial analyses made it clear that a comprehensive evaluation of miRs that inhibit GBMs was lacking. Therefore, we have undertaken an unbiased high throughput screen of 578 miRs against a panel of patient-derived GSCs representing all TCGA-GBM classes. We identified 50 miRs that are highly effective at inhibiting GSCs regardless of TCGA subtype. Further, we demonstrated that exosomes derived from ex-vivo cultured mesenchymal stem cells (MSCs) can systemically deliver anti-glioma miRs to GBMs. Exosomes are naturally occurring nanovesicles that function as intercellular transport vehicles. MicroRNA-loaded exosomes (Exo-miRs) can be isolated and then used to deliver the miR to GBMs. Most importantly, we have shown that when systemically administered into mice, Exo-miRs “home” to brain tumors resulting in down-regulation of the miR target genes. These results suggest that MSC-derived exosomes can be used as systemic delivery vehicles of anti-glioma miRs.
SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits
Authors: Sheldon D. Michaelson, Emin D. Ozkan, Massimiliano Aceti, Sabyasachi Maity, Nerea Llamosas, Monica Weldon, Elisa Mizrachi, Thomas Vaissiere, Michael A. Gaffield, Jason M. Christie, J. Lloyd Holder, Courtney A. Miller, Gavin Rumbaugh
Journal: Nature Neuroscience (2018)
RTHP-20. PEDIATRIC HIGH GRADE GLIOMAS: PATTERNS OF FAILURE AND OUTCOMES WITH LIMITED MARGIN RADIOTHERAPY
Authors: Tiffany Morgan, Kapil Chandora, Jeffrey Switchenko, Eduard Schreibmann, Mustafa Abugideiri, Matthew Schniederjan, Tobey MacDonald, Natia Esiashvili, Bree Eaton
Journal: Neuro-Oncology (2018)

The optimal treatment paradigm for pediatric high-grade glioma (HGG) is not clearly defined. Outcomes of patients treated with limited margin conformal radiotherapy (RT) with or without chemotherapy are reported. The charts of 39 patients with HGG treated from 2006–2017 were reviewed. In 25 patients, the MRI-defined T2/FLAIR abnormality plus a median 7mm CTV margin was treated to 45–54 Gy, while the T1 post-contrast abnormality plus a median 5mm CTV margin was treated to 57.6–60 Gy. Fourteen patients were treated with single volume approach to 54–59.4 Gy, using a median 7mm CTV margin. Overall survival (OS), progression free survival (PFS), and development of pseudoprogression and radiation necrosis were determined by the Kaplan Meier method. Twenty-nine patients had WHO grade IV disease and 10 had grade III disease. Median age at diagnosis was 11 years (range 4–18). Twenty-four patients underwent subtotal resection, 1 a gross total resection, and 14 biopsy alone. 69.2% of patients received chemotherapy. Median follow-up was 11.7 months. Median PFS and OS for the entire cohort was 8.9 months (95% CI 6.1, 12.2) and 12.2 months (95% CI 9.9, 19.4), respectively. On univariate analysis, only older age was significantly associated with a longer OS (p=0.028). Seventeen patients experienced pseudoprogression and 10 radiation necrosis at a median of 1.1 and 3.8 months after RT, respectively. 38% of patients with pseudoprogression/radiation necrosis were symptomatic, all of whom were treated with steroids. One patient experienced a grade 5 toxicity attributed to brainstem injury. In patients who progressed, 52% experienced an infield failure (90% within the 100% prescription isodose line), and 21% and 27% of patients experienced marginal and distant intracranial failures, respectively. CONCLUSIONS: Outcomes with limited margin RT appear comparable to conventional RT. HGG portends a poor prognosis in the pediatric population and novel treatment strategies are needed.
Researchers Reprogram Cells In Vivo to Restore Vision in Mice
Authors: Tracy Hampton
Journal: JAMA (2018)

