tbuckley/cabot-search huggingface dataset:
GENE-21. A COMMON FETAL DEVELOPMENTAL ORIGIN FOR PFA EPENDYMOMA, PFB EPENDYMOMA, AND CEREBELLAR PILOCYTIC ASTROCYTOMAS?
Authors: Maria Vladoiu, Ibrahim El-Hamamy, Laura Donovan, Borja Holgado Lopez, Hamza Farooq, Claudia Kleinman, Nada Jabado, Sheila Singh, Jennifer Chan, Faiyaz Notta, Vijay Ramaswamy, Lincoln Stein, Michael Taylor
Journal: Neuro-Oncology (2018)

Single cell RNA-sequencing (scRNAseq) of murine cerebellum at nine fetal and immediate post-natal (E10-P14) times points on >60,000 individual cells to identified >30 transcriptionally distinct cell clusters. Based on marker gene expression, many clusters resemble known cerebellar stem, progenitor, and differentiated cell types, while other clusters are more novel. Pseudo-time trajectory assisted in the reconstruction of known and novel developmental lineages, including the lineage of the cerebellar radial glia. A population of stem cells in the ventricular zone (VZ) gives rise to the progenitors of the GABAergic cerebellar interneurons, as well as the gliogenic progenitor cells, which subsequently become Bergmann glia and astrocytes. A novel, but clearly distinct and robust cluster of cells with transcriptional similarity to both the roof plate and the rhombic lip was identified. Comparison of bulk RNA-seq from human PFA, PFB, and cerebellar pilocytic astrocytomas (C-PA) reveals that all three-tumor types best transcriptionally match the gliogenic progenitor cells, with some similarity to VZ stem cells and the ‘roof plate like’ stem cells. Furthermore, all three tumor types are transcriptionally much more similar to the gliogenic progenitors at E16 than at E14 or E18. Subclustering of gliogenic progenitors reveals significant intra-cluster heterogeneity, with the ependymomas transcriptionally matching one subcluster, and the C-PA clearly matching a very different subcluster. scRNAseq of human PFA and PFB ependymomas reveals multiple tumor cell clusters within a given human ependymoma, with some clusters matching most closely to the gliogenic progenitors, and others matching best to the ‘roof plate like’ stem cells. Similarity to the ‘roof plate stem cells’ (E10-E14), and gliogenic progenitors (E14-E18) suggests an embryonic origin for PFA, PFB, and C-PA, suggests specific novel cells of origin, and offers a novel opportunity to understand posterior fossa tumor transcriptomic targets for novel therapy.
EPID-12. USING GERMLINE VARIANTS TO PREDICT GLIOMA RISK AND IDENTIFY GLIOMA SUBTYPE PRE-OPERATIVELY
Authors: Jeanette Eckel-Passow, Paul Decker, Matthew Kosel, Thomas Kollmeyer, Annette Molinaro, Terri Rice, Alissa Caron, Kristen Drucker, Corinne Praska, Melike Pekmezci, Helen Hansen, Lucie McCoy, Paige Bracci, Bradley Erickson, Joseph Wiemels, John Wiencke, Melissa Bondy, Beatrice Melin, Terry Burns, Caterina Giannini, Daniel Lachance, Margaret Wrensch, Robert Jenkins
Journal: Neuro-Oncology (2018)

To date, 25 single nucleotide polymorphisms (SNPs) have been shown to be associated with overall glioma risk or with risk of specific subtypes of glioma. We hypothesized that the inclusion of these 25 SNPs with patient age at diagnosis and sex could predict risk of glioma as well as predict IDH mutation status. Thus, case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for molecular subtypes. Case-case design and logistic regression were used to develop models to predict IDH mutation status. Each model included all 25 glioma risk SNPs, patient age at diagnosis and sex. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. We observed that patients in the highest 5% of the risk score had more than a 14-fold increased relative risk of developing an IDH-mutant glioma, compared to patients with median risk score. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile categories. For both IDH-mutated 1p/19q non-codeleted glioma and IDH-mutated 1p/19q-codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation c-index of 0.85. These results suggest that germline genotyping has the potential to provide a new tool for clinicians for the initial management of newly-discovered brain lesions. Specifically, given the low lifetime risk of glioma, SNP-based risk scores should not be useful for general population screening. However, with further research these risk scores may be useful in certain clinically-defined high-risk groups.
Abstract 18786: Real Time Gene Knock Out in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes Allows Rapid Evaluation of Gene Function in Cellular Electrophysiology
Authors: Ling Xiao, Gang Wang, Megan Jang, Jordan Leyton-Mange, William Pu, Patrick T Ellinor, David J Milan
Journal: Circulation (2015)

