bluuebunny/crossref_metadata_2025_split huggingface dataset:
BIMG-06. RESPONSE ASSESSMENT OF BEVACIZUMAB THERAPY FOR GLIOBLASTOMA BY USING MULTIPLE PET TRACERS
Authors: Miyake Keisuke , Ogawa Daisuke , Hatakeyama Tetsuhiro , Tamiya Takashi 
Published: March 2021

Abstract

OBJECTIVE
Use of the positron emission tomography (PET), such as 18F-fluorodeoxyglucose (FDG), 11C-Methionine (MET), 18F- Fluorothymidine (FLT), and 18F-Fluoromisonidazole (FMISO), is expected to lead the way for novel applications aimed at achieving efficient malignancy grading and treatment of gliomas. The aim of this study was to assess FDG, MET, FLT, and FMISO PET studies to evaluate the biological effects induced by bevacizumab (BEV) therapy in glioblastoma patients.

METHODS
Seventy-one patients with glioblastoma were treated biweekly with BEV from July 2013 to November 2020. FDG, MET, FLT, and FMISO PET scans were obtained at baseline and at follow-up (4 weeks after treatment onset). Measures of FDG, MET, FLT, and FMISO avidity were recorded; the measures were SUVmax, metabolic tumor volume (MTV; volume of tumor with SUV&gt;42% of SUVmax), SUVmean (within the MTV), tumor-to-normal ratio (TNR), tumor-to blood ratio (TBR), and total lesion avidity (TLA; calculated as MTV x SUVmean). The prognostic analysis was performed in relation to the response assessment by multiple PET tracers using progression-free survival (PFS) and overall survival (OS).

RESULTS
Under the assessment of the Cox proportional hazard model, increased changes of FDG SUVmax, MET TLA at follow-up, FLT TLA at follow up, increased changes of FLT TLA, increased changes of FMISO TBR and FMISO MTV were significant prognostic factor of PFS. Increase changes of FDG TLA and FLT TLA and increased changes of FMISO TBR were significant prognostic factor of OS.

CONCLUSION
Increased changes in FLT TLA and FMISO-PET after BEV therapy may be a useful biomarker for predicting PFS and OS in glioblastoma.
DDRE-03. IDH1-MUTANT GBM CELLS ARE HIGHLY SENSITIVE TO COMBINATION OF KDM6A/B AND HDAC INHIBITORS
Authors: Kayabölen Alişan , Sahin Gizem Nur , Seker Fidan , Cingöz Ahmet , Isik Bekir , Acar Simge , Wakimoto Hiroaki , Cahill Daniel P , Solaroglu Ihsan , Cribbs Adam , Oppermann Udo , Bagci-Onder Tugba 
Published: March 2021

Abstract
Mutations in IDH1 and IDH2 genes are common in low grade gliomas and secondary GBM and are known to cause a distinct epigenetic landscape in these tumors. To interrogate the epigenetic vulnerabilities of IDH-mutant gliomas, we performed a chemical screen with inhibitors of chromatin modifiers and identified 5-azacytidine, Chaetocin, GSK-J4 and Belinostat as potent agents against primary IDH1-mutant cell lines. Testing the combinatorial efficacy of these agents, we demonstrated GSK-J4 and Belinostat combination as a very effective treatment for the IDH1-mutant glioma cells. Engineering established cell lines to ectopically express IDH1R132H, we showed that IDH1R132H cells adopted a different transcriptome with changes in stress-related pathways that were reversible with the mutant IDH1 inhibitor, GSK864. The combination of GSK-J4 and Belinostat was highly effective on IDH1R132H cells, but not on wt glioma cells or nonmalignant fibroblasts and astrocytes. The cell death induced by GSK-J4 and Belinostat combination involved the induction of cell cycle arrest and apoptosis. RNA sequencing analyses revealed activation of inflammatory and unfolded protein response pathways in IDH1-mutant cells upon treatment with GSK-J4 and Belinostat conferring increased stress to glioma cells. Specifically, GSK-J4 induced ATF4-mediated integrated stress response and Belinostat induced cell cycle arrest in primary IDH1-mutant glioma cells; which were accompanied by DDIT3/CHOP-dependent upregulation of apoptosis. Moreover, to dissect out the responsible target histone demethylase, we undertook genetic approach and demonstrated that CRISPR/Cas9 mediated ablation of both KDM6A and KDM6B genes phenocopied the effects of GSK-J4 in IDH1-mutant cells. Finally, GSK-J4 and Belinostat combination significantly decreased tumor growth and increased survival in an orthotopic model in mice. Together, these results suggest a potential combination epigenetic therapy against IDH1-mutant gliomas.
DDRE-24. TARGETING PURINE METABOLISM TO OVERCOME GLIOBLASTOMA THERAPY RESISTANCE
Authors: Zhou Weihua , Yao Yangyang , Scott Andrew , Wilder-Romans Kari , Dresser Joseph , Werner Christian , Sun Hanshi , Pratt Drew , Sajjakulnukit Peter , Zaho Shuang , Davis Mary , Nelson Barbara , Halbrook Christopher , Zhang Li , Gatto Francesco , Srinivasan Sudharsan , Jairath Neil , Correa Luis , Umemura Yoshie , Walker Angela , Kachman Maureen , Qi Nathan , Sarkaria Jann , Xiong Jianping , Morgan Meredith , Rehemtulla Alnawaz , Castro Maria , Lowenstein Pedro , Chandrasekaran Sriram , Lawrence Theodore , Lyssiotis Costas , Wahl Daniel 
Published: March 2021