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INNV-43. NUCLEIC ACID ADEQUACY FROM ARCHIVED FORMALIN-FIXED PARAFFIN EMBEDDED (FFPE) TUMOR TISSUE FOR NEXT-GENERATION SEQUENCING (NGS) IN NATIONAL CANCER INSTITUTE (NCI)- NATURAL HISTORY STUDY (NHS) OF PRIMARY CNS TUMOR
Authors: Nicole Briceno, Sonja Crandon, Elizabeth Vera, Christine Siegel, Orwa Aboud, Miranda Brown, Hye-Jung Chung, Ming Ji, Jason Levine, Snehal Patel, Jennifer Reyes, Mark Raffeld, Mark Gilbert, Liqiang Xi, Terri Armstrong
Journal: Neuro-Oncology (2018)

A unified data collection system for interrogating the clinical trajectory of patients and their molecular pathology is of significant diagnostic, research, and therapeutic importance. The NCI-NHS follows primary CNS tumor patients throughout their disease. A targeted NGS panel was developed for clinical screening of mutations in 56 genes, 21 copy number alterations, and 25 gene fusion pairs using archived FFPE tissue. Due to the nature of study, available specimens range in age and source, posing a considerable challenge to obtaining an adequate quality and quantity of nucleic acid for genomic analysis. Tumor blocks or unstained slides were received for macrodissection of neuro-pathologist scored tumor tissue. DNA and RNA were extracted, using the Qiagen AllPrep FFPE Kit on a semi-automated QIAcube instrument, and sequenced on Ion Torrent NGS platform. Tissue material from 227 patients was submitted, 17(8%) were rejected for low tumor content (<10%) and/or insufficient tissue. In total, 221 specimens were processed from 210 patients. Specimen ages as follows: < 5 years old, 69%; 5–9 years, 22%; ≥10 years, 9%. DNA was successfully sequenced for 99.5% of these cases. RNA sequencing success rate was 85% overall, with 91% for specimens <5 years old, 73% for 5–9 years, and 53% for ≥ 10 years. There was no significant difference between NIH and outside cases. Clinically significant molecular findings were reported in 81% of the cases across 18 diagnoses. High grade tumors comprised 78% of those calls. Robust variant calling for a variety of clinical specimens is critical in genetic medicine. Using our protocol, archived FFPE tumor specimen provided high quality NGS results, regardless of originating institution. Additionally, RNA from tissue over 5 years of age had a 71% sequencing success rate. This study confirms the feasibility of using archived materials for molecular analysis with analyzable results.
NIMG-34. THE IMPACT OF TUMOR TREATING FIELDS (TTFIELDS) ON BRAIN ANATOMY USING COMPUTATIONAL ANATOMY ANALYSIS
Authors: Andreas Hottinger, Antoine Lutti, Estelle Dupuis, Rita De Micheli, Bogdan Draganski
Journal: Neuro-Oncology (2018)

TTFields is a glioblastoma (GBM) treatment based on focal electric field stimulation that inhibits tumor progression by disrupting cell division. In this pilot study, we sought to use computational anatomy analysis and quantitative magnetic resonance imaging (MRI) data to evaluate treatment effects over time looking at both the effects on the tumor tissue and normal brain parenchyma. MRI data were acquired at 3-month intervals before and during TTFields treatment in patients with glioblastoma (currently 10 patients enrolled, recruitment ongoing). The whole-brain MRI quantitative protocol comprises three multi-echo 3D fast low angle shot (FLASH) acquisitions with predominantly magnetization transfer-, proton density- and T1-weighted contrast. For statistical analysis, all MT images were classified by tissue classes: grey matter, white matter, cerebral-spinal fluid and non-brain tissue. All maps were warped in standardized space and then smoothed by convolution with an isotropic Gaussian kernel. Regional differences were examined in a paired t-test creating voxel-wise statistical parametric maps (SPMs). In whole-brain SPM analysis we observed a decrease in macromolecular and iron content confined to the tumor-affected area and corpus callosum between the pretreatment and post-treatment time points. No changes were identified in the non-affected hemisphere. CONCLUSIONS: These preliminary results show the potential of quantitative MRI as a biomarker sensitive to tissue changes to monitor TTFields or other treatment effects over time. We underscore the quantitative character of our data that renders them virtually free of time-related bias and the ability to provide a biological interpretation of the results linking them to macromolecular and iron content. Given the relative spatial heterogeneity of brain tumor location in our patients we attribute the paucity of significant results to common brain tissue property changes going beyond individual lesion spread. Future analyses will focus on within-subject analysis across time.
DDIS-03. EGFR AMPLIFICATION INDUCED INCREASED DNA DAMAGE RESPONSE AND PREDICTED SELECTIVE SENSITIVITY TO TALAZOPARIB (PARP INHIBITOR) IN GLIOBLASTOMA STEM-LIKE CELLS
Authors: Shaofang Wu, Feng Gao, Siyuan Zheng, Chen Zhang, Juan Emmanuel Martinez-Ledesma, Ravesanker Ezhilarasan, Jie Ding, Xiaolong Li, Ningping Feng, Erik Sulman, Roel Verhaak, John de Groot, Tim Heffernan, W K Alfred Yung, Dimpy Koul
Journal: Neuro-Oncology (2018)

