bluuebunny/crossref_metadata_2025_split huggingface dataset:
DDRE-33. MELATONIN AS A MASTER METABOLIC SWITCH FOR GLIOBLASTOMA
Authors: Fernandez-Gil Beatriz Irene , Vazquez-Ramos Carla , Bechtle Alexandra , Suarez-Meade Paola , Qosja Neda , Schiapparelli Paula , Sarabia-Estrada Rachel , Escames Germaine , Quinones-Hinojosa Alfredo 
Published: March 2021

Abstract
Glioblastoma (GBM) is the most common form of malignant primary brain cancer in adults with a median survival of only 15 months. Therefore, new therapies to suppress malignant brain cancer are needed. Brain Tumor Initiating Cells (BTICs) are a GBM subpopulation of cells with a highly glycolytic profile that are thought to be responsible of the resistance of GBM to treatments. Metabolic reprogramming allows tumor cells to survive in unsupportive microenvironments. Manipulating tumor metabolism to counteract GBM resistance arises as a powerful approach with minimum effects in normal counterparts. At pharmacological concentrations, melatonin displays oncostatic properties. This is thought to be due to an increase in mitochondrial oxidative phosphorylation through the effects of melatonin in mitochondria, key organelle in metabolic homeostasis. We hypothesize that melatonin could alter BTIC metabolism, by inducing an anti-Warburg effect and as consequence, melatonin will decrease the viability of GBM cells and tumor growth. We found that treatment of GBM cell lines with 3mM melatonin significantly altered tumor cell metabolism. We observed that melatonin downregulated the lactate symporter MCT4 (p&lt;0.002), inducing a significant intracellular accumulation of lactate (p&lt;0.002) while decreasing it in the extracellular media (p&lt;0.001). This was followed by a decrease in the internal pH (p&lt;0.002). These effects were compensated by an increase in the oxygen consumption rate (OCR) followed by decay that leaded to an increase in ROS production (p&lt;0.001). All these changes result in a depletion of cellular ATP (p&lt;0.001) and eventually drove to a decrease in the proliferation (p&lt;0.001) and cell death (p&lt;0.001). When applied in vivo we observed a significant reduction in the tumor growth (p&lt;0.001), volume (p&lt;0.002) and weight (p&lt;0.002), as well as a drop in the proliferation marker ki67 (p&lt;0.001) and a fibrosis increase in treated tumors. These results position melatonin as a strong therapeutic candidate for GBM therapy.
ETMM-06. ELEVATED MITOCHONDRIAL TOM20 EXPRESSION SUPPRESSES GLIOMA MALIGNANCY BY ENHANCING OXIDATIVE PHOSPHORYLATION
Authors: Li Mao , Zhang Shuxin , Yang Wanchun , Yang Yuan , Pang Dejiang , Mao Qing , Chen Mina , Liu Yanhui 
Published: March 2021

Abstract

BACKGROUND
Malignant glioma display a metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation (OXPHOs). However, the underlying mechanism for this metabolic switch in glioma is not well elucidated. Mitochondrial translocases of the outer/inner membrane (TOMs/TIMs) import proteins into mitochondria, and could thereby regulate OXPHOs. The objective of this study is to investigate the expression of TOM/TIM members in glioma, as well as their functional and therapeutic implications.

METHODS
Transcriptome sequencing (RNA-seq), real-time PCR, Western blot, and immunohistochemistry were used to identify Tom20 as a significantly downregulated TOM/TIM protein in 20 paired glioma/Peritumoral tissues. To study the biological function of Tom20 in glioma, we interrogated metabolic alterations in Tom20 overexpressed glioma cells by GC-MS metabolomics, acetyl-CoA assay, and Seahorse assay. We compared the cell proliferation and viability profiles between Tom20 overexpressed and control cells in vitro and in vivo. To investigate the therapeutic implication of Tom20 expression, we tested OXPHOs inhibitor metformin in Tom20 overexpressed cells and xenograft mouse models.