Abstract
Intratumoral genomic heterogeneity in glioblastoma (GBM) is a barrier to overcoming radiation (RT) resistance. To discover genotype-independent mediators of RT resistance, we correlated RT resistance with the concentration of approximately 700 metabolites across 23 GBM cell lines. Purine metabolites, especially those containing the base guanine, were most correlated with RT resistance. Similarly, increased abundance of tumor purines was associated with decreased survival in GBM patients treated with RT. This relationship is causal. Purine supplementation protected RT-sensitive GBMs from RT and promoted the repair of RT-induced double strand DNA breaks (DSBs). In vitro and in vivo stable isotope tracing confirmed that GBM cell lines and orthotopic patient-derived xenografts primarily generated purines through the de novo synthetic pathway. RT treatment further increased de novo purine synthesis in GBM through signaling via the DNA damage response. Inhibition of de novo GTP synthesis with mycophenolic acid (MPA) sensitized multiple GBM cell lines and neurospheres to RT by slowing the repair of RT-induced DSBs. MPA-induced radiosensitization was GTP-dependent as it was rescued by nucleoside supplementation. Modulating pyrimidine metabolism affected neither RT resistance nor DSB repair, suggesting these GTP-specific effects are due to active signaling rather than its ability to act as a physical substrate for DNA repair and candidate signaling molecules have been identified. These results were recapitulated in vivo with mycophenolate mofetil (MMF), the orally bioavailable FDA-approved prodrug of MPA. MMF potentiated RT efficacy, reduced tumor guanylates and slowed the repair of RT-induced DSBs across multiple models. Because de novo purine synthesis is activated by many of the oncogenic alterations that drive GBM, its inhibition is a promising genotype-independent strategy to overcome GBM RT resistance. We have now begun a clinical trial to determine whether combining MMF and RT is safe and potentially efficacious in patients with GBM.
ETMM-08 METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA
Authors: Kumar Sachin , Michealraj Antony , Kim Leo , Rich Jeremy , Taylor Michael 
Published: March 2021

