bluuebunny/crossref_metadata_2025_split huggingface dataset:
ETMM-02. PRECLINICAL MODELS REVEAL BRAIN-MICROENVIRONMENT SPECIFIC METABOLIC DEPENDENCIES IN GLIOBLASTOMA
Authors: Minami Jenna , Bayley Nicholas , Tse Christopher , Zhu Henan , Morrow Danielle , Yong William , Liau Linda , Cloughesy Timothy F , Graeber Thomas , Nathanson David A 
Published: March 2021

Abstract
Metabolic reprogramming is a hallmark of cancer, and malignant cells must acquire metabolic adaptations in response to a multitude of intrinsic and extrinsic factors to fuel neoplastic progression. Mutations or changes in metabolic gene expression can impose nutrient dependencies in tumors, and even in the absence of metabolic defects, cancer cells can become auxotrophic for particular nutrients or metabolic byproducts generated by other cells in the tumor microenvironment (TME). Conventional cell lines do not recapitulate the metabolic heterogeneity of glioblastoma (GBM), while primary cultured cells do not account for the influences of the microenvironment and the blood brain barrier on tumor biology. Additionally, these systems are under strong selective pressure divergent from that in vivo, leading to reduced heterogeneity between cultured tumor cells. Here, we describe a biobank of direct-from-patient derived orthotopic xenografts (GliomaPDOX) and gliomaspheres that reveal a subset of gliomas that, while able to form in vivo, cannot survive in vitro. RNA sequencing of tumors that can form both in vivo and in vitro (termed “TME-Indifferent”) compared to that of tumors that can only form in vivo (termed “TME-Dependent”) revealed transcriptional changes associated with altered nutrient availability, emphasizing the unique metabolic programs impacted by the tumor microenvironment. Furthermore, TME-dependent tumors lack metabolic signatures associated with nutrient biosynthesis, thus indicating a potential dependency of these tumors on scavenging specific nutrients from the extracellular milieu. Collectively, these data emphasize the metabolic heterogeneity within GBM and reveal a subset of gliomas that lack metabolic plasticity, indicating a potential brain-microenvironment specific metabolic dependency that can be targeted for therapy.
ETMM-03. CANCER CELLS DEPLOY LIPOCALIN- 2 TO COLLECT LIMITING IRON IN LEPTOMENINGEAL METASTASIS
Authors: Chi Yudan , Remsik Jan , Kiseliovas Vaidotas , Derderian Camille , Sener Ugur , Alghader Majdi , Saadeh Fadi , Nikishina Katie , Bale Tejus , Iacobuzio-Donahue Christin , Thomas Tiffany , Pe’er Dana , Mazutis Linas , Boire Adrienne 
Published: March 2021

Abstract
The tumor microenvironment plays a critical regulatory role in cancer progression, especially in central nervous system metastases. Cancer cells within the cerebrospinal fluid (CSF)-filled leptomeninges face substantial microenvironmental challenges, including inflammation and sparse micronutrients. To investigate the mechanism by which cancer cells in these leptomeningeal metastases (LM) overcome these constraints, we subjected CSF from five patients with LM to single-cell RNA sequencing. We found that cancer cells, but not macrophages, within the CSF express the iron-binding protein lipocalin-2 (LCN2) and its receptor SCL22A17. These macrophages generate inflammatory cytokines that induce cancer cell LCN2 expression but do not generate LCN2 themselves. In mouse models of LM, cancer cell growth is supported by the LCN2/SLC22A17 system and is inhibited by iron chelation therapy. A Phase Ia/1b clinical trial focused on this novel treatment approach is underway.
FSMP-02. CHANGES IN GLUTAMINE METABOLISM INDUCED BY OXALOACETATE IN GLIOBLASTOMA
Authors: Ijare Omkar , Conway David , Cash Alan , Baskin David , Pichumani Kumar 
Published: March 2021