RESULTS
We find that Tom20, a critical component of the mitochondrial outer membrane translocases, is downregulated in malignant gliomas. Using an integrative approach spanning bioinformatic analysis, metabolomics, and functional approaches, we reveal that Tom20 elevation activates mitochondrial OXPHOs in glioma cells and reduces tumor malignancy. We also find that Tom20 upregulation sensitizes glioma cells to metformin in vitro, and improves the therapeutic efficacy of metformin in glioma in vivo.

CONCLUSION
Our work defines Tom20 as a glioma suppressor and an indicator of metformin treatment in glioma.
FSMP-11. TARGETING CHOLESTEROL HOMEOSTASIS DYSREGULATION FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Han Mingzhi 
Published: March 2021

Abstract
Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24-hydroxylase (CYP46A1), a brain-specific enzyme responsible for elimination of cholesterol through conversion of cholesterol to 24(S)-hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared to normal brain tissue. In gliomas, a reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis. Functionally, ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA-seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signaling. Efavirenz (EFV), an activator of CYP46A1 that is known to penetrate the blood-brain barrier (BBB), inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target.
FSMP-12. A ROLE FOR PROLINE BIOSYNTHESIS IN HYPOXIC GLIOBLASTOMA
Authors: Vettore Lisa , Westbrook Rebecca , Roberts Jennie , Escribano-Gonzalez Cristina , Cuozzo Federica , Hodson David , Watts Colin , Nixon Colin , Tennant Daniel 
Published: March 2021

Abstract
Hypoxia is a common feature of glioblastoma, and a known driver of therapy resistance in brain tumours. Understanding the metabolic adaptations to hypoxia is key to develop new effective treatments for patients. A recent screening study highlighted Pyrroline-5-carboxylate reductase-like (PYCRL) as one of the top three genes that allowed tumour survival in hypoxia. PYCRL is one of the three enzymes involved in proline biosynthesis along with the mitochondrial pyrroline-5-carboxylate reductase 1 and 2 (PYCR1/2). The latter use glutamine as the carbon source to fuel the pyrroline-5-carboxylate (P5C)-to-proline reaction, whereas the cytosolic PYCRL is known to use ornithine to produce proline. Our investigations have shown that PYCRL differs from PYCR1 and 2 in the impact on cellular redox, which is a critical factor in hypoxic survival. Our data suggest that PYCRL activity is required for normal regulation of glioblastoma cell growth and the ability to deal with cellular stress, and that this enzyme may therefore represent a novel target in the treatment of these devastating tumours. Importantly, our study also begins to provide much-needed clarity over the network surrounding proline metabolism and redox maintenance.
FSMP-13. HYPOXIC REGULATION OF LACTATE DEHYDROGENASE GENES (LDHA/B) IN T98 GLIOBLASTOMA MULTIFORME CELLS
Authors: White Brian E , Buono Russell J 
Published: March 2021

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain cancer and carries a poor prognosis. GBM cells exhibit extensive metabolic alterations that enhance survival and proliferation in the mixed normoxic-hypoxic tumor microenvironment. Lactate dehydrogenase (LDH) enzymes are critical mediators of the normoxic to hypoxic transition in cells. Two LDH genes (A/B) encode monomers that combine to form five isoenzymes (LDH1-5) with different properties for pyruvate to lactate interconversion. Hypoxic induction of LDHA in all cells appears to occur via HIF-1 mediated transcription. However, little is known about hypoxic regulation of LDHB in cancer. We report on hypoxic regulation of LDHA/B in T98G, a rare cell line that has both normal and neoplastic features. Human T98 GBM cell lines were cultured in a humidified incubator at 37° C and 5% CO2 and were grown in normoxia (21% O2) or hypoxia (95% N2, 5% C02) for 72 hours. Relative expression of LDH isoforms 1-5 was assessed using native gel electrophoresis. Expression of the LDHA and LDHB genes was measured using qRT-PCR. LDHA-dominant isoforms (4/5) were detected in T98G cells subjected to normoxia and hypoxia via gel electrophoresis, however, LDHB-dominant isoforms (1/2) were not. The LDHA/B-equimolar isoform (3) was decreased in T98G cells subjected to hypoxia. LDHA gene expression was over two-fold greater than LDHB in normoxia (p = .00256 by one-tailed Mann-Whitney U test), and over nine-fold greater in hypoxia (p = .00256). LDHA:LDHB expression in hypoxia compared to normoxia was significantly different (p = .00256). LDHA expression increased three-fold in hypoxia (p = .00256), while LDHB expression decreased 0.3-fold in hypoxia (p = .03288). We document LDHB dysregulation in T98G cells as the gene is minimally responsive to oxygen. Therapeutic strategies aimed at promoting LDHB expression may complement inhibition of LDHA and reduce GBM survival in hypoxia.
FSMP-15. EVALUATING THE ROLE OF LONG-CHAIN FATTY ACID METABOLISM IN PROMOTING GLIOBLASTOMA GROWTH
Authors: Ravi Divya , del Genio Carmen , Ghiasuddin Haider , Gaur Arti 
Published: March 2021