Poly-ADP-ribose polymerase (PARP) is an enzyme critical for regulating a variety of DNA damage repair mechanisms. In this study, we report that PARP inhibitor, talazoparib, showed strong single-agent cytotoxicity and remarkable selective activity in glioma stem-like cells (GSCs). This single agent activity was strongly correlated with EGFR amplification as shown by genomic analysis. GSCs withEGFR amplification (which occurs in about 45% of GBMs) exhibited higher oxidative base damage, DNA breaks, and genomic instability than non-amplified GSCs. To sustain the elevated basal oxidative stress, EGFR amplified GSCs harbored increased basal expression of DNA repair proteins. As a result, DNA damage and PARP-DNA complexes increased in the amplified GSCs following talazoparib treatment, which may explain the sensitivity of these GSCs to talazoparib. Further, we show that EGFR kinase activity is important for talazoparib sensitivity, as kinase-inactive EGFR mutant and EGFR knockout cell lines were resistant to talazoparib. Intriguingly, another PAPR inhibitor Olaparib, with similar PARP enzymatic inhibition potential but less PARP-trapping ability compared with talazoparib, did not show selective sensitivity in EGFR amplified GSCs. Our data provide insight into the anti-cancer activity of talazoparib through PARP inhibition and by trapping PARP-DNA complexes. In conclusion we propose the potential of EGFR amplification as a biomarker for selection of the development of personalized therapy.
Abstract 17797: Protective Effects of Alda-1 on Post-Resuscitation 72h Survival and Myocardial Function in a Rat Model of Cardiac Arrest
Authors: Rui Zhang, Jiali Wang, Baoshan Liu, Wen Zheng, Qiuhuan Yuan, Chuanxin Zhang, Shuai Zhang, Wenjun Wang, Xinhui Fan, Luyao Gao, Yuguo Chen
Journal: Circulation (2017)

Introduction: Alda-1, an agonist of aldehyde dehydrogenase 2, has been demonstrated to protect against ischemia-reperfusion injury of multiple tissues mainly through reducing endogenous reactive ox...
Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema
Authors: Didde Haslund, Laura Barrett Ryø, Sara Seidelin Majidi, Iben Rose, Kristian Alsbjerg Skipper, Tue Fryland, Anja Bille Bohn, Claus Koch, Martin K. Thomsen, Yaseelan Palarasah, Thomas J. Corydon, Anette Bygum, Lene N. Nejsum, Jacob Giehm Mikkelsen
Journal: Journal of Clinical Investigation (2018)

