tbuckley/cabot-search huggingface dataset:
EXTH-07. DESIGN AND EVALUATION OF WP1122, AN INHIBITOR OF GLYCOLYSIS WITH INCREASED CNS UPTAKE.
Authors: Waldemar Priebe, Rafal Zielinski, Izabela Fokt, Edward Felix, Venugopal Radjendirane, Jayakumar Arumugam, Matthew Tai Khuong, Maciej Krasinski, Stanislaw Skora
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM), an aggressive primary brain tumor, relies on anaerobic glycolysis to produce energy. A known inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG) has been clinically tested but its poor drug-like characteristics limited its practical application for cancer treatment. To overcome this problem, we have performed latentiation of 2-DG. Chemical modification of biologically active 2-DG led to the formation of prodrugs with improved pharmacokinetic and pharmacodynamic properties and subsequently to selection of the lead compound WP1122 (3,6-di-O-acetyl-2-deoxy-D-glucose). Unlike 2-DG, its prodrug WP1222 enters cells and cross blood-brain barrier by passive diffusion rather than by specific glucose transporter, then undergoes deacetylation by esterases and is trapped inside the cell after phosphorylation at C-6 hydroxyl group. 6-phospho-2-deoxy glucose acts as a competitive inhibitor of hexokinase (HK) blocking phosphorylation of D-glucose and subsequently inhibiting glycolytic pathway. Our in vitro experiments confirmed inhibition of glycolysis in U87 cells and high sensitivity of broad spectrum of cancer cells to WP1122 both in hypoxic and normoxic conditions (IC50 range from 1–10 mM). In vivo studies showed that WP1122 is well tolerated by animals even with prolonged exposure and extend survival of mice in orthotopic U87 GBM model. Initial pharmacokinetic experiments demonstrated rapid uptake of WP1122 after oral administration allowing to achieve two orders of magnitude higher maximum concentration of 2-DG in plasma, compared to animals treated with an equal molar dose of pure 2-DG. We also observed significantly higher levels of 2-DG in brains of mice treated with WP1122 than in mice receiving equal dose of 2-DG. In summary, WP1122 is a biologically effective prodrug of 2-DG with a good toxicity profile and promising pharmacokinetic characteristics that warrants detail preclinical and clinical development as a potential therapeutic agent for glioblastomas and other highly glycolytic tumors.
Abstract 14664: Safety, Pharmacokinetics, and Pharmacodynamics of Single Ascending Doses of Recombinant Human Lecithin-Cholesterol Acyltransferase (MEDI6012) in Subjects With Stable Coronary Heart Disease
Authors: Richard T George, Liron Abuhsira, Susan Stoughton, Dewei She, Nicholas A Buss, Rebecca Bakker-Arkema, Michael Koren, Boaz Hirshberg
Journal: Circulation (2017)

Introduction: MEDI6012 is recombinant human lecithin-cholesterol acyltransferase (LCAT), the rate-limiting enzyme in reverse cholesterol transport (RCT) that facilitates the esterification of chole...
RDNA-03. TARGETING THE EPIGENETIC REMODELING FACTOR FACT TO RADIOSENSITIZE GLIOBLASTOMA CANCER STEM CELLS
Authors: Kristin Huntoon, Amanda Deighen, Monica Venere
Journal: Neuro-Oncology (2018)

