tbuckley/cabot-search huggingface dataset:
DRES-08. DYNAMIC KINOME PROFILING OF GENETICALLY-DEFINED, EGFRvIII-DRIVEN MURINE ASTROCYTE MODELS OF GLIOBLASTOMA REVEALS TARGETS FOR DUAL KINASE INHIBITOR THERAPY
Authors: Erin Smithberger, Abigail Shelton, Madison Butler, Alex Flores, Ryan Bash, Steven Angus, Noah Sciaky, Harshil Dhruv, Gary Johnson, Michael Berens, Frank Furnari, Ryan Miller
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) has poor survival and lacks effective treatments. Due to frequent amplification and mutation of epidermal growth factor receptor (EGFR), several EGFR tyrosine kinase inhibitors have been trialed, but none have proven successful. One potential reason for failure is acquired resistance, particularly acute, adaptive responses in the kinome. To study this adaptive resistance mechanism, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze transcriptomes and kinomes of genetically-engineered murine astrocytes with genotypes commonly seen in human GBM. We previously showed that 38% (86 of 228) of the expressed kinome varied among a panel of genetically diverse murine astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression, or both overexpressed EGFRvIII and Pten deletion (CEv3P). Pairwise genotype comparisons revealed multiple differentially activated kinases, including Pdgfrb, Fgfr2, Lyn, Ddr1, and several members of the Ephrin family. We further investigated these potential targets for dual therapy with EGFR TKI by examining the transcriptional response of our cultured astrocyte panel at 4, 24, and 48 hours after 3 μM afatinib. Afatinib induced no kinome changes in C and only 3 kinases (Fn3k, Prkg2, and Syk) were altered in CP astrocytes. Despite similar baseline gene expression profiles, CE astrocytes overexpressing wild-type EGFR responded significantly differently than C astrocytes without. Five kinases (Dclk1, Epha3, Epha7, Fgfr3, and Prkg1) were induced, while 14 were repressed. Six were similarly repressed in CEv3 (Bub1, Nek2, Pask, Plk4, Prkcb, and Vrk1). Whereas the kinase transcriptome response was blunted in C, CP, and CE astrocytes, afatinib induced altered expression of significantly more kinases in CEv3 (82) and CEv3P cells (49). One particularly attractive target in CEv3 astrocytes was Epha4, which afatinib induced >40-fold. Dual inhibition of EGFRvIII and Epha4 kinases may thus provide an opportunity for more effective targeted therapy.
Abstract 03: Antithrombin III Contributes to the Vascular Protective and Reparative Effects of Fresh Frozen Plasma Following Hemorrhagic Shock
Authors: Ernesto Lopez, Zhanglong Peng, Charles E Wade, Jessica C Cardenas
Journal: Circulation (2018)

Introduction: Endothelial damage and extravasation are deleterious consequences of hemorrhagic shock (HS), associated with inflammation, loss of the endothelial glycocalyx barrier and hyperpermeability. Fresh frozen plasma (FFP) has been shown to preserve the glycocalyx and mitigate endothelial dysfunction following HS, although the mediators of this phenomenon remain unknown. Antithrombin III (ATIII) is a plasma protein with potent anticoagulant and anti-inflammatory activity. ATIII levels are decreased following trauma and particularly in those suffering from HS. Previous work in other disease models has shown that ATIII plays an important role in preserving the endothelial glycocalyx. We hypothesized that following HS, the vascular protective effects of FFP therapy are mediated through ATIII. Methods and Results: In vitro: Confluent endothelial cells were pre-treated with FFP (n=12), ATIII deficient FFP (AT-Def FFP, n=12) or Vehicle (n=12) followed by treatment with TNF-α. The electrical impedance was monitored in real time over 24 H to detect changes in cell-to-cell junctions. We found that FFP treatment prevented the TNF-α -induced endothelial disruption showing a 1.6 and 1.5-fold improvement at 12 and 24 H respectively (vs. Vehicle, p&lt;0.0001). AT-Def FFP showed some protection at 12 H (1.2-fold vs. Vehicle, p=0.05), although it was not maintained at 24 H (0.86-fold vs. Vehicle, p=0.34). In vivo: Under anesthesia , 30 male mice were subjected to a well-described fixed pressure exsanguination model. HS was achieved by sustaining a MAP of 35 mmHg for 90 min followed by resuscitation with either FFP (n=10) or AT-Def FFP (n=10). The expression of the glycocalyx marker, syndecan-1, in lung tissue was measured by immunofluorescence. We found that syndecan-1 expression increased in the FFP treatment group (1.6±0.4, p=0.001) vs. Control (1.0±0.26, n=10). However, these effects were absent in the AT-Def FFP treated group (1.3 ±0.3, p=0.13). Conclusions: These results suggest that ATIII mediates both the protective and reparative effects of FFP. Further studies are needed to elucidate the endothelial intracellular and extracellular signaling pathways mediating the ATIII-induced endothelial barrier preservation.
IMMU-63. IDH1 MUTATION REGULATE MYELOID CELLS PLASTICITY MEDIATING ANTI-GLIOMA IMMUNOTHERAPY
Authors: Mahmoud Alghamri, Neha Kamran, Felipe Nunez, Padma Kadiyala, Li Zhang, Ruthvik Avvari, Pedro Lowenstein, Maria Castro
Journal: Neuro-Oncology (2018)