Background and objective: Modeling of human physiologic traits using pluripotent stem cell derived cardiomyocytes has been hampered in part by variability between cardiomyocytes derived from different stem cell lines. While the advent of genome editing affords unprecedented opportunities to evaluate gene function, the variation between cell lines creates challenges in distinguishing signal from noise. We recently developed a genetically encoded voltage sensing fluorescent protein, Arclight, that enables serial recording of cellular electrical activity. Using an inducible CRISPR-CAS9 nuclease we have developed a method to knockout genes of interest in differentiated cardiomyocytes. The use of the Arclight voltage reporter allows monitoring of the loss of gene function over time. This real-time knockout method is demonstrated for the KCNH2 gene and compared to shRNA mediated knockdown. Methods and Results: Human iPSCs that were genetically engineered to contain a doxycycline (DOX) inducible Cas9 allele were differentiated into cardiomyocytes and transduced with lentiviral vector carrying the genetically encoded fluorescent voltage indicator, A242-Arclight. These human Cas9 iPSC-CMs expressing Arclight were further transduced with lentiviral vector containing a guide RNA (gRNA) targeting KCNH2 to achieve knockout upon DOX treatment. Arclight fluorescence was repeatedly recorded in these cardiomyocytes at day 0, 3, 5, 7, and 9 after DOX treatment. APDs at 90% repolarization (APD90) were analyzed and compared to APD90 from CMs without DOX treatment. APD90 in DOX treated iPSC-CMs gradually prolonged from day 3 to day 5 and remained relatively stable between days 5 and 9. At day 7, APD90 was significantly prolonged in DOX treated iPSC-CMS (321 ± 21 ms) compared to untreated cardiomyocytes (231 ±15 ms). RNAi-mediated knockdown of KCNH2 using short hairpin RNA (shRNA) on the iPSC-CMs expressing Arclight did not significantly alter APD90 throughout the study time course. Conclusion: In this in vitro human cell model, Crispr/Cas9 knockout of KCNH2 results in APD prolongation in iPSC-CMs in a real-time manner, which provides a powerful cellular platform to evaluate gene function in cellular electrophysiology.
Long-Term Survival Following Multivessel Revascularization in Patients With Diabetes
Authors: Michael E. Farkouh, Michael Domanski, George D. Dangas, Lucas C. Godoy, Michael J. Mack, Flora S. Siami, Taye H. Hamza, Binita Shah, Giulio G. Stefanini, Mandeep S. Sidhu, Jean-François Tanguay, Krishnan Ramanathan, Samin K. Sharma, John French, Whady Hueb, David J. Cohen, Valentin Fuster, Samin K. Sharma, Tanim N. Zazif, Hoang Thai, Binita Shah, Krishnan Ramanathan, Jean-François Tanguay, Krishnan Ramanathan, Jeffrey R Burton, Erick Schampaert, Jorge Escobedo, Jean-Luc Dubois-Rande, Carlos Macaya, Didier Carrie, Gert Richardt, Ariel Roguin, Chaim Lotan, Ran Kornowski, Patrizia Presbitero, Whady Hueb, J. Eduardo Sousa, Jorge G. Velásquez, Alfredo Rodriguez, Gerry Devlin, John K. French, Upendra Kaul
Journal: Journal of the American College of Cardiology (2018)
Abstract 10313: Efficacy of Hybrid Approach With Saline-Induced Pd/Pa Ratio and Fractional Flow Reserve for Decision-Making of Percutaneous Coronary Intervention - Second Report of SPR Study
Authors: Yoshiharu Fujimori, Tomoko Baba, Kazuto Kurihara, Kyohei Yamazaki, Satoshi Hashimoto, Yasushi Yamanaka, Kenichiro Ebisuda, Naoki Koike, Nao Takeuchi, Shigeru Nishiyama, Yuya Terasawa, Tadamasa Wakabayashi, Taku Imai
Journal: Circulation (2018)