Radiotherapy remains standard of care for glioblastoma (GBM) but has limited efficacy due to the ability of cancer stem-like cells (CSCs) to drive tumor recurrence through their enhanced malignant properties (i.e., radioresistance, angiogenicity, and invasiveness). Our overall objective is to address an unmet clinical need by identifying strategies to overcome the inherent radioresistance of GBM CSCs and develop effective treatment modalities that will inclusively target this recurrence-driving subset of cells. We have previously shown that components of the cell cycle and DNA damage response (DDR) machinery are required for CSC malignancy. More recently, we reported that the facilitates chromatin transcription (FACT) complex, which serves to reorganize nucleosomes to facilitate RNA polymerase II (Pol II)-mediated transcription, is a key mediator of the CSC phenotype. FACT has also been reported to have a role in DNA replication and the DDR. We hence sought to evaluate the impact of FACT disruption using the small molecule inhibitor curaxin-137, with proven blood brain barrier penetration, on the ability of CSCs to tolerate irradiation induced DNA damage. We first combined curaxin-137 treatment with irradiation and followed the resolution of DNA damage by immunofluorescence for γH2A.X or 53BP1, markers of DNA damage. Results indicated that the combinatorial treatment induced a significantly greater amount of DNA damage that failed to be resolved in the CSCs. We next explored the impact of treatment on CSC viability. Results indicated that combination treatment with curaxin-137 did reduce clonogenic survival of CSCs. Ongoing studies aim at evaluating the in vivo efficacy of this treatment as a radiosentizing agent. The ability to identify paradigms that increase the radiosensitivity of CSCs will have immense therapeutic implications on reducing the propensity of CSCs to drive the malignant phenotype of GBM.
Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand
Authors: Julia Luther, Timur Alexander Yorgan, Tim Rolvien, Lorenz Ulsamer, Till Koehne, Nannan Liao, Daniela Keller, Nele Vollersen, Stefan Teufel, Mona Neven, Stephanie Peters, Michaela Schweizer, Andreas Trumpp, Sebastian Rosigkeit, Ernesto Bockamp, Stefan Mundlos, Uwe Kornak, Ralf Oheim, Michael Amling, Thorsten Schinke, Jean-Pierre David
Journal: Science Translational Medicine (2018)

Wnt1 is a physiologically relevant bone-anabolic molecule that does not require the expression of the bone-anabolic Wnt co-receptor Lrp5.
PATH-46. NEURONAL DIFFERENTIATION IS INDUCED BY Gli3 IN WNT- AND SHH- ACTIVATED MEDULLOBLASTOMA
Authors: Manabu Natsumeda, Hiroaki Miyahara, Junichi Yoshimura, Satoshi Nakata, Yoshihiro Tsukamoto, Jun Watanabe, Takafumi Wataya, Charles Eberhart, Akiyoshi Kakita, Yukihiko Fujii
Journal: Neuro-Oncology (2018)

We have previously investigated the expression of Gli3, a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular (D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In the present study, we investigated the expression of Gli3 in the molecular subgroups. METHOD: Thirty-one medulloblastomas treated at Department of Neurosurgery, Niigata University between 1982 and 2013 were retrospectively studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) was performed using Nanostring. HE and NeuN, GFAP, beta-catenin, GAB-1, and YAP-1 immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in each molecular subgroup was assessed in the public data base R2. Nanostring was considered reliable (confidence > 0.9) in 28 cases. Four cases were classified as WNT- activated, 5 cases as SHH-activated, 4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 out of 9 (78%) WNT-/SHH- cases, whereas Gli3 was positive in only 8 out of 19 (42.1%) non-WNT-/SHH- subgroup (p = 0.1145, Fishers exact test). R2 database analysis confirmed that Gli3 was significantly elevated in WNT- and SHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases but suppressed in WNT-activated cases. IHC analysis revealed that Gli3 was elevated inside the nodules of D/N type medulloblastoma. Neuronal differentiation was seen in these nodules. These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 suppresses HH signaling in the entire tumor.
PATH-27. IDENTIFYING THE GENETIC SIGNATURE OF RESPONSE IN A PHASE II STUDY OF TUMOR TREATING FIELDS IN RECURRENT GLIOBLASTOMA
Authors: David Tran, Sonisha Warren, William Friedman, Ashley Ghiaseddin, Gregory Murad, Maryam Rahman, Steven Roper, Anne Allen, Valerie Greene, Anthony Yachnis
Journal: Neuro-Oncology (2018)