Molecular characterization studies have illustrated that mutation in isocitrate dehydrogenase (mIDH1) enzyme, which is present in most patients with low grade glioma (LGG) and secondary glioma is correlated with better prognosis and survival [1]. We hypothesize that mIDH1 impacts tumor immunity by altering the phenotype and function of tumor infiltrating immune cells. To examine the role of mIDH1 on the immune tumor microenvironment (TME), we generated LGG glioma models using sleeping beauty system [2]. Mice bearing mIDH1 tumors exhibited longer median survival (MS) compared to the tumors harboring wtIDH1 (MS=163 vs. MS=70-day post-injection). Transcriptome analyses showed a positive enrichment in immune-stimulatory related gene families in mIDH1 tumors vs. wtIDH1 tumors; consistent with Human RNA-seq analysis from TCGA analysis. Using co-culture experiments followed by the in vivo characterization of immune cells within the TME, we showed that mIDH1 have higher expansion of CD11b+ Gr-1+ myeloid cells compared to wtIDH1 tumors (%MDSC/CD45+: 67.0% vs. 45.06%; P<0.05). Interestingly, CD11b+ Gr-1+ myeloid cells (MDSCs) from mIDH1 tumor expressed lower levels of immunosuppressive markers such as PD-L1 and CD80 which are involved in T-cell checkpoint inhibition. Consistent with this, TME-derived CD11b+ Gr-1+ myeloid cells from mIDH1 tumors didn’t inhibit tumor antigen specific T-cells’ expansion. Further analysis indicated that mIDH1 MDSCs also express lower levels of maturation markers suggesting that MDSCs from mIDH1 are at earlier maturation/differentiation stage. Interestingly, MDSCs depletion did not improve efficacy of immunotherapy in mIDH1; whilst in wtIDH1 bearing animals, survival increased to 70% when MDSCs depletion was combined with immunotherapy. In conclusion, mIDH1 expression in glioma cells impact the myeloid cells’ compartment possibly by changing the cytokine’s repertoire secreted by the tumor cells. This leads to reprogramming of myeloid cells within the TME which exhibit a non-immunosuppressive phenotype. 1. Ceccarelli, M., et al., 2016 2. Koschmann, C, et al., 2016
EXTH-14. REPURPOSING OF APPROVED DRUGS FOR THE TREATMENT OF GLIOMA STEM CELLS
Authors: Sang Lee, Becky Slagle-Webb, Brad Zacharia, James Connor
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common and malignant primary brain tumor. Glioma stem cells (GSCs), a subpopulation of GBM cells with stem cell properties, are responsible for the tumor initiation and recurrence, and therapeutic resistance. To develop novel therapeutic agents for sphere-forming patient derived GSCs, we utilized a new drug screening system and FDA approved drugs. The cell viability of the drugs on GSCs and normal human dermal fibroblast (nHDF) cells was determined by CellTiter-Glo 3D Cell Viability Assay or MTT assay. The relative cytotoxicity of drugs was compared with LC50. We identified 8 drugs, including 4 that have not been studied for GSCs, which showed strong cytotoxic effect on sphere-forming GSCs but were not toxic to nHDF cells in in vitro cell cultures. The LC50 of these identified drugs to GSCs is 10 fold to over 100 fold less than that for normal cells. Among the identified drugs, only one drug was not cytotoxic to GBM cells but toxic to GSCs. Based on the LC50 data and previous reports for the drugs on GSCs, we determined anti-tumor effects of two drugs in orthotopic brain tumor mouse models of human GBM cells. Animals treated with either drug (10 mg/kg once a week for 7 weeks or 30 mg/kg twice a week for 4 weeks) had significantly greater survival in Kaplan-Meier survival curve compared to vehicle treated control mice (p=0.03 or 0.05 in logrank test). Studies for structure-activity-relationship and mechanism of action are on-going. In summary, the present results provide compelling evidence that repurposing of approved drugs can be developed for GSCs and the study identified several selective cytotoxic drugs against sphere-forming GSCs. [This work was supported in part by the Tara Leah Witmer Endowment]
Abstract 20198: Length of Stay and 30 Day Mortality in Patients Suffering an Uncomplicated ST-Elevation Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention in New York State
Authors: Gregory Yost, Edward L Hannan, Ye Zhong, Peter B Berger
Journal: Circulation (2014)