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by recurrent edema attacks associated with morbidity and mortality. HAE results from variations in the SERPING1 gene that encodes the C1 inhibitor (C1INH), a serine protease inhibitor (serpin). Reduced plasma levels of C1INH lead to enhanced activation of the contact system, triggering high levels of bradykinin and increased vascular permeability, but the cellular mechanisms leading to low C1INH levels (20%–30% of normal) in heterozygous HAE type I patients remain obscure. Here, we showed that C1INH encoded by a subset of HAE-causing SERPING1 alleles affected secretion of normal C1INH protein in a dominant-negative fashion by triggering formation of protein-protein interactions between normal and mutant C1INH, leading to the creation of larger intracellular C1INH aggregates that were trapped in the endoplasmic reticulum (ER). Notably, intracellular aggregation of C1INH and ER abnormality were observed in fibroblasts from a heterozygous carrier of a dominant-negative SERPING1 gene variant, but the condition was ameliorated by viral delivery of the SERPING1 gene. Collectively, our data link abnormal accumulation of serpins, a hallmark of serpinopathies, with dominant-negative disease mechanisms affecting C1INH plasma levels in HAE type I patients, and may pave the way for new treatments of HAE.
Prescriber Patterns of SGLT2i After Expansions of U.S. Food and Drug Administration Labeling
Authors: Muthiah Vaduganathan, Vasanth Sathiyakumar, Avinainder Singh, Cian P. McCarthy, Arman Qamar, James L. Januzzi, Benjamin M. Scirica, Javed Butler, Christopher P. Cannon, Deepak L. Bhatt
Journal: Journal of the American College of Cardiology (2018)
Abstract 18267: Does High Triglycerides/High-Density Lipoprotein Cholesterol Ratio Predict Outcomes in an Australian Population of Patients After Coronary Angiography?
Authors: Rohullah Sultani
Journal: Circulation (2016)

Aims: High Triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are major cardiovascular risk factors. A positive association between elevated TG/HDL-C ratio and all-cause mortal...
Novel methods to diagnose leptomeningeal metastases in breast cancer
Authors: Lindsay Angus, John W M Martens, Martin J van den Bent, Peter A E Sillevis Smitt, Stefan Sleijfer, Agnes Jager
Journal: Neuro-Oncology (2018)

Leptomeningeal metastases (LM) in breast cancer patients are rare but often accompanied by devastating neurological symptoms and carry a very poor prognosis, even if treated. To date, two diagnostic methods are clinically used to diagnose LM: gadolinium MRI of the brain and/or spinal cord and cytological examination of cerebrospinal fluid (CSF). Both techniques are, however, hampered by limited sensitivities, often leading to a long diagnostic process requiring repeated lumbar punctures and MRI examinations. To improve the detection rate of LM, numerous studies have assessed new techniques. In this review, we present the current workup to diagnose LM, set out an overview of novel techniques to diagnose LM, and give recommendations for future research.
Abstract 17015: Lymphangioleiomyomatosis (LAM)-Induced Pluripotent Stem Cell (iPSC) Derived Smooth Muscle Cells Destabilze Capillary-Like Networks and Disrupt Angiogenic Gene Expression in Co-Culture With Endothelial Cells
Authors: Mirabelle Ho, Lisa Julian, William L Stanford, Duncan J Stewart
Journal: Circulation (2017)

Background: During angiogenesis, healthy smooth muscle cells (SMCs) stabilize newly formed endothelial cell (EC) tubes and maintain vascular homeostasis. However, LAM smooth muscle-like cells invad...
Abstract P043: Subclinical Atherosclerosis and Cognitive Functioning in Middle-Aged Black and White Adults: The CARDIA Study
Authors: Jared P Reis, Lenore Launer, James G Terry, Catherine M Loria, Stephen Sidney, Kristine Yaffe, David R Jacobs, Christopher T Whitlow, Na Zhu, J J Carr
Journal: Circulation (2013)

Background: Cardiovascular risk factors in middle-age are associated with cognitive impairment and dementia in older adulthood. Less is known about the burden of subclinical atherosclerosis and cog...
RTHP-10. LESS IS MORE OR BIGGER IS BETTER? RADIATION TREATMENT VOLUME FOR GLIOBLASTOMA PATIENTS DOES NOT IMPACT SURVIVAL
Authors: Andrew Song, Sonia Gowda, Maria Werner-Wasik, Voichita Bar-Ad, Lyndon Kim, Jon Glass, Kevin Judy, Christopher Farrell, David Andrews, Wenyin Shi
Journal: Neuro-Oncology (2018)

