bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETMM-07. HYPOXIC REGULATION OF METABOLIC AND STRUCTURAL GENES IN T98 GLIOBLASTOMA MULTIFORME CELLS BY RNA SEQUENCING
Authors: White Brian E , Liu Edward , Hakonarson Hakon , Buono Russell J 
Published: March 2021

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain cancer and carries a very poor prognosis. The GBM tumor microenvironment is characterized by regions of profound hypoxia, which are associated with a variety of alterations in gene expression that confer survival, proliferation, and resistance to therapy. Multiple mechanisms have been implicated in hypoxia-associated GBM behavior including upregulation of pathways involved in angiogenesis, immunosuppression, and glucose metabolism. Our study aimed to identify changes in gene expression induced by hypoxia among T98G cells via total RNA sequencing. 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. Total RNA was harvested, and global gene expression was evaluated via total RNA sequencing. Standard bioinformatics analysis was performed to identify changes in expression associated with hypoxia. Hypoxia in T98 cells led to significant upregulation of genes implicated in canonical glycolysis, focal adhesion, extracellular matrix reorganization, and endoplasmic reticulum-associated protein processing. We document 690 genes and 11 associated KEGG pathways that demonstrated significant enrichment (p ≤0.01 with Bonferroni, Benjamini, and False Discovery Rate corrections) induced by hypoxia. Notably, upregulation of the IRE1-mediated unfolded protein response was observed. DrugBank database analysis identified four molecules targeting genes upregulated in hypoxic T98G cells: tenecteplase (p = 0.013, 5 gene targets), succinic acid (p = 0.02, 7 targets), artenimol (p = 0.013, 13 targets), and copper (p = 0.0015, 22 targets). We document 733 genes and 6 associated KEGG pathways significantly downregulated (p ≤0.01) in hypoxia, including genes associated with DNA replication and repair, mitotic processes, and spliceosome function. Total RNA sequencing showed hypoxic upregulation of genes involved in various pathways associated with neoplastic GBM behavior and identified multiple candidate molecules which may hold therapeutic potential.
ETMM-09 TARGETING GLIOBLASTOMA MULTIFORME METABOLISM AT THE INVASIVE TUMOR FRONT
Authors: Garcia Joseph H , Jain Saket , Akins Erin A , Beniwal Angad S , Wolfe Kayla J , Cha Jungwha , Kumar Sanjay , Aghi Manish K 
Published: March 2021

Abstract
Glioblastoma (GBM) is a primary malignant brain tumor with a median survival under two years. The poor prognosis GBM caries is largely due to cellular invasion, which enables escape from resection and drives inevitable recurrence. Numerous factors have been proposed as the primary driving forces behind GBM’s ability to invade adjacent tissues rapidly, including alterations in its cellular metabolism. Though studies have investigated links between GBM’s metabolic profile and its invasive capabilities, these studies have had two notable limitations. First, while infiltrating GBM cells utilize adaptive cellular machinery to overcome stressors in their microenvironment, the cells at the invasive tumor front have rarely been sampled in previous studies, which have primarily used banked tissue taken from the readily accessible tumor core. Second, studies of invasion have primarily used two-dimensional (2D) culture systems, which fail to capture the dimensionality, mechanics, and heterogeneity of GBM invasion. To address these limitations, our team developed two complementary approaches: acquisition of site-directed biopsies from patient GBMs to define regional heterogeneity in invasiveness, and engineering of three dimensional (3D) platforms to study invasion in culture. Through utilization of these platforms, and by taking advantage of the system-wide, unbiased screens of metabolite profile and gene expression available, our team looked to accomplish the goal of identifying targetable metabolic factors which drive cellular invasion in GBM. Pilot RNA-Sequencing data revealed 87 of the top 250 (35%) genes preferentially expressed in the tumor invasive edge, and 30 of the top 250 (12%) genes preferentially expressed in the tumor core were involved in cellular metabolism. KEGG pathways analysis demonstrated enrichment of glycolytic, pentose phosphate, and response to amino acid starvation pathways at the tumor invasive edge. These preliminary studies demonstrate a distinct metabolic phenotype in invasive GBM cells which will be further explored with system wide screens.
FSMP-01. ID1 MEDIATES ONE-CARBON MEDIATED PURINE SYNTHESIS IN GLIOBLASTOMA
Authors: Ghannad-Zadeh Kimia , Wu Megan , Wilson Taylor , Flick Robert , Das Sunit 
Published: March 2021