Introduction: Little is known about the most appropriate duration of hospitalization in patients suffering an STEMI treated with primary PCI. Methods: We reviewed the prospective New York State (NYS) Department of Health PCI database and identified all patients admitted with STEMI between 2007-2009. Patients with no complications (stroke, heart failure, ejection fraction <40%, malignant ventricular arrhythmia, abrupt closure or the treatment site or major side branch, vascular complication requiring intervention, renal failure, cardiac surgery, stent thrombosis, repeat PCI, and coronary perforation) from the onset of infarction throughout the hospitalization were identified. Patients who were discharged after 2 nights vs 3 nights in the hospital were analyzed and compared. Clinical, angiographic and procedural characteristics; and 30 days outcomes, were compared for the 2 groups. Results: During the study period, 13,399 patients were admitted with STEMI in NYS; 4,939 patients (36.9%) did not develop or me...
Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance
Authors: Mounia S. Braza, Mandy M.T. van Leent, Marnix Lameijer, Brenda L. Sanchez-Gaytan, Rob J.W. Arts, Carlos Pérez-Medina, Patricia Conde, Mercedes R. Garcia, Maria Gonzalez-Perez, Manisha Brahmachary, Francois Fay, Ewelina Kluza, Susanne Kossatz, Regine J. Dress, Fadi Salem, Alexander Rialdi, Thomas Reiner, Peter Boros, Gustav J. Strijkers, Claudia C. Calcagno, Florent Ginhoux, Ivan Marazzi, Esther Lutgens, Gerry A.F. Nicolaes, Christian Weber, Filip K. Swirski, Matthias Nahrendorf, Edward A. Fisher, Raphaël Duivenvoorden, Zahi A. Fayad, Mihai G. Netea, Willem J.M. Mulder, Jordi Ochando
Journal: Immunity (2018)
RTHP-12. COMPARATIVE ANALYSIS OF TUMOR TREATING FIELDS USING CONVENTIONAL VERSUS ALTERNATIVE ARRAY PLACEMENT FOR POSTERIOR FOSSA GLIOBLASTOMA
Authors: Edwin Lok, Pyay San, Victoria White, Eric Wong
Journal: Neuro-Oncology (2018)

There is an alternative transducer array placement configuration to treat infratentorial tumors using TTFields but coverage for posterior fossa glioblastoma is unknown. Patient anatomy-based models were created by segmenting MRI images into tissue “masks”. The physical properties and boundary conditions for physics modeling were set up within COMSOL Multiphysics. Electric field maps were compared for models using conventional array placement for supratentorial tumors versus alternative array placement for infratentorial tumors. Electric field–volume histograms (EVHs) and specific absorption rate–volume histograms (SARVHs) were constructed to evaluate volumetric differences between models. The alternative configuration consists of array placement at the vertex, the bi-occipital regions and the upper neck. Highest EAUC was found at the epidural space surrounding the spinal cord and scalp for both types of configurations, whereas the lowest was located at the tongue and orbits. Using the conventional configuration, the gross tumor volume (GTV) had an electric field area under the curve (EAUC) of 40.5 V/m, volume covered with electric field intensity of 150 V/m (VE150) of 0.01%, 95% electric field intensity (E95%) of 30.9 V/m, E50% of 41.1 V/m, and E20% of 46.6 V/m. The GTV also had a SARAUC of 4.0 W/kg, volume covered with SAR of 6 W/kg (VSAR6) of 0%, SAR95% of 0.6 W/kg, SAR50% of 0.7 W/kg, and SAR20% of 0.8 W/kg. The alternative configuration produced EAUC of 52.3 V/m, VE150 of 3.6%, E95% of 29.1 V/m, E50% of 44.7 V/m, and E20% of 58.1 V/m, as well as SARAUC of 0.9 W/kg, VSAR6 of 0.3%, SAR95% of 0.6 W/kg, SAR50% of 0.8 W/kg, and SAR20% of 0.9 W/kg. CONCLUSIONS: The alternative array placement provides a higher coverage of electric field (+29%) to the posterior fossa glioblastoma when compared to the conventional configuration.
DDIS-02. NOVEL BISPECIFIC ACTIVATOR OF MACROPHAGES FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Miguel Salgado, Teilo Schaller, Patrick Gedeon, David Snyder, Gary Archer, Luis Sanchez-Perez, John Sampson
Journal: Neuro-Oncology (2018)