Abstract
Anhydrous Enol-Oxaloacetate (AEO) has been shown to significantly increase survival and decrease tumor growth rates in animal models of glioblastoma and hepatocellular carcinoma. In the body, AEO is metabolized to “oxaloacetate” (OAA). Earlier, we demonstrated that AEO drastically reduced Warburg glycolysis in glioblastoma cells which was determined by the increase in pyruvate to lactate ratio and a 48.8% decrease in lactate production in 13C-labeled glucose metabolism studies. We have expanded this previous work to examine 13C-labeled glutamine metabolism. Cultured solid tumor cancer cells strongly rely on both glucose and glutamine to synthesize carbon intermediates for anaplerotic reactions. With treatment of OAA, we hypothesize that glutamine-derived OAA may be reduced which can be tracked through the use GC-MS based 13C-labeled glutamine isotopomer experiments. Patient-derived glioblastoma cells were grown in 15 mM glucose and 2 mM glutamine containing DMEM medium supplemented with 2 mM OAA for 10 days. 24 hours prior to harvesting the cells, 4 mM of [U-13C]glutamine was introduced to the medium. OAA treated cells showed significant decrease in the protein levels of lactate dehydrogenase A and C which indicates the switching off of glycolysis to support the utilization of elevated OAA levels during glutamine metabolism in the TCA cycle. 13C mass distribution analysis showed significant decrease in malate, aspartate and citrate pools (malate: 8.8%, p = 0.0098; aspartate: 9.2%, p = 0.0064; citrate: 9.5%, p = 0.0036) in their M+4 isotopomer labeling in OAA treated group compared to the control group. Decrease in lactate generation may reduce cancer proliferation, migration and invasion. Together, these data provide alternative way to modulate energy metabolism in glioblastoma using AEO treatment. Similarly, AEO treatment in other solid tumors (e.g. pancreatic ductal adenocarcinoma) may produce altered glutamine metabolism which may be of therapeutic value.
FSMP-03. INVESTIGATING CO-OPTED ASTROCYTIC METABOLISM IN MELANOMA BRAIN METASTASIS
Authors: Farnan Julia , Jackson Joshua , Hartsough Edward 
Published: March 2021

Abstract
Melanoma, an aggressive form of skin cancer, frequently metastasizes to the brain. While peripheral melanoma is largely treatable, MBM fail to respond to current therapeutics and is a clear unmet clinical need. Initial clinical symptoms of Melanoma Brain Metastases (MBM) typically include headaches, seizures and other neurological deficits, suggesting that MBM disrupt normal brain functions. One of the major cell types that melanoma encounter and interact with during brain metastasis are astrocytes. Astrocytes, the most abundant cell in the brain, interact with neurons and the vasculature, provide trophic and energetic support to neurons, and regulate local blood flow. Metabolic pathways in astrocytes, particularly the glutamate-glutamine cycle, are essential for the recycling and resupply of neurotransmitters needed to maintain the excitation/inhibition balance. We propose that MBM co-opt astrocytic metabolism, fueling MBM growth, and deplete metabolic intermediates crucial for neuronal activity leading to altered neurologic function. We begin to unravel the metabolic interactions between astrocytes and MBM using novel modeling platforms with genetic and pharmacological tools to manipulate the tumor microenvironment. This project investigates the contribution of astrocytic metabolism to MBM growth. We intend on dissecting the distinct metabolic needs of metastatic brain melanoma in the CNS microenvironment and the subsequent neurological consequences. Completion of this project will provide a platform to study MBM and interaction with the local brain microenvironment. Inhibiting metabolic interactions between melanoma and glial cells may provide new avenue for therapeutic targeting of MBM.
FSMP-10. CYSTEINE INDUCES CYTOTOXICITY IN GLIOBLASTOMA THROUGH MITOCHONDRIAL HYDROGEN PEROXIDE PRODUCTION
Authors: Noch Evan , Palma Laura , Yim Isaiah , Binder Bhavneet , Benedetti Elisa , Krumsiek Jan , Elemento Olivier , Cantley Lewis 
Published: March 2021