Abstract
Inhibitor of DNA-binding-1 (ID1) is a transcriptional regulatory protein involved in maintenance of self-renewal and inhibition of differentiation, and acts as a key regulator of tumorigenesis in glioblastoma. Studies suggest that de novo purine synthesis is essential for the maintenance of rapid proliferation rates in glioma initiating cells. We hypothesise that ID1 plays a role in reprogramming one-carbon mediated de novo purine synthesis, thereby metabolically contributing to the tumorigenic advantage seen in ID1-high glioblastoma cells. The effect of ID1 regulation on metabolic reprogramming of glioblastoma was studied using ID1-knockout U251 glioblastoma cell lines. Protein expression analysis and liquid chromatography mass-spectrometry were respectively used to assess expression and concentration of metabolic enzymes and intermediates of one-carbon and de novo purine synthesis pathways. CD44 expression was analyzed as a marker of cancer stem cells. The expression of DHFR and MTHFD2 was significantly decreased after ID1 knockout. Furthermore, PAICS expression, and overall concentration of IMP, AMP, GMP, and ATP were reduced after ID1 knockout. ID1 expression in glioblastoma tumor xenografts was associated with positive expression of one-carbon metabolism and purine synthesis enzymes, while ID1-/- cells within the same xenograft had significantly reduced expression of these enzymes. The expression of CD44 was reduced after ID1 knockout. This data suggests that ID1 mediates an increase in one-carbon mediated de novo purine synthesis, thereby regulating metabolic reprogramming in glioblastoma cells. The correlation between CD44 and ID1 expression provides further support that ID1 maintains a less differentiated phenotype in a subset of glioblastoma cells, and metabolic reprogramming is one of the mechanisms through which this phenotype, and the capacity for self-renewal are maintained. Further elucidation of the mechanisms through which ID1 mediates metabolic reprograming of glioblastoma cells can lead to developing effective combination therapies coupling chemotherapeutic strategies with targeting of metabolic programs used by cancer initiating cells.
FSMP-05. KETOGENIC DIETS FOR HIGH-GRADE GLIOMA
Authors: Immidisetti Amanda , Boison Detlev 
Published: March 2021

Abstract

BACKGROUND
Given therapeutic challenges posed by high-grade glioma (HGG), multiple concomitant therapies, including metabolic adjuncts to standard of care, are warranted. Tumor cells are almost exclusively energy-dependent on glucose. Preclinical data supports the use of ketogenic diets (KDs) in this population to deplete the tumor microenvironment of glucose, thereby exerting anti-tumor effects while the surrounding parenchymal tissue utilizes ketones.

OBJECTIVE
The aim of this study was to conduct an up-to-date systematic review of the clinical use of ketogenic diets (KD) in the setting of high-grade glioma treatment and compare study designs, outcomes, and challenges in the translation of these methods from bench to bedside.

METHODS
We conducted comprehensive searches of both the national clinical trials database (clinicaltrials.gov) and pubmed.gov. Trials were included in our review if they were conducted in a patient population with high-grade glioma (either early or refractory) and at least one study arm included the use of a KD.

RESULTS
The clinicaltrials.gov search yielded 12 studies of which 11 met inclusion criteria. Five of these trials reported results. The PubMed search yielded 2 additional studies. Seven clinical trials with reported results on a total of 69 patients were considered.