Patients undergoing current treatment for glioblastoma (GBM) still face a poor prognosis with a median survival of ~16 months. Current therapy is incapacitating and limited by non-specific toxicity to the surrounding brain. We have developed an immunotherapeutic approach that selectively targets GBM by redirecting the patients’ own macrophages present within the natural glioma milieu (representing up to 30% of the tumor volume) towards the tumor in an antigen-specific manner. This novel molecule, called bispecific activator of macrophages (BAM), bridges the macrophages with the tumor cells through the binding of CD64 and EGFRvIII, a tumor-specific antigen, respectively. We generated a stable fully human EGFRvIII-specific BAM Chinese hamster ovary cell line, and confirmed expression of BAM by western blot. Binding to CD64 and EGFRvIII was confirmed by flow cytometry on human CD64+ (hCD64) transgenic murine macrophages and EGFRvIII+ gliomas. Simultaneous BAM engagement of hCD64 on macrophages, and EGFRvIII led to the induction of macrophage tumoricidal activity measured by reactive oxygen species release. Furthermore, in vivo BAMadministration into glioma bearing mice significantly reduced tumor growth. In conclusion, we have developed a novel immunotherapeutic approach capable of harnessing the body’s own tumoricidal capacity by redirecting macrophages towards tumors via the administration of a bispecific activator of macrophages (BAM). While further studies are needed, this therapy offers promising results for the treatment of GBM.
NIMG-27. RADIOGENOMIC ANALYSIS OF GLIOBLASTOMA REVEALS TEXTURAL FEATURES FROM MRI THAT CORRELATE WITH GENOMIC IMMUNE SCORE AND ARE ALSO PREDICTIVE OF CHEMO-RADIATION TREATMENT RESPONSE
Authors: Niha Beig, Nathaniel Braman, Prateek Prasanna, Vinay Varadan, Anant Madabhushi, Pallavi Tiwari
Journal: Neuro-Oncology (2018)

Elevated immune response in Glioblastoma (GBM) is known to improve chemo-radiation therapy (CRT) response. Understanding this manifestation at a radiologic scale may establish non-invasive features as potential predictive biomarkers. We seek to discover pre-treatment radiomic MRI features associated with immune response, and further evaluate their capability to predict CRT response. 74 GBM patients from TCIA and TCGA with pre-treatment MRI and corresponding RNA sequencing prior to CRT were retrospectively analyzed. Immune score (IS) was derived from a 140-gene immune signature via the ESTIMATE algorithm. 1400 3D-radiomic features (Gabor, Haralick, Laws) were extracted from T1w, T2w, FLAIR within expert annotated regions (enhancing tumor, edema, necrosis) per patient. Least absolute shrinkage and selection operator (LASSO) was performed in 100 iterations of 3-fold cross-validation on the training set (n=40) with respect to IS. The 4 most selected radiomic features were used to derive a multilinear regression model of IS. This model was applied to predict IS within an independent set (n=34). Within test set, responders (R) were defined as patients with progression-free survival (PFS) of >= 4-months, while non-responders (NR) had PFS of <4-months. Unsupervised clustering of radiomic features was then implemented to categorize every study as R (n=18) or NR (n=16) to CRT. The radiomic model was significantly associated with IS in training (R2=.61, p <.0001) and testing (R2=.16, p =.018) sets. Top IS-associated features captured wave-like enhancement patterns and intensity value heterogeneity within the tumor or peritumoral edema on T1w and T2w. Within the testing set, unsupervised clustering yielded accuracy=.71 (Sensitivity=0.78, Specificity=.63) in distinguishing R from NR. Elevated IS, indicative of a robust immune response preceding treatment, may manifest as subtle changes in peritumoral edema detectable on pre-treatment MRI. Radiomic correlates of IS may provide means of quantifying immune activity and help predict response to CRT.
Abstract 15800: Impact of an Early Extubation Clinical Practice Guideline on Hospital Costs in Infants Undergoing Cardiac Surgery: Results From the Pediatric Heart Network Collaborative Learning Study
Authors: Kimberly E McHugh, William T Mahle, Matthew Hall, Mark A Scheurer, Michael-Alice Moga, John K Triedman, Susan C Nicolson, Venugopal Amula, David S Cooper, Marcus S Schamberger, Michael Wolf, Lara S Shekerdemian, Kristin M Burns, Kathleen Ash, Dustin M Hipp, Sara K Pasquali
Journal: Circulation (2017)