Abstract
Glioblastomas (GBM) or Stage IV gliomas, are the most aggressive of primary brain tumors and are associated with high mortality and morbidity. Patients diagnosed with this lethal cancer have a dismal survival rate of 14 months and a 5-year survival rate of 5.6% despite a multimodal therapeutic approach, including surgery, radiation therapy, and chemotherapy. Aberrant lipid metabolism, particularly abnormally active de novo fatty acid synthesis, is recognized to have a key role in tumor progression and chemoresistance in cancers. Previous studies have reported a high expression of fatty acid synthase (FASN) in patient tumors, leading to multiple investigations of FASN inhibition as a treatment strategy. However, none of these have developed as efficacious therapies. Furthermore, when we profiled FASN expression using The Cancer Genome Atlas (TCGA) we determined that high FASN expression in GBM patients did not confer a worse prognosis (HR: 1.06; p-value: 0.51) and was not overexpressed in GBM tumors compared to normal brain. Therefore, we need to reexamine the role of exogenous fatty acid uptake over de novofatty acid synthesis as a potential mechanism for tumor progression. Our study aims to measure and compare fatty acid oxidation (FAO) of endogenous and exogenous fatty acids between GBM patients and healthy controls. Using TCGA, we have identified the overexpression of multiple enzymes involved in mediating the transfer and activation of long-chain fatty acids (LCFA) in GBM tumors compared to normal brain tissue. We are currently conducting metabolic flux studies to (1) assess the biokinetics of LCFA degradation and (2) establish exogenous versus endogenous LCFA preferences between patient-derived primary GBM cells and healthy glial and immune cells during steady state and glucose-deprivation.
Seasons of Coronavirus Disease 2019
Authors: Macnofsky Robin , Chow Eric J 
Published: March 2021

Abstract
The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality. Although much of the focus has been on the management and treatment of acute COVID-19, some patients have experienced prolonged symptoms after their acute infection had resolved. In this perspective, a patient shares her experience of postacute COVID-19, highlighting a journey of a revolving door of symptoms. Her infectious disease physician summarizes the next steps required to better care for this growing group of patients.
Institutional Architecture
Authors: Schillig Michael 
Published: March 2021

Abstract
Recovery and resolution planning and early intervention constitute an integral part of an enhanced and strengthened framework for regulation and supervision with a focus on resolution planning and resolvability assessment. As an institution’s financial position deteriorates, the supervisory process may naturally lead on to crisis management and resolution. As a result of the global financial crisis and the eurozone crisis, the jurisdictions under consideration here have restructured their institutional frameworks for regulation, supervision, and resolution. This chapter seeks to provide an overview of these institutional changes and developments. From an institutional perspective, it contextualizes the discussion in the following chapters.
Identity Disclosure
Authors: Riordan Jaani 
Published: March 2021

Abstract
Internet intermediaries frequently acquire information about tortious activity which is relevant to a claim against a third party. Such information can be relevant in two ways: first, it may reveal the identity of an anonymous user who is alleged to have committed a wrong; and second, it may supply evidence of the acts carried out by that user and the rights which the claimant says have been infringed. Obtaining access to this information is often essential for a claim to proceed, since without it the true tortfeasor may remain unknown. However, disclosure is unlike many other remedies because it is available without proof of wrongdoing by the disclosing party.
Defamation
Authors: Riordan Jaani 
Published: March 2021