CONCLUSIONS
The use of KD has proven to be safe and tolerable in early trials, however, further studies are warranted to examine efficacy. Challenges to feasibility include low patient enrollment and compliance, as dietary changes were reported to negatively affect quality of life. Additionally, variability between animal and plant-based KDs, duration of KD regimen, carbohydrate: fat ratio, underlying genetic factors that affect the induction of ketosis, and use of steroid therapy in this patient population may all contribute to inconsistent clinical data when compared to preclinical studies. Future larger scale clinical trials and prospective studies are needed to clarify the role of KDs in the treatment of HGG.
FSMP-06. IN VIVO MONITORING OF LDHA EXPRESSION IN GLIOBLASTOMA USING QUANTITATIVE EXCHANGED-LABEL TURNOVER 1H MRS TECHNIQUE
Authors: Bagga Puneet , Rich Laurie , Haris Mohammad , Wilson Neil , Schnall Mitch , Detre John , Patay Zoltan , Gajjar Amar , Akers Walter , Steinberg Jeffrey , Krenciute Giedre , Baker Suzanne , Reddy Ravinder 
Published: March 2021

Abstract
Most cancers, including glioblastomas (GBMs), rely extensively on glycolysis to support growth, proliferation, and survival. A hallmark of this elevated glycolysis is overexpression of Lactate dehydrogenase-A (LDHA) protein leading to increased uptake of glucose and overproduction of lactate. Various clinical trials using LDHA as a target for diagnosis and treatment have yielded encouraging results. However, in vivo monitoring of LDHA expression has been challenging due to either requirement of administration of radioactive substrates or specialized hardware. In this presentation, we will demonstrate a new method-quantitative exchanged-label turnover MRS (QELT, or simply qMRS)-that increases the sensitivity of magnetic resonance-based metabolic mapping without the requirement for specialized hardware. qMRS relies on the administration of deuterated (2H-labeled) substrates to track the production of downstream metabolites. Since 2H is invisible on 1H MRS, replacement of 1H with 2H due to metabolic turnover leads to an overall reduction in 1H MRS signal for the corresponding metabolites. We applied our qMRS technique to monitor the rate of lactate production in a preclinical GBM model. Infusion of [6,6’-2H2]glucose led to downstream deuterium labeling of lactate, thereby resulting in a reduction in the 1.33 ppm lactate-CH3 peak on 1H MRS over time. The subtraction of post-administration 1H MR spectra from the pre-infusion spectra aided in the determination of the kinetics of the lactate turnover. We believe that the detection and quantification of lactate production kinetics may provide crucial information regarding tumor LDHA expression non-invasively in GBMs without requiring biopsies. Hence, qMRS is expected to open up new opportunities to probe LDHA expression differences in a variety of gliomas, including GBMs and astrocytomas. This method takes advantage of the universal availability and ease of implementation of 1H MRS on all clinical and preclinical magnetic resonance scanners.
FSMP-08. TARGETING PYRIMIDINE SYNTHESIS ACCENTUATES MOLECULAR THERAPY RESPONSE IN GLIOBLASTOMA STEM CELLS
Authors: Yang Kailin , Wang Xiuxing , Wu Qiulian , Kim Leo , Morton Andrew , Gimple Ryan , Prager Briana , Tao Weiwei , Qiu Zhixin , Zhao Linjie , Agnihotri Sameer , Mischel Paul , Mack Stephen , Bao Shideng , Rich Jeremy 
Published: March 2021

Abstract
Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.
Outcomes and Risk Factors of Septic Shock in Patients With Infective Endocarditis: A Prospective Cohort Study
Authors: Pericàs Juan M , Hernández-Meneses Marta , Muñoz Patricia , Álvarez-Uría Ana , Pinilla-Llorente Blanca , de Alarcón Arístides , Reviejo Karlos , Fariñas M Carmen , Falces Carlos , Goikoetxea-Agirre Josune , Gálvez-Acebal Juan , Hidalgo-Tenorio Carmen , Gómez-Nebreda Eloy , Miro Jose M 
Published: March 2021

Abstract

Background
Little is known about the characteristics and impact of septic shock (SS) on the outcomes of infective endocarditis (IE). We aimed to investigate the characteristics and outcomes of patients with IE presenting with SS and to compare them to those of IE patients with sepsis (Se) and those with neither Se nor SS (no-Se-SS).

Methods
This is a prospective cohort study of 4864 IE patients from 35 Spanish centers (2008 to 2018). Logistic regression analyses were performed to identify risk factors for SS and mortality.

