tbuckley/cabot-search huggingface dataset:
RYR2 Channel Inhibition Is the Principal Mechanism of Flecainide Action in CPVT
Authors: Dmytro O. Kryshtal, Daniel J. Blackwell, Christian L. Egly, Abigail N. Smith, Suzanne M. Batiste, Jeffrey N. Johnston, Derek R. Laver, Bjorn C. Knollmann
Journal: Circulation Research (2020)

Rationale: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive RyR2 (cardiac ryanodine receptor) mediated calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro, reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide’s efficacy in CPVT. Objective: To determine whether RyR2 block independently contributes to flecainide’s efficacy for suppressing spontaneous sarcoplasmic reticulum Ca release and for preventing ventricular tachycardia in vivo. Methods and Results: We synthesized N-methylated flecainide analogues (QX-flecainide and N -methyl flecainide) and showed that N -methylation reduces flecainide’s inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N -methylation did not alter flecainide’s inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. Antiarrhythmic efficacy was tested utilizing a Casq2 (cardiac calsequestrin) knockout (Casq2−/−) CPVT mouse model. In membrane-permeabilized Casq2−/− cardiomyocytes—lacking intact sarcolemma and devoid of sodium channel contribution—flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2−/− cardiomyocytes pretreated with tetrodotoxin to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous sarcoplasmic reticulum Ca release, while QX-flecainide and N -methyl flecainide did not. In vivo, flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2−/− mice, whereas N -methyl flecainide had no significant effect on arrhythmia burden, despite comparable sodium channel block. Conclusions: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.
INNV-12. A SINGLE-INSTITUTION RETROSPECTIVE REVIEW OF PATIENTS WITH CNS TUMORS WHO INITIATED A KETOGENIC DIET
Authors: Lauren Amaral, Amelia Welborn, Laura Lockshon, Gillian Gresham, Cristina Panhans, Jeremy Rudnick, Scott Irwin, Stephen Freedland, Jethro Hu
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Many patients with CNS tumors express interest in initiating a ketogenic diet (KD). Following a discussion with the physician regarding the limited clinical evidence of KD for CNS tumors, interested patients were referred for evaluation by an oncology-certified dietitian. METHODS We performed a single institution retrospective chart review of patients with CNS tumors on a KD. Demographics, clinical characteristics, and diet information were extracted from patient charts. Descriptive statistics were conducted to summarize patterns of adherence to KD across patient characteristics. RESULTS From May 2016 to May 2018, 40 patients expressed interest in KD; 24 initiated it. M:F = 18:6, median age 46 (range 27–62). Diagnoses: 18 glioblastoma, 1 anaplastic astrocytoma, 2 grade 2 astrocytoma, 1 grade 2 oligodendroglioma, 1 spinal grade 2 astrocytoma, 1 chordoma. 18 tumors with methylated MGMT, 8 with mutant IDH1. At diet initiation, median KPS 80 (range 70–100); median BMI 25.6 (20.8–39). Median days on diet = 190 days; interquartile range 126–673 days; range 24–1479 days. Diet composition: 15 patients on 3:1 diet (grams fat: grams protein + carbs), 7 patients on 2:1, 2 patients on 1:1. 14 patients monitored blood ketone levels. 11 patients stopped KD: 5 for restrictiveness of diet (median 158 days, range 60–239); 1 for decreased KPS (673 days); 1 for excessive weight loss (108 days); 2 for disease progression (24 and 217 days); 2 lost to follow-up (109 and 125 days). In this small sample, no statistically significant associations between time on diet and age / gender / BMI / KPS / diet composition. However, trend toward longer adherence to diet in females, age &amp;lt; 50, 2:1 diet. CONCLUSION It is feasible for patients with CNS tumors to adopt KD. Results from prospective studies are needed to assess effects on QOL, neurocognition, performance status, and survival.