Abstract
Glioblastoma (GBM) is a poorly treatable disease with high mortality. Tumor metabolism in GBM is a critical mechanism responsible for growth because of upregulation of glucose, amino acid, and fatty acid utilization. However, little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate metabolic signatures unique to GBM, we interrogated the TCGA and a cancer metabolite database for alterations in glucose and amino acid signatures in GBM relative to other human cancers and relative to low-grade glioma. From these analyses, we found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers and that GBM exhibits high levels of cysteine metabolites compared to low-grade gliomas. To study the role of cysteine in GBM pathogenesis, we treated patient-derived GBM cells with FDA-approved cyst(e)ine-promoting compounds in vitro, including N-acetylcysteine (NAC) and the cephalosporin antibiotic, Ceftriaxone (CTX), which induces cystine import through system Xc transporter upregulation. Cysteine-promoting compounds, including NAC and CTX, inhibit growth of GBM cells, which is exacerbated by glucose deprivation. This growth inhibition is associated with reduced mitochondrial metabolism, manifest by reduction in ATP, NADPH/NADP+ ratio, mitochondrial membrane potential, and oxygen consumption rate. Mechanistic experiments revealed that cysteine compounds induce a rapid increase in the rate of H2O2 production in isolated GBM mitochondria, an effect blocked by the H2O2 scavenger, catalase. Such findings are consistent with reductive stress, a ROS-producing process whereby excess mitochondrial reducing equivalents prevent electron transfer to oxidized electron acceptors, inducing O2 reduction to H2O2. We show that cysteine-promoting compounds reduce cell growth and induce rapid mitochondrial toxicity in GBM, which may be due to reductive stress. This pathway is targetable with FDA-approved cysteine-promoting compounds and could synergize with glucose-lowering treatments, including the ketogenic diet, for GBM.
The Liability of Internet Intermediaries
Authors: Riordan Jaani 
Published: March 2021

Abstract
Internet intermediaries play a central role in modern commerce and society. Although their economic and social importance is well-recognised, their legal liability remains poorly understood, and, until now, no work has specifically addressed their legal responsibility for wrongdoing carried out by third parties using their facilities or platforms. This work fills that gap by providing comprehensive coverage of the legal duties owed by intermediaries and the increasingly complex schemes that regulate their activities. The first part of the work introduces the concept of an internet intermediary, general doctrines of primary and secondary liability, and the European enforcement regime. The second part examines the liability of intermediaries in specific areas of law, with a detailed analysis of the applicable liability rules, and the major English case law, and decisions of the Court of Justice that interpret and apply them. The final part of the work provides guidance on remedies and limitations. Written by an expert author from the intellectual property chambers at 8 New Square, Lincoln's Inn, this is an essential guide for lawyers advising on liability, privacy, and online regulation.
Article 4(1). Personal data
Authors: Bygrave Lee A , Tosoni Luca 
Published: March 2021

Abstract
The principles of data protection should apply to any information concerning an identified or identifiable natural person. Personal data which have undergone pseudonymisation, which could be attributed to a natural person by the use of additional information should be considered to be information on an identifiable natural person. To determine whether a natural person is identifiable, account should be taken of all the means reasonably likely to be used, such as singling out, either by the controller or by another person to identify the natural person directly or indirectly.
Article 4(7). Controller
Authors: Bygrave Lee A , Tosoni Luca 
Published: March 2021

Abstract
Controllers are key actors in the operationalisation of data protection law as they are the primary bearers of the obligations set by such law towards data subjects. Thus, definition of the criteria for attaining the role of controller is essential for understanding the law’s application. As detailed below, the tendency under EU data protection law is to apply these criteria in an expansive and flexible way, thus rendering the threshold for attaining controller status quite low.
Article 8 Conditions applicable to child’s consent in relation to information society services
Authors: Kosta Eleni 
Published: March 2021