Introduction: We reported in Scientific Sessions ’17 that saline-induced Pd/Pa ratio (SPR) could accurately predict fractional flow reserve (FFR) ≤0.80. This is the second report of the SPR study. ...
RARE-19. CHEMOTHERAPY FOR SPINAL GLIOMAS IN ADULTS: A RETROSPECTIVE STUDY
Authors: Dorothee Gramatzki, Jörg Felsberg, Oliver Baehr, Bettina Hentschel, Manfred Westphal, Gabriele Schackert, Jörg-Christian Tonn, Ulrich Herrlinger, Joachim Steinbach, Guido Reifenberger, Patrick Roth, Michael Weller
Journal: Neuro-Oncology (2018)

Chemotherapy is a treatment option in patients diagnosed with anaplastic gliomas or glioblastomas of the spinal cord, or with recurrent lower World Health Organization (WHO) grade spinal gliomas that are no longer amenable to local treatment. The low incidence of spinal cord gliomas, particularly in adults, limits the ability to perform clinical trials. The role of chemotherapy in these tumors has remained unclear. We performed a retrospective study of 21 patients diagnosed with spinal gliomas who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Response assessment in neuro-oncology criteria. Patients were diagnosed with myxopapillary ependymoma (N=3), anaplastic ependymoma (N=5), pilocytic astrocytoma (N=4), astrocytoma (N=2), anaplastic astrocytoma (N=3) or glioblastoma (N=4). Median follow-up from start of chemotherapy was 59 months. Nine of 12 patients with known MGMT status had tumors with MGMT promoter methylation. Eight patients had chemotherapy as part of first-line treatment: patients with glioblastoma received temozolomide (TMZ) (N=3) or vincristine/etoposide/cisplatin/ifosfamide (N=1); patients with astrocytoma (N=1), with anaplastic astrocytoma (N=2) and with anaplastic ependymoma (N=1) received TMZ. All other patients had chemotherapy at progression which included alkylating agents (N=9), carboplatin-based chemotherapy (N=2), hydroxycarbamid (N=1), or ifosfamide/etoposide/doxorubicin (N=1). Response rates were as follows: myxopapillary ependymoma 3 stable diseases; anaplastic ependymoma 1 partial response (N=2 data missing); pilocytic astrocytoma 1 stable disease; astrocytoma 1 stable disease, anaplastic astrocytoma 2 stable diseases (N=2 data missing); glioblastoma 1 complete response and 1 stable disease. There was no indication for a favorable prognostic role of MGMT promoter methylation. CONCLUSIONS: Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.
PATH-32. BRAIN TUMOR CLASSIFICATION UPDATES FROM cIMPACT-NOW, THE CONSORTIUM TO INFORM MOLECULAR AND PRACTICAL APPROACHES TO CNS TUMOR CLASSIFICATION
Authors: David Louis, Daniel Brat, David Ellison
Journal: Neuro-Oncology (2018)

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was created to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. While it is understood that the major impact on international brain tumor classification comes about through the WHO classification update process, it is anticipated that this additional process will see impact in selected tumor types and in time periods between the WHO classification updates. Over the past year, cIMPACT-NOW has convened three working committees (WC), each of which has focused on different classification issues. WC1 has debated the grading of diffuse gliomas relative to IDH status, and has formulated criteria for IDH-wildtype grade II and grade III diffuse astrocytic tumors that are likely to behave as glioblastomas, such as EGFR amplification and +7/-10 copy number changes. WC2 is developing a molecular classification of pediatric low-grade gliomas, focusing on the diffuse gliomas. WC3 has addressed miscellaneous issues, including clarifications of Not Otherwise Specific (NOS) and Not Elsewhere Classified (NEC) diagnoses and refined criteria for diffuse astrocytoma (e.g., the use of ATRX and p53 immunohistochemistry relative to 1p/19q testing) and diffuse midline glioma, H3 K27M-mutant. To date, two publications have resulted from WC3 and guidelines are expected soon from WC1 and WC2. The combined recommendations of the current cIMPACT-NOW WCs will be discussed in light of the WHO classification.
Tick-borne encephalitis in Europe, 2012 to 2016
Authors: Julien Beauté, Gianfranco Spiteri, Eva Warns-Petit, Hervé Zeller
Journal: Eurosurveillance (2018)