Abstract
Ependymomas are malignant glial tumours that occur throughout the central nervous system. Of the nine distinct molecular subgroups of ependymoma, Posterior Fossa A (PFA), is the most prevalent, occurring in the hindbrain of infants and young children. Lacking highly recurrent somatic mutations, PFAs are thought to be a largely epigenetically driven entity, defined by hypomethylation at the histone 3 lysine 27 residue. Previous transcriptional analysis of PFAs revealed an enrichment of hypoxia signaling genes. Thus, we hypothesized that hypoxic signaling, in combination with a unique metabolic milieu, drive PFA oncogenesis through epigenetic regulation. In this study, we identified that PFA cells control the availability of specific metabolites under hypoxic conditions, resulting in diminished H3K27 trimethylation and increased H3K27 acetylation in vitro and in vivo. Unique to PFA cells, transient exposure to ambient oxygen results in irreversible cellular toxicity. Furthermore, perturbation of key metabolic pathways is sufficient to inhibit growth of PFA primary cultures in vitro. PFA cells sequester s-adenosylmethionine while upregulating EZHIP, a polycomb repressive complex 2 (PRC2) inhibitor, resulting in decreased H3K27 trimethylation. Furthermore, hypoxia fine-tunes the abundance of alpha-ketoglutarate and acetyl-CoA to fuel demethylase and acetyltransferase activity. Paradoxically, a genome-wide CRISPR knockout screen identified the core components of PRC2 as uniquely essential in PFAs. Our findings suggest that PFAs thrive in a narrow “Goldilocks” zone, whereby they must maintain a unique epigenome and deviation to increased or decreased H3K27 trimethylation results in diminished cellular fitness. Previously, we showed that PFAs have a putative cell of origin arising in the first trimester of development. Using single-cell RNAseq and metabolomics, we demonstrate that PFAs resemble the natural metabolic-hypoxic milieu of normal development. Therefore, targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
FSMP-14. METABOLIC SYMBIOSIS IN GLIOBLASTOMA: LACTATE DEHYDROGENASES TAKE THE LEAD
Authors: Guyon Joris , Romero-Garmendia Irati , Bikfalvi Andreas , Daubon Thomas 
Published: March 2021

Abstract
Glioblastoma (GBM) is a common and devastating brain tumor, associated with a low median survival, despite standard therapeutic management. Among its major features, GBMs are highly angiogenic, infiltrative, and exhibit paradoxically an elevated glycolysis. Most of differentiated cells convert glucose into pyruvate that enters into the Krebs cycle to maximize energy production in the presence of oxygen. For cancer cells, glucose uptake and catabolism are increased regardless of oxygen level. However, tumor cell energy needs are important, mainly for rapid growth, which require a much faster production flow. Lactate dehydrogenase (LDH) are involved at this step. LDHA converts pyruvate into lactate, and generates NAD+ to maintain glycolysis. Thus, lactate is exported into the extracellular compartment inducing an acidification of the microenvironment. Moreover, LDHB, another LDH isoform, metabolizes lactate into pyruvate for generating energy in mitochondria. LDHB is generally expressed in oligodendrocytes or neurons, but also in GBM cells. Though LDHA has already been studied in many cancers including GBM, the simultaneous role of LDH enzymes have not yet been investigated in GBM development. Our results showed that hypoxia significantly increased LDHA expression and lactate production, but no changes were observed for LDHB. In presence of lactate, cell invasion was significantly increased. In vitro results showed that, under hypoxic condition, double sgLDHA/B cell growth and invasion was dramatically decreased in comparison to control cells, mainly caused by an increase in apoptosis. In vivo experiments showed that double impairment of LDHA and B significantly reduced tumor growth and cell invasion, and induces a massive increase in mouse survival. Considered for a long time as a metabolic waste, lactate is shown here to play a critical role in the tumor niche. This study highlighted GBM adaptability through the LDH isoforms and their involvement in GBM development.
FSMP-18. COMPREHENSIVE METABOLIC PROFILING OF HIGH MYC MEDULLOBLASTOMA REVEALS KEY DIFFERENCES BETWEEN IN VITRO AND IN VIVO GLUCOSE AND GLUTAMINE USAGE
Authors: Pham Khoa , Poore Brad , Hanaford Allison , Maxwell Micah J , Sweeney Heather , Parthasarathy Akhila , Alt Jesse , Rais Rana , Slusher Barbara S , Eberhart Charles G , Raabe Eric H 
Published: March 2021