Prognosis of relapsed glioblastoma (GBM) is dismal and current treatment fails to provide prolonged survival. Small subsets of patients respond well to some novel therapeutics probably due to the genetic variations of tumors and patients. In the Phase 3 EF-11 recurrent GBM trial, a small subset of patients derived significant benefit from TTFields alone. This proof-of-concept trial [NCT01954576] will study adult patients with relapsed GBM treated with TTFields by genetic analysis of primary and recurrent tumors. Post-hoc correlations will be used between clinical response, mutational analyses and quantitative gene expression to define genomic signatures of response. Whole exome and RNA sequencing will be used to identify genomic signature of responders to TTFields. Fifteen patients with bevacizumab-naïve recurrent GBM and 15 patients with bevacizumab-refractory GBM will be treated with TTFields for 6 and 4 months respectively. Patients will undergo standard brain MRI scans without and with gadolinium contrast and perfusion imaging every 8 weeks. Tissue from the primary tumor at recurrence will be genetically analyzed. Genomic DNA (gDNA) will be extracted from patients tumor and blood samples. Purified gDNA fragments will be used for Illumina sequencing library construction. Certain germ-line variants may contribute to gliomagenesis and be associated with somatic mutations within the tumor and subtypes of GBM more or less sensitive to TTFields. Analyses will be conducted on all patients: bevacizumab-naïve and bevacizumab-refractory GBM separately, and patients with objective radiographic response (complete response + partial response (CR + PR) and stable disease (SD) separately. With 50% bevacizumab-refractory GBM patients, response rate will be significantly higher than the baseline rate of 14%. Using an Exact test with type I error of 0.05 and 80% power, the estimated sample sizes will detect a statistical difference on response rate in the TTFields group compared to historical controls. To-date 4 patients have been enrolled.
Considerations on Retrospective Identification and Classification of Learning Disabilities
Authors: Michele Poletti
Journal: JAMA Neurology (2018)

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CBMT-23. MODULATION OF HYPERSYNAPTIC MICROENVIRONMENT DIFFERENTIALLY PROMOTES GLIOMAGENESIS ACROSS PIK3CA VARIANTS
Authors: Kwanha Yu, Asante Hatcher, Jungsung Woo, Chia-Ching John Lin, Kathleen Kong, Carrie Mohila, Brittney Lozzi, Chad Creighton, Jeffrey Noebels, Benjamin Deneen
Journal: Neuro-Oncology (2018)

Genetic mutations remain one of the principle drivers for glioblastoma multiforme, a devastating disease with the poorest prognosis; however, much like other cancers mutations are both a cause and consequence of glioma. While there is a wealth of patient genomics data, they do not properly discern or address whether annotated genetic perturbations are causative “driver” events or consequential “passenger” mutations. To address this, we developed a screening platform where we can screen up to 50 different genetic factors, in vivo. In combination with next generation sequencing, we identified the most potent candidate drivers. Additionally, we’ve comparatively analyzed 30 different alleles of PIK3CA in vitro. Using these approaches, we identified candidate drivers and individually validated these alleles. Testing 7 variants in vivo, we identified C420R and M1043I as rare and previously uncharacterized driver mutations in GBM. Additionally, we identified variants that do not promote tumor growth, demonstrating that each variant differentially drives gliomagenesis. Subsequent molecular profiling of driver variants suggested differential synaptic environments which correlated with seizure activity. We further characterized this synaptic deregulation, revealing that individual variants can differentially modulate the hypersynaptic microenvironment, independent of tumor context. Taken together with recent work revealing that local synaptic activity can promote tumor growth, this would suggest that specific variants of PIK3CA differentially drive gliomagenesis by differentially modulating the hypersynaptic profile of the tumor microenvironment. In sum, our study reveals: 1) a novel screening approach whereby we can screen 50 different factors in vivo, 2) novel GBM-relevant driver alleles C420R and M1043I previously not characterized in vivo, 3) that even single amino acid alterations across driver mutations can drastically alter gliomagenic programs, and 4) one differential mechanism by which PIK3CA variants differentially promote gliomagenesis is by deregulating synaptic microenvironment.
Abstract 14850: Serum Soluble Urokinase-type Plasminogen Activator Receptor is Associated With the Prevalence of Atrial Fibrillation
Authors: Masatoshi Miyamura, Noboru Ichihara, Yohei Yamauchi, Yuki Fujimura, Daichi Maeda, Tomohiro Fujisaka, Shu-ichi Fujita, Hideaki Morita, Yoshihiro Takeda, Takahide Ito, Koichi Sohmiya, Masaaki Hoshiga, Nobukazu Ishizaka
Journal: Circulation (2017)