Abstract
Fuelled by the scale, ubiquity, and persistence of internet content, and by the public’s appetite for scandal and intrigue, online defamatory statements possess unparalleled potential to harm a person’s reputation indelibly. Necessarily, when such statements are promulgated, it is an internet intermediary which processes, stores, and transmits them. This chapter considers when such a party is liable to pay damages to the claimant.
Data Protection
Authors: Riordan Jaani 
Published: March 2021

Abstract
This chapter examines the liability of internet intermediaries for contraventions of the data protection regime. Data protection duties, like those upholding rights of privacy and confidentiality, can impose significant burdens upon internet intermediaries. This is because much of the information in which these services deal will contain ‘personal data’, and in some cases sensitive personal data, while almost all of the activities undertaken by them will involve some form of ‘processing’ of those data.
Parallel Imports
Authors: Mühlendahl Alexander , Botis Dimitris , Maniatis Spyros , Wiseman Imogen 
Published: March 2021

Abstract
Free movement of goods, one of the ‘four freedoms’ together with free movement of persons, services, and capital covered in the Treaties, is a fundamental principle with two purposes. The first is purely economic; a customs union and common market comprising individual Member States cannot be established unless goods from all the Member States are sold freely and compete effectively in all the Member States. The second is political, if there is to be a single common market then goods must flow freely within its borders. The effect of national measures that block the importation of goods from one Member State to another, make their marketing more difficult, or raise their price, is the distortion of the free flow of goods and competition. Inevitably, in a single market such measures have to be eliminated.
The Nature of the Re Hastings-Bass Duty
Authors: Ashdown Michael 
Published: March 2021

Abstract
Lord Walker’s analysis in Pitt v Holt in the Supreme Court accords in all essential respects with the reasons put forward in Chapter 3 to prefer a duty (‘weak’) rather than results-oriented (‘strong’) account of the Re Hastings-Bass rule, as does the approach adopted by Lloyd LJ in the Court of Appeal, which Lord Walker expressly endorses. Yet Lord Walker’s judgment does not yet provide a wholly comprehensive basis for the future development of the law. There remain a number of loose ends, arising predominantly from issues not specifically before the court in Pitt, but which have been matters of concern in earlier Re Hastings-Bass cases, including: how a ‘relevant consideration’ is defined; the significance of establishing that the trustees ‘would’ or ‘might’ have acted differently, in view of Lord Walker’s refusal to choose between these two alternatives; the specific problems arising from the use of professional advisers, and in cases concerning tax liability and pension trusts. These matters are addressed in detail in chapters 5 to 8. But in order to do this it is first necessary to clarify the juridical nature of the ‘duty of consideration’ upon which Lord Walker’s analysis depends.
Introduction
Authors: Bork Reinhard , Mangano Renato 
Published: March 2021

AbstractThis chapter is an introduction to the issues involved in cross-border insolvency cases and their regulation as covered by the EIR, which recast the OR. It also provides a view-from-the-cathedral of EU Regulation 2015/848; a concise description of its history, aims, and principles; as well as a list of the other relevant sources of law, including those of soft law such as the UNCITRAL Model Law and the European Communication and Cooperation Guidelines for Cross-border Insolvency (the so-called ‘CoCo Guidelines’). Finally, the role of the Court of Justice of the European Union (CJEU) for the interpretation of European insolvency law and its judicial activism are analysed.
Secondary Insolvency Proceedings
Authors: Bork Reinhard , Mangano Renato 
Published: March 2021