Abstract
Reprograming of cellular metabolism is a hallmark of cancer. Altered metabolism can overcome unfavorable conditions, allowing cancer cells to proliferate and invade in different tumor microenvironments. Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of human MYC-amplified medulloblastoma by comparing the metabolic profiles of tumor cells in different environments – in vitro, in flank xenografts and in orthotopic xenografts. Principal component analysis showed that the metabolic profiles of brain and flank high-MYC medulloblastoma tumors clustered closely together and separated away from normal brain and the high-MYC medulloblastoma cells in culture. Compared to normal brain, MYC-amplified medulloblastoma orthotopic brain tumor xenografts showed upregulation of nucleotide, amino acid and glutathione pathways. Glucose was the main carbon source for the nucleotide synthesis and the TCA cycle in vivo. The glutaminase ii pathway was the main pathway utilizing glutamine in MYC-amplified medulloblastoma. In brain and flank xenografts, glutathione was the most abundant upregulated metabolite. Glutamine derived glutathione was synthesized through glutamine transaminase K (GTK) enzyme in vivo. The glutamine analog 6-diazo-5-oxo-l-norleucine (DON) significantly inhibited glutathione, amino acid, and nucleotide synthesis. In conclusion, we found that MYC-amplified medulloblastoma relied on glutamine metabolism in synthesizing glutathione in vivo. Glutamine antagonists may have therapeutic applications in human patients.
FSMP-19. SEX DIFFERENCES IN REDOX REGULATION UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA
Authors: Sponagel Jasmin , Zhang Shanshan , Frankfater Cheryl , Jones Jill , Selmanovic Din , Chinnaiyan Prakash , Rubin Joshua B , Ippolito Joseph E 
Published: March 2021

Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. GBM occurs more commonly in males but female patients survive significantly longer. Understanding the molecular mechanisms underlying this clinical sex disparity could support novel treatment strategies to improve outcomes for GBM patients. In this regard, we found that male and female GBM patient tissues differ in their metabolite profiles and that male GBM exhibit a higher abundance of amino acid metabolites. We confirmed these findings in a murine model of GBM. Furthermore, we found that male GBM cells are more sensitive to amino acid deprivation. This male-specific dependency on amino acids is almost entirely driven by amino acids involved in reactive oxygen species (ROS) regulation and glutathione synthesis. We found that male GBM cells are more sensitive to depletion of glutathione, which resulted in a significant increase in ROS and cell death in male GBM cells. Moreover, assays of glutathione oxidation demonstrated that male GBM cells exist in a chronically oxidized state. GLS1 mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells are more sensitive to GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased ROS and glutathione levels as well as significantly decreased TCA cycle metabolites in male GBM. Lastly, we found that the TCA cycle metabolite α-ketoglutarate rescues the effects of CB-839 in male GBM cells. Together, these data suggest that (1) male and female GBM differ in their amino acid requirements, (2) male GBM are more dependent on glutathione to regulate ROS levels, and (3) male GBM increase glutathione synthesis at the expense of TCA cycle metabolites upon GLS1 inhibition, suggesting an increased susceptibility to drugs targeting the glutamate/glutathione axis in male GBM. Our data underline the importance of considering sex in metabolic targeting approaches.
Molecular design and application of luminescent materials composed of group 13 elements with an aggregation-induced emission property
Authors: Ito Shunichiro , Gon Masayuki , Tanaka Kazuo , Chujo Yoshiki 
Published: March 2021

Abstract
Complexation of π-conjugated ligands by metal or semimetal ions leads to the enhancement of the planarity and rigidity of π-conjugated systems. Boron, especially, has played a central role in the design of luminescent main-group complexes. However, these complexes still suffer the disadvantage of aggregation-caused quenching as well as typical organic fluorophores. It has recently been reported that some types of boron complexes exhibit the aggregation-induced emission (AIE) property. Moreover, AIE behavior from complexes and organometallic compounds composed of the other group 13 elements, such as aluminum and gallium, has emerged in this decade. These observations greatly encourage us to develop advanced functional materials based on the group 13 elements. Indeed, recent research has demonstrated that these classes of materials are potentially versatile scaffolds for constructing chromic luminophores, efficiently emissive π-conjugated polymers and so on. This review mainly describes AIE-active group 13 complexes with four-coordinate structures and their application as photo-functional materials. Proposed mechanisms of the origins of AIE behavior are briefly discussed.
Dual Microcatheter Technique for Coiling of Intracranial Aneurysms: 2-Dimensional Operative Video
Authors: Waqas Muhammad , Dossani Rimal H , Cappuzzo Justin M , Sonig Ashish , Becker Alexander B , Levy Elad I 
Published: March 2021