Introduction: Circulating soluble urokinase-type plasminogen activator receptor (suPAR), which can reflect immune activation, low-grade inflammation, and certain types of malignancies, may also rep...
TMIC-27. GLIOMA CELLS INDUCE ‘EPIGENETIC MEMORY’ IN MICROGLIA AND BLOCK INFLAMMATORY GENE EXPRESSION- IN VITRO AND IN VIVO FINDINGS
Authors: Bozena Kaminska, Marta Maleszewska, Aleksandra Steranka, Magdalena Smiech, Beata Kaza, Paulina Pilanc, Michal Dabrowski
Journal: Neuro-Oncology (2018)

Macrophages are polarized to perform dedicated functions by microenvironmental signals and upon re-stimulation display a memory. Macrophages could be trained to respond to a specific signal, and upon re-stimulation display a “memory” of a prior insult which could be relatively stable. A subsequent stimulus evokes lesser reaction or is unable to induce a reaction comparable to primary one. Microglia (brain resident macrophages) and peripheral macrophages accumulate in malignant gliomas, and acquire the immunosuppressive, tumor supporting phenotype. This phenotype is difficult to overcome and could be a big obstacle in reestablishing antitumor immunity. Here, we demonstrate that microglia pre-exposed to glioma attain an “epigenetic memory” and display reduced inflammatory gene expression after stimulation with lipopolysaccharide (LPS). We studied if those changes rely on DNA methylation and histone modifications. We found that unstimulated microglia have unmethylated DNA and active histone marks at selected gene promoters indicating chromatin accessibility. Stimulation of cultured microglia with glioma conditioned medium (GCM) or LPS induces distinctive changes of histone modifications: histone acetylation is erased at tested genes due to increased activity of histone deacetylases (Hdac) only in glioma-activated microglia. Inflammatory genes acquire repressive histone marks (H3K27 trimethylation) at later times in a process of epigenetic memory formation. Hdac inhibitors block glioma-induced changes in histone modifications and restored cell ability to linduce effective inflammatory gene expression. Microglia (CD11b+ cells) isolated by flow cytometry from rat brains implanted with C6 glioma cells exhibit changes in activating and repressive marks at the promoters of the tested genes: Cxcr1, Id1, Id3, Mark1, Zbp1, Irf7 and iNOS in comparison to control microglia. Our study reveals important contribution of epigenetic mechanisms to glioma-induced polarization of tumor infiltrating microglia towards a tumor-supportive phenotype. This study was supported by HOMING PLUS/2011–3/7 grant from Foundation for Polish Science (MM).
The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis
Authors: Eva Santamaría, Carlos M. Rodríguez‐Ortigosa, Iker Uriarte, Maria U. Latasa, Raquel Urtasun, Gloria Alvarez‐Sola, Marina Bárcena‐Varela, Leticia Colyn, Sara Arcelus, Maddalen Jiménez, Kathleen Deutschmann, Ana Peleteiro‐Vigil, Julian Gómez‐Cambronero, Malgorzata Milkiewicz, Piotr Milkiewicz, Bruno Sangro, Verena Keitel, Maria J. Monte, Jose J.G. Marin, Maite G. Fernández‐Barrena, Matias A. Ávila, Carmen Berasain
Journal: Hepatology (2018)

Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ’s function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha‐naphthyl‐isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up‐regulated. Importantly, Areg–/– mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL‐induced liver injury and reduced BA‐triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up‐regulation in both tissues. Most interestingly, Areg–/– mice displayed high hepatic cholesterol 7 α‐hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg–/– mice, and recombinant AREG down‐regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr–/– mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA‐FXR through activation of suppressor of cytokine signaling‐3 (SOC3). Conclusion: AREG‐EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.
RTHP-33. APPLICATION OF PRESURGICAL NAVIGATED TRANSCRANIAL MAGNETIC STIMULATION MOTOR MAPPING FOR ADJUVANT RADIOTHERAPY TREATMENT PLANNING IN PATIENTS WITH BRAIN TUMORS
Authors: Christian Diehl, Maximilian Schwendner, Nico Sollmann, Markus Oechsner, Bernhard Meyer, Stephanie Combs, Sandro Krieg
Journal: Neuro-Oncology (2018)