RTID-07. HUMAN PLACENTAL HEMATOPOIETIC STEM CELL DERIVED NATURAL KILLER CELLS (CYNK-001) FOR TREATMENT OF RECURRENT GLIOBLASTOMA
Authors: Nazanin Majd, Maha Rizk, Solveig Ericson, Kris Grzegorzewski, Sharmila Koppisetti, Junhong Zhu, Lin Kang, Shawn He, Tanel Mahlakoiv, William van Der Touw, Xiaokui Zhang, Nassir Habboubi, Robert Hariri, Kathy Hunter, Kristin Alfaro-Munoz, Amy Heimberger, John de Groot, Linda Chi, Samer Srour
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with dismal prognosis. Recent advances of immunotherapy in cancer have sparked interest in the use of cell therapy for treatment of GBM. Active transfer of Natural Killer (NK) cells is of particular interest in GBM because NK cells are capable of exerting anti-tumor cytotoxicity without the need for antigen presentation and sensitization, processes that are impaired in GBM. CYNK-001 is an allogeneic, off-the-shelf product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells manufactured by Celularity. Here, we demonstrate in vitro cytotoxicity of CYNK-001 against several GBM lines and its in vivo anti-tumor activity in a U87MG orthotopic mouse model via intracranial administration resulting in 94.5% maximum reduction in tumor volume. We have developed a phase I window-of-opportunity trial of CYNK-001 in recurrent GBM via intravenous (IV) and intratumoral (IT) routes. In the IV cohort, subjects receive cyclophosphamide for lymphodepletion followed by 3-doses of IV CYNK-001 weekly. In the IT cohort, subjects undergo placement of an IT catheter with an ommaya reservoir followed by 3-doses of IT CYNK-001 weekly. Patients are monitored for 28-days after last infusion for toxicity. Once maximum safe dose (MSD) is determined, patients undergo IV or IT treatments at MSD followed by surgical resection and the tumor tissue will be analyzed for NK cell engraftment and persistence. We will utilize a 3 + 3 dose de-escalation design (maximum n=36). Primary endpoint is safety and feasibility. Secondary endpoints are overall response rate, duration of response, time to progression, progression free survival and overall survival. Main eligibility criteria include age ≥18, KPS ≥60, GBM at first or second relapse with a measurable lesion on ≤2mg dexamethasone. This is the first clinical trial to investigate CYNK-001 in GBM and will lay the foundation for future NK cell therapy in solid tumors.
EXTH-41. THE microRNA miR-138 MAY BE RESPONSIBLE FOR SOME OF THE EFFECTS OF METABOLIC KETOSIS ON MALIGNANT GLIOMA
Authors: Richard Perryman, Qingyu Zeng, Oishik Raha, Kevin O’Neill, Adrienne Scheck, Nelofer Syed
Journal: Neuro-Oncology (2020)

Abstract We and others have demonstrated that altering metabolism through the use of a ketogenic diet (KD) has numerous effects in mouse models of malignant glioma including slowed growth, reduced hypoxia and angiogenesis, enhanced survival and potentiation of the effects of radiation and chemotherapy. These effects are recapitulated in vitro when the ketone β-hydroxybutyrate (BHB) is added to mouse and human malignant glioma cells grown under high glucose conditions. BHB has been demonstrated to be an epigenetic modifier, providing a potential mechanism for the pluripotent effects of ketones even in the presence of high glucose. Therefore, we have analyzed alterations in microRNA (miRNA) expression in tumors and cells treated with a KD or BHB, respectively. MicroRNAs are short, single-stranded, noncoding RNAs that posttranscriptionally control gene expression. Each miRNA can affect the expression of many genes and they are implicated in all hallmarks of cancer. We found a number of miRNAs deregulated in tumor tissue from mice fed a KD, particularly mmu-miR-138 which was increased over 30-fold relative to tumors from mice fed a standard diet. MiR-138 is involved in a variety of anti-tumor effects that correlate with our data from KD treated gliomas. We have shown that ketones radiosensitize glioma cells, potentially through a reduction in DNA damage repair. MiR-138 has been shown to reduce the expression of H2AX which plays a key role in sensing and repairing DNA damage. Hypoxia inducible factor-1α (HIF-1α) is also a target of miR-138, and we have demonstrated a reduction in hypoxia, angiogenesis and the expression of HIF-1α in tumors from mice fed a KD. Furthermore, when we genetically engineered tumor cells to express miR-138 and injected them into mice, only necrotic tumor foci were found. Thus, we suggest that miR-138 is an important regulatory mechanism for the anti-tumor actions of metabolic ketosis in glioma.