Abstract
Primary coiling of large intracranial aneurysms with complex morphology, such as multiple lobes and a wide neck, is challenging. In these aneurysms, achieving adequate intra-aneurysmal packing density while preventing coil herniation into the parent vessel may be difficult with traditional coiling technique. In the setting of acute aneurysm rupture, alternative treatment options such as stent-assisted coiling or flow diversion may not be feasible due to the need for dual antiplatelets. In this video, we demonstrate the use of a dual microcatheter technique to achieve adequate packing density within a wide-necked, bilobed saccular aneurysm. The patient presented with a ruptured posterior communicating artery aneurysm with Hunt and Hess grade 2 and Fisher grade 4 subarachnoid hemorrhage. A biaxial catheter system was used for primary coiling of the aneurysm. Two .017-inch microcatheters were strategically positioned in the aneurysm lobes. The first coil was deployed through the distal catheter, which created a basket for the second coil to be deployed through the proximal microcatheter. Subsequent simultaneously deployed coils were weaved into each other to form a stable coil mass that prevented coil herniation into the parent vessel. Complete obliteration of the aneurysm was achieved.
The patient gave informed consent for the procedures and video recording. Institutional review board approval was deemed unnecessary.

Video. ©University at Buffalo Neurosurgery, Inc., January 2020. With permission.
Financial Stability, Systemic Risk, and Taxpayers’ Money—The Rationale for a Special Resolution Regime
Authors: Schillig Michael 
Published: March 2021

Abstract
Special resolution regimes are generally introduced with the objective of helping to ‘maintain financial stability, minimize systemic risk, protect consumers, limit moral hazard and promote market efficiency’. The recurring themes are financial stability, systemic risk, and taxpayers’ exposure to losses. This chapter explores whether and to what extent a special resolution regime for banks and financial institutions can contribute to the enhancement of financial (system) stability and can limit systemic risk. It seeks to clarify these concepts and discusses possible ex ante incentives that a (recovery and) resolution regime may provide for controlling systemic risk. Further, it focuses on ex post remedies for the curtailment of systemic risk, and considers the international and cross-border implications.
The International Dimension: Cross-border Groups
Authors: Schillig Michael 
Published: March 2021

Abstract
The difficulties associated with the supervision and failure resolution of cross-border financial groups were among the key issues that came into renewed focus as a result of the global financial crisis. The cross-border dimension affects the recovery and resolution process in its entirety from the initial planning phase right through to liquidation. The chapter summarizes the elements of cross-border group law mentioned in previous chapters. It looks briefly at the US framework and the changes introduced through the Dodd–Frank Act. It discusses international jurisdiction of authorities and courts, the applicable law that governs proceedings, and the recognition and effects of foreign proceedings, in particular, in accordance with Directive 2001/24/EC on the reorganization and winding up of credit institutions and investment firms and the UNCITRAL Model Law on Cross-Border Insolvency. It also analyses the new European framework for co-operation in the cross-border group resolution context.
Case Study—Apple v Samsung
Authors: Stone David 
Published: March 2021

Abstract
In June 2011, Californian technology company Apple commenced proceedings against Korean electronics company Samsung. The global dispute concerned a range of mobile phone and tablet designs (in addition to a number of patents owned by each side). The various decisions in the European Union provide a useful insight into the treatment of design disputes by various Community design courts, and some of the procedural, jurisdictional, and other matters that may arise.
Introduction
Authors: Riordan Jaani 
Published: March 2021

Abstract
Internet intermediaries are essential features of modern commerce, social and political life, and the dissemination of ideas. Some act as conduits through which our transmissions pass; others are custodians of our personal data and gatekeepers of the world’s knowledge. They supply the infrastructure and tools which make electronic communications possible. These services encompass a vast ecosystem of different entities: internet service providers, website operators, hosts, data centres, social networks, media platforms, search engines, app developers, marketplaces, app stores, and others—many of which are household names.
Blocking Injunctions
Authors: Riordan Jaani 
Published: March 2021

Abstract
A blocking injunction is an order requiring an internet intermediary to implement technical measures directed at preventing or disabling access to a specified internet location. The essential purpose of such an order is to restrict the ability of individuals located in a particular jurisdiction to access or download material the subject of the order using the respondent’s service. Although theoretically available against any service provider, blocking injunctions are most commonly sought against ISPs, who possess a comparatively high degree of control at the network layer and may operate systems that can drop or re-route packets based on criteria including the destination of a request. Blocking injunctions require the respondent to adopt these technical measures in an attempt to prevent others from using its service to infringe the applicant’s rights. Section 2 provides an overview of the most common technical measures employed by ISPs.