Lately navigated transcranial magnetic stimulation (nTMS) has been implemented in the neurosurgical routine to detect motor-eloquent areas for safe and complete resection of high-grad gliomas (HGG). However, in radiotherapy (RT) planning, the primary motor cortex is not respected in target volume delineation. This study evaluates the implementation of nTMS motor mapping for RT planning in patients harbouring motor-eloquent HGGs. nTMS motor maps of 30 patients diagnosed with motor-eloquent HGGs were fused with RT planning and imaging and volumetric modulated RT plans were optimized using nTMS maps as organ at risk (OAR). Doses to nTMS motor maps were evaluated using dose-volume histogramm (DVH) parameters. Mean dose (Dmean) to the nTMS motor maps was 42.3 Gray (Gy) (3.7–61.1 Gy) and was significantly reduced by 14.3% to 37.0 Gy (3.6 - 55.8 Gy, p<0.05) when constraining the dose to nTMS motor areas to 45 Gy. Yet, the dose to the planning total volume (PTV) was not compromised. Even with an additional dose escalation of 70 Gy to the tumor area, nTMS motor maps can be spared by 4.6 +/- 3.5 Gy (12.8%, p<0.05). CONCLUSIONS: nTMS motor maps can be easily implemented in standard RT planning and applied for target contouring in the treatment of HGGs. Doses to motor-eloquent areas can be significantly reduced when considering nTMS motor maps without affecting treatment doses to the PTV. Thus, nTMS could be used as a valuable tool in RT planning.
Gynaecologist whose erasure was quashed in High Court is fit to practise
Authors: Clare Dyer
Journal: BMJ (2018)

A consultant gynaecologist who in March 2017 won a High Court ruling quashing a decision to strike him off the UK medical register has scored a further victory against the General Medical Council.

After a new hearing, a medical practitioners tribunal has decided that Joseph Onwude’s fitness to practise was not impaired and that his conduct merited only a formal warning.

An earlier tribunal had decided that he had been dishonest in treating two friends and business partners free of charge and then sending them an invoice after the relationship broke down. That tribunal determined in December 2016 that he should be struck off the register. Onwude subsequently exercised his right of appeal to the …
PATH-14. SURGICAL STRATEGY FOR LOWER GRADE GLIOMAS USING INTRAOPERATIVE RAPID MOLECULAR AND PATHOLOGICAL DIAGNOSIS
Authors: Masayuki Nitta, Yoshihiro Muragaki, Shunichi Koriyama, Takashi Maruyama, Takashi Komori, Taiichi Saito, Shunsuke Tsuzuki, Takakazu Kawamata
Journal: Neuro-Oncology (2018)

In the 2016 WHO classification, genetic information was introduced in the pathological diagnosis of gliomas, and the correlation between molecular subtype and prognosis has been shown. High extent of removal (EOR) provides survival benefit for some subtype of lower grade gliomas (LGGs), but it is often difficult to achieve both high EOR and preservation of brain function. Our institute has been working on intraoperative rapid molecular diagnosis of LGGs using HRM method for IDH mutation and immunostaining of p53/ATRX for 1p/19q codeletion for an intraoperative decesion making. We report the clinical results of patients with LGGs treated in our facility and discuss the significance of the surgical strategy based on intraoperative rapid molecular diagnosis. In 366 cases (G2: 219 cases, G3: 147 cases) with newly diagnosed LGGs that could be classified according to 2016 WHO classification in our hospital (2004–2014), the relation between the EOR and prognosis was retrospectively analyzed. Accuracy of intraoperative rapid molecular diagnosis of IDH mutation and 1p/19q codeletion using HRM method and p53 /ATRX immunostaining was evaluated. Result: The 10-year survival rate of oligodendroglioma was 88% in G2 (121 cases), 80% in G3 (59 cases), the 10-year survival rate of DA-IDH mutant was 63% in G2 (66 cases), MST of G3 (46 cases) was 13.6 years, MST of DA - IDH wild-type was G2 (32 cases) 12.6 years, G3 (42 cases) 3.9 years. The EOR strongly correlated with prognosis in DA-IDH wild-type. The results of intraoperative IHC of p53/ATRX were 82.6% consistent with FISH based results of 1p/19q codeletion. The HRM results (55 cases) were 100% consistent with sequence based IDH mutation results. The prognosis and the significance of EOR was significantly different between subtypes in LGGs. Rapid intraoperative molecular diagnosis seems to be useful for determining the removal strategy in LGG surgery.