Pharmacological Differences of Glitazones: Does Peroxisome Proliferator-Activated Receptor-α Activation Make the Difference?⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Ulrich Kintscher
Journal: Journal of the American College of Cardiology (2008)
Intraocular Pressure, Glaucoma, and Dietary Caffeine Consumption
Authors: Jihye Kim, Hugues Aschard, Jae H. Kang, Marleen A.H. Lentjes, Ron Do, Janey L. Wiggs, Anthony P. Khawaja, Louis R. Pasquale
Journal: Ophthalmology (2020)

We examined the association of habitual caffeine intake with intraocular pressure (IOP) and glaucoma and whether genetic predisposition to higher IOP modified these associations. We also assessed whether genetic predisposition to higher coffee consumption was related to IOP.Cross-sectional study in the UK Biobank.We included 121 374 participants (baseline ages, 39-73 years) with data on coffee and tea intake (collected 2006-2010) and corneal-compensated IOP measurements in 2009. In a subset of 77 906 participants with up to 5 web-based 24-hour-recall food frequency questionnaires (2009-2012), we evaluated total caffeine intake. We also assessed the same relationships with glaucoma (9286 cases and 189 763 controls).We evaluated multivariable-adjusted associations with IOP using linear regression and with glaucoma using logistic regression. For both outcomes, we examined gene-diet interactions using a polygenic risk score (PRS) that combined the effects of 111 genetic variants associated with IOP. We also performed Mendelian randomization using 8 genetic variants associated with coffee intake to assess potential causal effects of coffee consumption on IOP.Intraocular pressure and glaucoma.Mendelian randomization analysis did not support a causal effect of coffee drinking on IOP (P > 0.1). Greater caffeine intake was associated weakly with lower IOP: the highest (≥232 mg/day) versus lowest (<87 mg/day) caffeine consumption was associated with a 0.10-mmHg lower IOP (Ptrend = 0.01). However, the IOP PRS modified this association: among those in the highest IOP PRS quartile, consuming > 480 mg/day versus < 80 mg/day was associated with a 0.35-mmHg higher IOP (Pinteraction = 0.01). The relationship between caffeine intake and glaucoma was null (P ≥ 0.1). However, the IOP PRS also modified this relationship: compared with those in the lowest IOP PRS quartile consuming no caffeine, those in the highest IOP PRS quartile consuming ≥ 321 mg/day showed a 3.90-fold higher glaucoma prevalence (Pinteraction = 0.0003).Habitual caffeine consumption was associated weakly with lower IOP, and the association between caffeine consumption and glaucoma was null. However, among participants with the strongest genetic predisposition to elevated IOP, greater caffeine consumption was associated with higher IOP and higher glaucoma prevalence.