PURPOSE: To investigate if the extent of the planning target volume (PTV) for glioblastoma (GBM) patients receiving adjuvant radiation treatment (XRT) has correlation with survival. We retrospectively examined patients with newly diagnosed GBM received adjuvant radiation at our institution from 2011 to 2016. Our institution follows the RTOG guidelines for GBM volumes. We included 87 patients with sufficient follow up. We examined the treatment plan documents to determine the PTV treated to 46 Gy (PTV46) and 60 Gy (PTV60). We measured overall survival (OS) as well as progression-free survival (PFS). We performed summary statistics on baseline patient characteristics, Kaplan-Meier analysis for outcomes with log-rank tests to compare PTV subgroups as well as Cox regression analysis for treatment volume. Of the 87 patients for analysis, 42 were female and 45 were male. Median age was 61 y/o, with median follow-up of 16.6 months (range 2.6 to 61.1 months). For PTV46 analysis, 1 patient was excluded due to receiving whole brain radiation to 40 Gy before receiving cone down to total 60 Gy. Median PTV60 was 297.9 cc (120.04 to 907.6 cc) while median PTV46 was 452 cc (120.04 to 907.6 cc). OS at 1 year was 67.8% and at 2 years was 32.2%, with median OS of 16.6 months. PFS at 6 months was 58.6% and at 1 year was 27.6%, with median time to progression of 6.8 months. On Cox regression analyses, neither PTV46 nor PTV 60 were statistically significant correlated with OS (p=0.11 and 0.68) and PFS (p=0.54 and 0.64). On log rank test, neither PTV46 nor PTV60 subgroups have any statistically significant survival differences, for PFS or OS. Extent of PTV does not appear to have an impact on recurrence or survival for GBM. Further validation with an independent dataset is warranted.
PDTM-37. THE ROLE OF EXOSOME miRNA DURING THE PROGRESSION OF MEDULLOBLASTOMA
Authors: Qing Chang, Liang-Yi Zhu, Xiao-Yu Wu, Jing Zhang
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant paediatric brain tumor. Activation of the RAS/MAPK signaling pathway in some Shh subtype of MBs may induce target drug resistance and tumor progression. But the mechanism is not yet clear. Many studies show that exosomes carried miRNAs have close relationship with tumor invasion. The aim of present study is to clarify the relationship between exosome miRNA and RAS/MAPK signaling pathway during the progression of MBs. We performed miRNA sequencing by Ion Proton technology to analyze the miRNAs expression level between MB cells with different invasion ability. Dozens of miRNAs were identified with different expression level. Among them, 11 miRNAs were the most significant. Further gene function (GO) and signaling pathways (KEGG) analysis showed that 7 of 11 miRNAs participate in RAS/MAPK signal pathways, including miR - 221 and miR – 7, with SNCA as their candidate target gene. It was known that SNCA can interact with MAPK pathways and reduce their activation and induce cell death. It encodes the protein, a-synuclein, a well-known biomarker in PD patients. We demonstrated that expression of SNCA is rather low in Shh subtype of MB based on Nanostring Assay. Our data showed that SNCA acts as a tumor suppressor by inhibiting MB invasion and inducing cell apoptosis. In summary, exosome miRNAs of MB cells have close relationship with RAS/MAPK signaling pathway during the progression of MBs. SNCA may play a critical role in this process as a tumor suppressor. Exosome miRNAs may also be involved in regulating SNCA and be the candidate biomarkers for estimating the early recurrent and metastasis of MBs. Further investigations are needed to further clarify the interactions between a-synuclein and RAS/MAPK signal pathways, as well as to evaluate the availability of miRNA being the noninvasive biomarker for tumor invasion.