Since 2012, tick-borne encephalitis (TBE) is a notifiable in the European Union. The European Centre for Disease Prevention and Control annually collects data from 28 countries plus Iceland and Norway, based on the EU case definition. Between 2012 and 2016, 23 countries reported 12,500 TBE cases (Ireland and Spain reported none), of which 11,623 (93.0%) were confirmed cases and 878 (7.0%) probable cases. Two countries (Czech Republic and Lithuania) accounted for 38.6% of all reported cases, although their combined population represented only 2.7% of the population under surveillance. The annual notification rate fluctuated between 0.41 cases per 100,000 population in 2015 and 0.65 in 2013 with no significant trend over the period. Lithuania, Latvia and Estonia had the highest notification rates with 15.6, 9.5 and 8.7 cases per 100,000 population, respectively. At the subnational level, six regions had mean annual notification rates above 15 cases per 100,000 population, of which five were in the Baltic countries. Approximately 95% of cases were hospitalised and the overall case fatality ratio was 0.5%. Of the 11,663 cases reported with information on importation status, 156 (1.3%) were reported as imported. Less than 2% of cases had received two or more doses of TBE vaccine.
Treatment of Hypertension
Authors: Arman Qamar, Eugene Braunwald
Journal: JAMA (2018)

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GENE-22. RE-PROGRAMING CHROMATIN WITH A BIFUNCTIONAL LSD1/HDAC INHIBITOR INDUCES THERAPEUTIC DIFFERENTIATION IN DIPG
Authors: Jamie Anastas, Mariella Filbin, Mirhee Kim, Jay Kalin, Barry Zee, Andres Blanco, Jayanta Das, Todd Golub, Philip Cole, Yang Shi
Journal: Neuro-Oncology (2018)

Diffuse intrinsic high grade glioma (DIPG) is an almost universally fatal tumor of childhood characterized by epigenetic dysregulation driven by somatic H3.3/H3.1 K27M mutations observed in >80% of tumors. We conducted a chromatin-focused CRISPR screen and identified a novel strategy to inhibit the growth of patient-derived DIPG cells by co-targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs). Consistent with the genetic data, we demonstrate that a bifunctional inhibitor of HDACs and LSD1, Corin, inhibits the growth of DIPG cells both in vitro and in orthotopic xenografts. Mechanistically, co-targeting LSD1 and HDACs with Corin synergistically alters the levels of histone modifications in DIPG, rescuing H3K27me3 levels suppressed by the dominant negative effects of K27M mutant histones and inducing simultaneous increases in both HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at thousands of genomic locations. Coincident with these chromatin changes, we observe robust transcriptional changes in DIPG cells, including the repression of cell cycle-related genes and the activation of neuronal differentiation genes. Consistently, phenotypic assays reveal that Corin reduces S-phase and Ki67+ proliferating cells, induces a neuronal-like morphology, alters the expression of stem and differentiation markers, and increases DIPG cell death. Finally, analyses of patient DIPG expression datasets indicate that Corin-dependent transcriptional signatures are overrepresented in normal brain compared to DIPG tumors and correlate with increased patient survival time. Together, these data reveal that co-inhibiting LSD1 and HDACs synergistically reduces DIPG growth by re-programming the chromatin landscape to activate a latent differentiation response, and suggest a strategy of co-inhibiting LSD1 and HDACs with Corin to treat DIPG.
TMIC-37. TARGETING THE EXTRACELLULAR MATRIX OF GLIOBLASTOMAS CHANGES THE POLARIZATION OF TUMOR-ASSOCIATED MACROPHAGES AND INCREASES ANTI-TUMOR INFLAMMATORY RESPONSES
Authors: Roshini Arivazhagan, Mohan Nandhu, Sharon Longo, Lawrence Chin, Mariano Viapiano
Journal: Neuro-Oncology (2018)