Abstract
The European Insolvency Regulation permits the opening of territorial proceedings conducted parallel to main proceedings, thereby modifying the concept of universality through the existence of so-called secondary proceedings. Secondary proceedings serve different purposes and are characterized by the fact that they are limited in their scope, as they only affect assets within the Member State in which the secondary proceedings have been opened. While the requirements for the opening of secondary proceedings as well as their effects are largely governed by the lex fori concursus secundarii, the EIR not only modifies some of these requirements but also contains an entire set of rules concerning the coordination of secondary and main proceedings to ensure efficient administration of the debtor’s assets. This chapter will therefore examine the principles of secondary proceedings, the requirements for and the effects of the opening of such proceedings, and the relationship between main and secondary proceedings.
Austria
Authors: Gassner Gottfried , Schirmer Thomas 
Published: March 2021

Abstract
The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and authors bear no responsibility for any errors or omissions contained therein.
The Republic of Korea
Authors: Han Min , Choi Woo Young 
Published: March 2021

Abstract
The material contained herein is intended as a general guide only. The information and opinions which it contains are not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and authors bear no responsibility for any errors or omissions contained therein.
Singapore
Authors: Jeremiah Herman , Xue Joan 
Published: March 2021

Abstract
The material contained herein is intended as a general guide only and is not intended to be a memorandum of law study, nor to provide legal advice, and should not be treated as a substitute for legal advice concerning particular situations. Legal advice should always be sought before taking any action based on the information provided. The publishers, editors, and authors bear no responsibility for any errors or omissions contained therein.
The Settlor: Reserved Powers and Private Trust Companies
Authors: Panico Paolo 
Published: March 2021

Abstract
The development of trust law in Victorian England, which led to many of the rules of equity still in force today, followed a social and economic evolution where the typical settlors were no longer members of the landed gentry but professionals and businessmen living in the cities and settling movable wealth, mainly financial assets, rather than landed estates. A similar development is taking place in the first decades of the twenty-first century, where the typical settlors are successful business people from various areas of the world, whose background is not the Anglo-American legal system and who have often accumulated an impressive wealth by running their own business. Their families may have interests in various parts of the world and succession planning is required in order to hand over the business to the next generation.
Trustee Liability to Third Parties
Authors: Panico Paolo 
Published: March 2021

Abstract
Trusts are not corporate entities: they have no legal personality and so are capable neither of owning property in their own right nor of suing or being sued. Title to the trust property vests in the trustees, who in turn have standing to sue or to be sued in their capacity as such. Of course, this is a basic notion in trust law, yet it entails some intractable consequences for trustees contracting with third parties.
Asset Protection Trusts
Authors: Panico Paolo 
Published: March 2021

Abstract
The phrase ‘asset protection trust’ is generally used to describe a set of statutory provisions intended to enhance a settlor’s ability to ringfence assets and place them beyond the reach of his or her creditors. Instances of asset protection trust legislation have been enacted in a number of offshore centres since the mid-1980s and in some US states since the late 1990s.
Appointment Of Directors
Authors: Griffiths Martin 
Published: March 2021

Abstract
This chapter deals with directors who are formally appointed to the role (including cases where the formal process is defective). It does not consider de facto or shadow directors. It describes the rules relating to the required numbers of directors, their eligibility for appointment, the appointment process, and the publicity rules relating to the appointment. Appointed directors may be either executive or non-executive directors. The relevant statutory provisions are now found in Part 10 of the Companies Act. The sections about the appointment of directors are ss 154–61. The sections about publicity, concerning the register of directors and directors’ residential addresses, are ss 162–7 and 240–6. Reference should also be made to the company’s own constitution.
Taxation of Directors’ Earnings and Benefits
Authors: Chacko Thomas 
Published: March 2021

Abstract
This chapter outlines the tax issues that arise in the context of directorships. The great majority of these concern the director’s income tax liability, which is in most circumstances the same as that of any other employee. However, there are a number of more elaborate ways of remunerating employees which are likely to be encountered in the context of directors, both because they are often among the higher-paid employees of a business and because their employers often wish to link their remuneration to performance. This chapter therefore covers ‘golden hellos’ and termination payments, other ways of benefiting an employee (including the reimbursement of expenses and making them loans), and pension contributions, before outlining the tax implications of various share schemes that might be used. More complex remuneration planning is mentioned in Section D, but the wider area of remuneration structures is outside the scope of this work.