Exome Sequencing as Part of a Multidisciplinary Approach to Diagnosis—Reply
Authors: Jan M. Friedman, Kenneth Lyons Jones, John C. Carey
Journal: JAMA (2020)

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MBCL-16. EFFICACY OF CARBOPLATIN GIVEN CONCOMITANTLY WITH RADIATION AND ISOTRETINOIN AS A PRO-APOPTOTIC AGENT IN MAINTENANCE THERAPY IN HIGH-RISK MEDULLOBLASTOMA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Sarah Leary, Roger Packer, Alok Jaju, Linda Heier, Peter Burger, Kyle Smith, Jeff Michalski, Yimei Li, Catherine Billups, Eugene Hwang, Amar Gajjar, Ian Pollack, Maryam Fouladi, Paul Northcott, James Olson
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Metastasis, residual disease, and diffuse anaplasia are high-risk features in medulloblastoma. METHODS This was a randomized phase 3 study. Patients age 3–21 years with high-risk medulloblastoma received (+/-) daily carboplatin with 36Gy craniospinal radiation and weekly Vincristine followed by six cycles of maintenance chemotherapy with Cisplatin, Cyclophosphamide and Vincristine (+/) 12 cycles of isotretinoin during and following maintenance. The primary endpoint was event-free survival, with exact log-rank test to compare arms. Retrospective molecular analysis included DNA methylation and exome sequencing. RESULTS Of 294 medulloblastoma patients enrolled, 261 were eligible by central review of radiology and pathology, median age 8.6 years (range 3.3–21.2), 70% male, 189 (72%) with metastatic disease, 58 (22%) with diffuse anaplasia, 14 (5%) with &amp;gt;1.5cm2 residual disease. The 5-year EFS and OS for all subjects was 63%+4 and 73%+3, respectively. Isotretinoin randomization was closed due to futility. 5-year EFS was 66 + 5 with carboplatin versus 59 + 5 without (p=0.11), with effect exclusively observed in Group 3 subtype: 73%+8 with carboplatin versus 54%+9 without (p&amp;lt;0.05). Overall survival differed by molecular subgroup (p=0.006): WNT 100%, SHH 54%+11, Group 3 74%+6, Group 4 77%+5 at 5 years. MYC amplification or isochromosome 17 were unfavorable in Group 3 (p=0.029). Chromosome 11 loss or chromosome 17 gain were favorable in group 4 (p&amp;lt;0.001). No survival difference was observed with TP53 mutation in SHH subtype in this high-risk cohort. CONCLUSIONS Therapy intensification with carboplatin improved survival for high-risk group 3 medulloblastoma. These findings further support an integrated clinical and molecular risk stratification for medulloblastoma.
TMOD-01. DEVELOPING CLINICALLY RELEVANT BRAIN METASTATIC TUMOR MODELS FOR TARGETED STEM CELL THERAPEUTICS
Authors: Yohei Kitamura, Susana Moleirinho, Nobuhiko Kanaya, Arnaldo Franco, Khalid Shah
Journal: Neuro-Oncology (2020)

Abstract Brain metastasis is associated with increased mortality in patients with cancer, 15-20% of patients will develop brain metastasis during the course of the disease. Characterizing clinically relevant brain metastasis models and exploring different options to deliver drugs across blood brain barrier in such models are fundamental for the development of novel therapies for metastatic brain tumors. We have created imageable breast to brain metastasis tumor models using patient derived brain seeking basal like breast cancer (BLBC) lines. We show a widespread distribution of micro- and macro-metastasis and the close association of tumor cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. These models enables us to investigate the pathophysiology of this little-known phenomenon and test the efficacy of new approach targeting the dormant cancer cells in perivascular niche. Next, we assessed the EGFR and DR4/5 levels in BLBC and show that brain seeking BLBC have higher EGFR and DR5 levels than their primary counterparts. We also show that intracarotid artery injection or intrathecal injection of stem cells engineered to express optical imaging markers home to metastatic brain tumors. These findings provide useful models for testing treatments for metastatic brain tumors and also provide insights into the changes in gene expression in metastatic BLBC and means to deliver therapeutics to metastatic tumors in the brain.
DIPG-47. HISTONE MUTATIONS ENHANCE RAS MEDIATED ERK5 GROWTH SIGNALING IN DIFFUSE MIDLINE GLIOMAS
Authors: Ann-Catherine Stanton, Robert Koncar, Brian Golbourn, Brittany Dey, Nishant Agrawal, Stephen Mack, Ian Pollack, Sameer Agnihotri
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline gliomas (DMGs) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DMG, who have a median survival time of less than one year. Most DMG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DMG growth. Suppression of ERK5 decreased DMG cell proliferation and induced apoptosis in vitro and in vivo. In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DMG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Additionally, persistent ERK5 depletion does not result in complete growth inhibition and therefore we set out to determine potential adaptation or resistance mechanisms in response to ERK5 loss. Using RNA-sequencing and Immunoprecipitation (IP) mass spectrometry (IP-MS), we have identified several positive and negative feedbacks involved in ERK5 that are also targetable. These findings identify the H3K27M mutation as an enhancer of RAS activation in DMG with ERK5 and ERK5 regulated networks immediately actionable pathways.