Results
Septic shock and Se presented in 597 (12.3%) and 559 (11.5%) patients, respectively. Patients with SS were younger and presented significantly higher rates of diabetes, chronic renal and liver disease, transplantation, nosocomial acquisition, Staphylococcus aureus, IE complications, and in-hospital mortality (62.5%, 37.7% for Se and 18.2% for no-Se-SS, P &lt; .001). Staphylococcus aureus (odds ratio [OR], 1.94; 95% confidence interval [CI], 1.34–2.81; P &lt; .001), Gram negative (OR, 2.21; 95% CI, 1.25–3.91; P = .006), nosocomial acquisition (OR, 1.44; 95% CI, 1.07–1.94; P = .015), persistent bacteremia (OR, 1.82; 95% CI, 1.24–2.68; P = .002), acute renal failure (OR, 3.02; 95% CI, 2.28–4.01; P &lt; .001), central nervous system emboli (OR, 1.48; 95% CI, 1.08–2.01; P = .013), and larger vegetation size (OR, 1.01; 95% CI, 1.00–1.02; P. = 020) were associated with a higher risk of developing SS. Charlson score, heart failure, persistent bacteremia, acute renal failure, mechanical ventilation, worsening of liver disease, S aureus, and receiving aminoglycosides within the first 24 hours were associated with higher in-hospital mortality, whereas male sex, native valve IE, and cardiac surgery were associated with lower mortality.

Conclusions
Septic shock is frequent and entails dismal prognosis. Early identification of patients at risk of developing SS and early assessment for cardiac surgery appear as key factors to improve outcomes.
Resolution and Insolvency of Banks and Financial Institutions
Authors: Schillig Michael 
Published: March 2021

Abstract
This book provides a detailed analysis and critical assessment of the EU and US resolution regimes for banks and financial institutions on a comparative basis. The book analyses the EU legal framework under the Bank Recovery and Resolution Directive, and considers the challenges in national implementation through the two largest economies within the EU, Germany and the UK. The very influential laws of the US, (Securities Investor Protection Act 1970, and the Wall Street Reform and Consumer Protection Act: Dodd-Franck) are used as a comparative reference point. Through analysis of the new EU framework and of the more mature system in the US, the book considers whether and to what extent the EU framework and national regimes contribute to ensuring resolvability of financial institutions, how their efficacy may be increased with a view, in particular, to the resolution of cross border groups, and what the future may hold, especially in respect of a single European resolution authority.
Private Sector Transfer, Bridge Bank, and Asset Separation
Authors: Schillig Michael 
Published: March 2021

Abstract
The assisted transfer of the viable parts of a failing institution’s business to a private sector purchaser, or the temporary transfer to a bridge bank, are well-tested bank resolution tools. The same is true for the ‘good bank/bad bank’ model, where performing assets are separated from non-performing assets and the latter are parked in a separate entity until market conditions have stabilized. This chapter analyses the European legal framework for the sale of business, bridge bank, and assets separation tools, as well as their implementation in the UK and Germany. The experience with similar tools under the US FDIC receivership regime for depository institution and their extension under Title II of the Dodd–Frank Act will be used as a comparative reference point.
European Union Design Law
Authors: Stone David 
Published: March 2021

Abstract
Over ten years after the beginning of the Community Registered Designs system of the European Union (EU), the Office for Harmonization in the Internal Market (OHIM) and European courts continue to grapple with many of the new legal concepts introduced, making this a complex and fluctuating area of law. This new edition of the highly-respected English-language text offers a concise, accessible and highly readable volume covering the complete design law of the European Union. It offers a concise history of the legislation's development and aims, tracing the introduction of fundamental changes to the protection of industrial and ornamental designs throughout the EU. This is followed by a detailed and comprehensive examination of the interpretations provided by OHIM, the Court of Justice and General Court, and the Community Design Courts of EU Member States. The book quotes primary legal provisions in context, supported by extensive citation of case law from the Court of Justice, OHIM and many European jurisdictions. Chapters cover topics including the definition of terms, the system of courts and tribunals with jurisdiction for Community design disputes, overlap with other intellectual property rights, exclusions from protection, the right to the Community design, interpreting designs, disclosure, invalidity of prior design and novelty arguments, the procedure of OHIM, infringement and applicable defences, jurisdictional issues, and the Design Directive. European Union Design Law: A Practitioners' Guide is an essential reference text for practitioners throughout the European Union and beyond.
Preliminary Considerations
Authors: Riordan Jaani 
Published: March 2021