Abstract
Article 7 (Conditions for consent); Article 12 (Transparent information, communication and modalities of exercise of the rights of the data subject) (see also recital 58); Article 40(2)(g) (Codes of conduct); Article 22 (Automated individual decision-making) (see also recital 71); Article 35 (Data Protection Impact Assessments).
Committal for Sentence
Authors: Sprack John , Engelhardt–Sprack Michael 
Published: March 2021

Abstract
Where a defendant is convicted or pleads guilty in the magistrates’ court, the magistrates will usually proceed to sentence, in accordance with the procedure detailed in Chapter 22. In doing so, however, they are limited by the restrictions on their powers of punishment. Notwithstanding these restrictions, they may be able to commit the offender to the Crown Court for sentence, and this Chapter deals with such committals.
The Course of the Trial
Authors: Sprack John , Engelhardt–Sprack Michael 
Published: March 2021

Abstract
The judge at a trial on indictment must be a professional judge (i.e., a High Court judge, circuit judge or deputy circuit judge, or recorder). The distribution of work between these various types of judge is described at 14.14. The prosecution must be legally represented; the accused usually chooses to be so, and will probably be able to obtain representation from the Legal Aid Agency. Although some solicitors now have rights of audience in the Crown Court, legal representation for trial on indictment still usually involves instructing solicitors who in turn brief counsel (see 14.21 to 14.23). The following Paragraphs deal with some aspects of the role of prosecuting and defence counsel, and their relationship with the judge. The discussion is based upon decided cases and also upon the Code of Conduct for the Bar. The Code does not have the force of law, but is of great persuasive value, and a barrister who conforms with its spirit cannot be guilty of a breach of professional discipline.
Copyright, Moral Rights, and the Right to One’s Image
Authors: Bate Stephen , Wilde Gervase de 
Published: March 2021

Abstract
UK copyright is a right created by statute and is now contained in the Copyright, Designs and Patents Act 1988 (CDPA). Copyright is mainly regarded as a means of protecting the economic interests of creators of original works. However, it has a significant role to play in protecting privacy interests. Private correspondence and diaries are obvious examples of material that may attract copyright protection in the domestic sphere. In the commercial context, examples include corporate memoranda, other documents, and recordings containing confidential information. Copyright subsists in various descriptions of ‘works’, such as ‘literary works’, ‘films’ and ‘sound recordings’ and there may be more than one copyright work in any article. For example, a recording may include a ‘literary work’ as well as a ‘sound recording’ for copyright purposes. A copyright work may contain private information or the work may be unpublished and therefore private in that sense. Copyright is apt to protect privacy interests, because it gives the copyright owner the legal right to prohibit reproductions, ie copying, as well as other means of dissemination.
Interest Groups’ Recruitment of Incumbent Parliamentarians to Their Boards
Authors: Huwyler Oliver 
Published: March 2021

AbstractInterest groups (IGs) recruit incumbent parliamentarians to their boards to influence policy, improve their resources and signal political connectedness. To detect parliamentarians’ characteristics that drive recruitment, this study analyses three decades of annual data (1985–2016) of 903 Swiss parliamentarians and their board seats. It compares 5249 cases of parliamentarians’ successful recruitment by 3291 different organisations to counterfactual cases where no recruitment took place. The results show that IGs recruit parliamentarians for both knowledge and networks (professions, other board seats) and influence (committee seats) in IGs’ policy areas. Moreover, recruited parliamentarians are more likely newcomers, ideologically proximate to IGs, moderate and from the same district as them.
Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020
Authors: Norris-Grey Caitlin , Cambridge Geraldine , Moore Samantha , Reddy Venkat , Leandro Maria 
Published: March 2021

Abstract

Objectives
B cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment.

Methods
Retrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998–2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan–Meier survival curves, log-rank test and Cox regression analysis.

Results
A total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan–Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs.