Glioblastomas (GBMs) are heavily infiltrated by tumor-associated microglia and macrophages (TAMs), which represent the predominant immune cell population in the tumor and may contribute to GBM progression in response to signals from the tumor cells. Fibulin-3 is an extracellular matrix protein secreted by GBM cells that promotes tumor invasion, angiogenesis, and survival of the GBM stem cell population (GSC) by activation of ADAM17/NFkB signaling. We recently developed a function-blocking antibody (“mAb428.2”) against fibulin-3 that inhibits the molecular mechanisms of this protein and reduces GSC viability (Nandhu et al., Clin. Cancer Res. 2018). mAb428.2 (8 days x 30 mg/kg, q24h, IV) exerted a significant anti-tumor effect and prolonged the survival of mice carrying patient-derived GBM xenografts implanted sub-cutaneously (N=8/arm p=0.0032) or intracranially (N=10/arm p=0.0005). Importantly, the cyto-reductive effect of mAb428.2 was accompanied by significant necrosis of the tumor core and increased infiltration of IBA1-positive TAMs. Remarkably, TAMs in anti-fibulin-3-treated tumors showed very little expression of Arginase-1, a bona-fide marker of M2 (“tumor-promoting”) polarization. Analysis of gene expression in the TAMs recovered from the tumors confirmed significantly increased expression of inflammatory cytokines (IFN-gamma, IL-1beta, IL-10) and downregulation of M2 markers (CD163, CD206, ARG1), suggesting that mAb428.2 had blocked the usual M2 polarization of TAMs observed in GBMs. Moreover, mAb428.2-treated tumors also showed drastically decreased expression of CSF-1a, an M2-inducing cytokine. Knockdown of fibulin-3 in GSCs also reduced CSF-1a expression, which is likely regulated by fibulin-3 through NFkB signaling. Finally, co-culture of PMA-activated U937 macrophages with GSCs caused a significant decrease of tumor cell viability when mAb428.2 was added to the cultures, suggesting that anti-fibulin-3 treatment enables TAMs to attack tumor cells. Taken together, our results strongly suggest that anti-fibulin-3 and possibly other anti-ECM approaches may induce a marked inflammatory reaction driven by innate immune cells, potentiating anti-tumor therapy.
NIMG-63. ADVANCED IMAGING FOR ASSESSING VOLUMETRIC RESPONSES IN BRAIN METASTASES TREATED WITH CHECKPOINT BLOCKADE
Authors: Elizabeth Gerstner, Jonathan Cardona, Ken Chang, Andrew Beers, James Brown, Jayashree Kalpathy-Cramer, Eudocia Lee, Nancy Lin, Sara Tolaney, Lakshmi Nayak, Ugonma Chukwueke, Kevin Oh, Helen Shih, Michael White, Donald Lawrence, Beverly Moy, Justine Cohen, Anita Giobbie-Hurder, Daniel Cahill, Ryan Sullivan, Priscilla Brastianos
Journal: Neuro-Oncology (2018)

Immunotherapy has been effective therapy for brain metastases (BM) from melanoma and lung cancer, prompting interest in using PD-1 targeting drugs in more patients with BM. However, accurately assessing response in patients undergoing immunotherapy continues to be a challenge. Thus, we prospectively evaluated radiographic characteristics and changes during immunotherapy. As part of an ongoing Phase 2 study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology, patients underwent advanced MRI that includes tumor volume measurements and perfusion imaging with dynamic susceptibility contrast MRI.. To calculate volumetric radiographic response, all enhancing voxels were summated. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Forty-eight patients have been enrolled of whom 38 have undergone at least baseline advanced MR imaging. Histologies include 16 with breast cancer (12 HER2-, 4 HER2+), 5 with non-small cell lung cancer, 4 with melanoma, and 11 with other cancers. At baseline, the total number of BM was 1–50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 25 evaluable patients include 2 PR, 9 SD, and 14 PD. Cerebral blood volume tended to increase with increasing tumor size. Correlation of volumetric response to patient outcome and standardized response criteria (iRANO) is ongoing. CONCLUSIONS: Pembrolizumab may have activity in metastatic brain cancer. Ongoing analyses are evaluating if physiological MRI can shed light on the biological impact of pembrolizumab and response mechanisms in this patient population.