Abstract
This chapter discusses five issues which commonly arise before the commencement of proceedings in disputes involving internet intermediaries. Broadly, these issues relate to the identification and selection of proper defendants, access to sources of information about online wrongdoing, and the taking of appropriate pre-action measures which may remove or reduce the need for litigation. Additionally, this chapter introduces several tools which practitioners may find useful in detecting and monitoring online wrongdoing.
Copyright
Authors: Riordan Jaani 
Published: March 2021

Abstract
Copyright, it is said, is one of the great balancing acts of the law. The rights it confers embody the basic tension between encouraging optimal creation and consumption of works; their boundaries reflect delicate compromises between creators, consumers, disseminators, and many other interest groups. These conflicts are exemplified in the enforcement of copyright against internet intermediaries. Copyright owners assert that almost one-quarter of global internet traffic, 80 per cent of YouTube videos, and 97 per cent of BitTorrent transmissions infringe their copyrights. Although the prevalence of unauthorised content appears to be declining with the growth of legitimate services, digital piracy remains widespread. The services responsible for routing, storing, and processing these data deny responsibility for policing infringements, citing the impracticability of monitoring and their inability to adjudicate claims of infringement, while internet users fear disproportionate interferences with privacy, internet access, and innovation.
European Union Trade Mark Law
Authors: Mühlendahl Alexander , Botis Dimitris , Maniatis Spyros , Wiseman Imogen 
Published: March 2021

Abstract
Trade mark law at the European Union (EU) level has developed following two parallel paths. One led to the harmonization of disparate national systems of trade mark protection; the other to the creation of a ‘federal’ trade mark right, unitary in nature and effective throughout the territory of the European Union. The aim of this chapter is to describe briefly the destinations reached by the ‘harmonization’ and the ‘federal’ paths.
Formalities and the Definition of Goods and Services
Authors: Mühlendahl Alexander , Botis Dimitris , Maniatis Spyros , Wiseman Imogen 
Published: March 2021

Abstract
This chapter is the first of a series of three that will examine the jurisprudence of the Court on formalities and specification (Chapter 4), on absolute grounds for refusing registration (Chapter 5), and on acquired distinctiveness through use (Chapter 6), as a means of of overcoming some of the objections discussed in Chapters 4 and 5.
Distinctiveness Acquired Through Use
Authors: Mühlendahl Alexander , Botis Dimitris , Maniatis Spyros , Wiseman Imogen 
Published: March 2021

Abstract
Trade marks that are not inherently distinctive or that are descriptive or generic may nevertheless be registered if they have, as a result of the use that has been made of them, acquired distinctiveness, or what is called in US American trade mark law, ‘secondary meaning’. The legal basis for this basis for registration is found in Article 3(3) of the Directive and in Article 7(3) CTMR.
Trustee Decision Making
Authors: Ashdown Michael 
Published: March 2021

Abstract
The book provides analysis of the principal rules of trust law which control the exercise of powers and discretions by trustees. The primary focus is on the principle known as "the Rule in Re Hastings-Bass", and this is considered alongside the doctrines of fraud on a power and mistake. This is the first book-length treatment focussed on this specific aspect of trust law, and in particular the first on the Rule in Re Hastings-Bass, which is the subject of much professional and academic interest especially following consideration by the Supreme Court in Pitt v Holt and Futter v Futter [2013] UKSC 26. Whilst considering Pitt and the Rule in Re Hastings-Bass alongside mistake and fraud on a power, the book also explains how these doctrines interact, and how the law regulates trustee decision-making as a whole. It sets out examples and considers extensive practical problems, allowing the reader to understand not only the core trust law rules, but also the broader consequences of those rules which arise in real cases. This aspect of trust law is of great practical importance for practitioners as it arises frequently in the context of trust litigation, and in advising trustees and beneficiaries of their rights and obligations. The newly settled state of the law after Pitt will encourage reliance on the Re Hastings-Bass and mistake rules by practitioners in challenges to trustees' conduct and decisions. This book equips all involved with the key principles and arguments in this area.