Conclusion
Many patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation.
Reduction of Smad2 caused by oxidative stress leads to necrotic death of hypertrophic chondrocytes associated with an endemic osteoarthritis
Authors: He Ying , Fan Lihong , Aaron Nicole , Feng Yiping , Fang Qian , Zhang Ying , Zhang Dan , Wang Hui , Ma Tianyou , Sun Jian , Chen Jinghong 
Published: March 2021

Abstract

Objective
The occurrence and development of an endemic OA, Kashin–Beck disease (KBD), is closely related to oxidative stress induced by free radicals. The aim of the study was to find the key signalling molecules or pathogenic factors as a potential treatment strategy for KBD.

Methods
Real-time PCR and western blotting were performed to detect the mRNA and protein expression levels in cells and tissues. Immunohistochemical staining was assayed in rat models and human samples obtained from children. The type of cell death was identified by annexin V and propidium iodide staining with flow cytometry.

Results
Oxidative stress decreased levels of Smad2 and Smad3 in hypertrophic chondrocytes both in vitro and in vivo. In the cartilage of KBD patients, the expression of Smad2 and Smad3 proteins in the middle and deep zone was significantly decreased with an observed full deletion in the deep zone of some samples. Reduction of Smad2 protein induced necrotic death of hypertrophic chondrocytes, while reduction of Smad3 protein induced apoptosis. The reduction of Smad2 protein was not accompanied by Smad3 protein reduction in hypertrophic chondrocyte necrosis. Furthermore, the reduction of Smad2 also impaired the construction of tissue-engineered cartilage in vitro.

Conclusion
These studies reveal that oxidative stress causes necrosis of hypertrophic chondrocytes by downregulating Smad2 protein, which increases the pathogenesis of KBD cartilage. The importance of Smad2 in the development of KBD provides a new potential target for the treatment of KBD.
EXPERIMENTAL EXAMINATION OF RADIATION DOSES OF DUAL- AND SINGLE-ENERGY COMPUTED TOMOGRAPHY IN CHEST AND UPPER ABDOMEN IN A PHANTOM STUDY
Authors: Bos Denise , König Britta , Blex Sebastian , Zensen Sebastian , Opitz Marcel , Maier Sandra , Forsting Michael , Zylka Waldemar , Kühl Hilmar , Wetter Axel , Guberina Nika 
Published: March 2021

Abstract
The aim of this phantom study is to examine radiation doses of dual- and single-energy computed tomography (DECT and SECT) in the chest and upper abdomen for three different multi-slice CT scanners. A total of 34 CT protocols were examined with the phantom N1 LUNGMAN. Four different CT examination types of different anatomic regions were performed both in single- and dual-energy technique: chest, aorta, pulmonary arteries for suspected pulmonary embolism and liver. Radiation doses were examined for the CT dose index CTDIvol and dose-length product (DLP). Radiation doses of DECT were significantly higher than doses for SECT. In terms of CTDIvol, radiation doses were 1.1–3.2 times higher, and in terms of DLP, these were 1.1–3.8 times higher for DECT compared with SECT. The third-generation dual-source CT applied the lowest dose in 7 of 15 different examination types of different anatomic regions.
Seismic running safety of trains and a new type of seismic-isolation railway structure
Authors: Luo Xiu 
Published: March 2021

Abstract
Until now, seismic-isolation structures have not yet been applied in the railway field. The reason is that though a seismic-isolation structure can reduce the inertial force to the structure, the energy absorption causes big response displacement on the structure, which adversely effects the running safety of the trains supported by the structure. In this paper, a methodology for seismic running safety assessment is introduced, and a new type of seismic-isolation foundation is proposed, which can convert the seismic response displacement in the lateral direction of track to the longitudinal direction that has a less adverse effect on the running safety of the train. The isolation foundation is composed of FPS (Friction Pendulum System) slider, concave plate and guide ditch. Moreover, through model experiments and 3D numerical simulation, it is verified that the proposed foundation can keep both the effects of the seismic isolation and the running safety of the train during an earthquake.