Introduction: The Pediatric Heart Network (PHN) Collaborative Learning Study successfully increased early extubation rates after Tetralogy of Fallot (TOF) and coarctation (CoA) repair across participating sites by implementing a clinical practice guideline (CPG). The impact of the CPG on hospital costs remains unclear. Methods: PHN study data were linked to cost data from Children’s Hospital Association through matching on indirect identifiers. Costs were evaluated across active and control sites in the year before and after CPG implementation (with a 3-month washout period) using generalized linear mixed effects models accounting for within center clustering, the skewed distribution of costs, and important patient characteristics. A difference-in-difference approach was used to assess whether any changes observed in active sites were above and beyond secular trends in control sites. Results: Data were successfully linked on 471/510 (94.3%) eligible patients from 4 active and 4 control sites (1 model site...
MNGI-33. RESULTS OF TRANSCRANIAL RESECTION OF OLFACTORY GROOVE MENINGIOMAS IN RELATION TO IMAGING-BASED CASE SELECTION CRITERIA FOR THE ENDOSCOPIC APPROACH
Authors: Krunal Patel, Angelos Kolias, Mannion Richard, Ramez Kirollos, Thomas Santarius
Journal: Neuro-Oncology (2018)

Endoscopic endonasal surgery (EES) is increasingly used for Olfactory Groove Meningiomas (OGMs). The role of EES for large (4cm) or complex OGMs is debated. Specific imaging features have been reported to affect the degree of gross total resection (GTR) and complications following EES for OGMs. The influence of these factors on transcranial resection (TCR) is unknown. We examined the impact of specific imaging features on outcome following TCR to provide a standard for large and endoscopically less favorable OGMs against which endoscopic outcomes can be compared. Retrospective study of patients undergoing TCR for OGMs 2002–2016. 50 patients (mean age 62.1 years, mean maximum tumor diameter 5.04 cm and average tumor volume of 48.8 cm3) were studied. Simpson grade 1 and 2 resections were achieved in 80% and 12%, respectively. A favorable functional outcome [modified Rankin Scale (mRS) 0–2] was attained in 86%. The degree of resection, mRS, mortality (4%), recurrence (6%), infection (8%) and CSF leak requiring intervention (12%) was not associated with tumor calcification, absence of cortical cuff, T2 hyperintensity, tumor configuration, tumor extension beyond midpoint of superior orbital roof or extension to posterior wall of frontal sinus. There was no difference in resection rates but a trend towards greater complications between three arbitrarily divided groups of large meningiomas of increasing complexity based on extensive extension or vascular adherence. Favorable outcomes can be achieved with TCR for large and complex OGMs. Factors which may preclude endoscopic resection do not negatively affect outcome following TCR.
EXTH-29. MULTI-RECEPTOR TARGETING IN GBM
Authors: Puja Sharma, Denise Herpai, John Rossmeisl, Stephen Tatter, Waldemar Debinski
Journal: Neuro-Oncology (2018)

Glioblastoma is a heterogeneous tumor for which all single-targeted agents failed. Being that a cytotoxic cocktail targeting IL-13RA2 and EphA2 receptors is effective in the treatment of spontaneous gliomas in dogs, we have been further pursuing molecular resection by targeting four tumor-specific/associated receptors at once: IL-13RA2, EphA2, EphA3 and EphB2. These receptors are over-expressed in most GBM tumor compartments responsible for tumor progression and recurrence. To this end, we have engineered a protein based on an immunoglobulin scaffold with a ligand targeting the three Eph receptors, ephrinA5 (eA5), at the N-terminal end and a ligand targeting IL-13RA2, IL-13.E13K, at the C-terminal end (QUAD). However, the protein produced in insect cells had frequently two bands on SDS-PAGE. We have therefore decided to change the order of the ligands and placed the ligand targeting IL-13RA2 at the N-terminal end of the protein and the other ligand and the C-terminus. We also started using High-Five cells for codon and yield optimization. The newer construct is produced as a single protein band on the SDS-PAGE and Western blot and can be purified to homogeneity. It bound all four receptors effectively in ELISA while the affinity toward the EphA3 was even better than in the original multivalent compound. We also obtained higher yields of the protein. To make our vector even more versatile, we have added a C-terminal cysteine providing a free thiol group for chemical conjugation with drugs. The QUAD-Cys was also obtained as a single band protein homodimer and the multi-targeted protein bound effectively to all targets of interest. Thus, we have optimized the production of a functional multivalent targeted vector protein for making drug conjugates. QUAD and QUAD-Cys based conjugates will be tested for their utility in glioma treatment using relevant clinical models like spontaneous brain tumors in dogs.