IMG-06. PREDICTING SURVIVAL FROM PERFUSION AND DIFFUSION MRI BY MACHINE LEARNING
Authors: James T Grist, Stephanie Withey, Christopher Bennett, Heather Rose, Lesley MacPherson, Adam Oates, Stephen Powell, Jan Novak, Laurence Abernethy, Barry Pizer, Simon Bailey, Dipayan Mitra, Theodoros N Arvanitis, Dorothee P Auer, Shivaram Avula, Richard Grundy, Andrew C Peet
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Magnetic Resonance Imaging (MRI) is routinely used in the assessment of children’s brain tumours. Reduced diffusion and increased perfusion on MRI are commonly associated with higher grade but there is a lack of quantitative data linking these parameters to survival. Machine learning is increasingly being used to develop diagnostic tools but its use in survival analysis is rare. In this study we combine quantitative parameters from diffusion and perfusion MRI with machine learning to develop a model of survival for paediatric brain tumours. METHOD: 69 children from 4 centres (Birmingham, Liverpool, Nottingham, Newcastle) underwent MRI with diffusion and perfusion (dynamic susceptibility contrast) at diagnosis. Images were processed to form ADC, cerebral blood volume (CBV) and vessel leakage correction (K2) parameter maps. Parameter mean, standard deviation and heterogeneity measures (skewness and kurtosis) were calculated from tumour and whole brain and used in iterative Bayesian survival analysis. The features selected were used for k-means clustering and differences in survival between clusters assessed by Kaplan-Meier and Cox-regression. RESULTS Bayesian analysis revealed the 5 top features determining survival to be tumour volume, ADC kurtosis, CBV mean, K2 mean and whole brain CBV mean. K-means clustering using these features showed two distinct clusters (high- and low-risk) which bore significantly different survival characteristics (Hazard Ratio = 5.6). DISCUSSION AND CONCLUSION Diffusion and perfusion MRI can be used to aid the prediction of survival in children’s brain tumours. Tumour perfusion played a particularly important role in predicting survival despite being less routinely measured than diffusion.
IMMU-34. LANDSCAPE OF GLIOBLASTOMA-ASSOCIATED IMMUNITY BY INTEGRATION OF scRNA-SEQ AND SPATIAL TRANSCRIPTOMICS
Authors: Vidhya Ravi, Nicolas Neidert, Kevin Joseph, Juergen Beck, Oliver Schnell, Dieter Heiland
Journal: Neuro-Oncology (2020)

Abstract The diversity of molecular states and cellular plasticity of immune cells within the glioblastoma (GBM) environment remain poorly investigated. Here, we conduct deep transcriptional profiling of lymphoid and myeloid cell populations by scRNA-sequencing, map potential cellular interactions and cytokine responses that lead to the dysfunctional and exhausted phenotype of T cells. We identified Interleukin 10 (IL-10) response during T cell activation, which lead to a dysfunctional state of T cells. By the use of a novel method: The nearest functionally connected neighbor (NFCN), an in-silico model to explore cell-cell interaction, the dysfunctional/exhausted phenotype was found to be driven by subset of myeloid cells defined by high expression of HMOX1. By using spatial transcriptomic RNA-sequencing, we identified a correlation between T cell exhaustion and colocalized mesenchymal gene expression. We found that HMOX1 expressing myeloid cells occupying regions marked by T cell exhaustion. Using a human neocortical slice model with myeloid cell depletion we confirmed the functional interaction of myeloid and lymphoid cell leading to the dysfunctional state of T cells. A comprehensive understanding of cellular states and plasticity of lymphoid cells in GBM aids in providing successful immunotherapeutic approaches.