bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiarrhythmic drug loading at home using remote monitoring: a virtual feasibility study during COVID-19 social distancing
Authors: Shah Rajan L , Kapoor Ridhima , Bonnett Colleen , Ottoboni Linda K , Tacklind Christine , Tsiperfal Angela , Perez Marco V
Published: March 2021

The epidemiological necessity for distancing during the COVID-19 pandemic has resulted in postponement of non-emergent hospitalizations and increase use of telemedicine. The feasibility of virtual antiarrhythmic drug (AAD) loading specifically with digital QTc electrocardiographic monitoring (EM) in conjunction with telemedicine video visits is not well established. We tested the hypothesis that existing digital health technologies and virtual communication platforms could provide EM and support medically guided AAD loading for patients with symptomatic tachyarrhythmia in the ambulatory setting, while reducing physical contact between patient and healthcare system. A prospective pilot, case series was approved by the institutional ethics committee, entailing three subjects with symptomatic arrhythmia during the COVID-19 pandemic who were enrolled for virtual AAD loading at home. Clinicians met with participants twice daily via video visits conducted after QTc analysis (Kardia 6L mobile sensor) and telemetry review (Mobile Cardiac Outpatient Telemetry of silent arrhythmias). Participants received direct instruction to either terminate the study or proceed with the next single dose of AAD. All participants completed contactless loading of five AAD doses, without untoward event. Scheduled video visits allowed dialogue and participant counselling where decision-making was guided by remote review of EM. Participant adherence with transmissions and scheduled visits was 98.3%; a single electrocardiogram was delayed beyond the 2 hours of post-dose schedule. This virtual approach reduced overall expenditures based on retrospective comparison with previous AAD load hospitalizations. We found that a ‘virtual hospitalization’ for AAD loading with remote EM and twice-daily virtual rounding is feasible using existing digital health technologies.
Pulmonary artery augmentation using decellularized equine pericardium (Matrix Patch™): initial single-centre experience
Authors: Murin Peter , Weixler Viktoria H M , Kuschnerus Kira , Romanchenko Olga , Lorenzen Victoria , Nordmeyer Johannes , Cho Mi-Young , Sigler Matthias , Photiadis Joachim
Published: March 2021

OBJECTIVES

The aim of this study was to report our initial experience when using Matrix Patch™ a cell-free equine-derived pericardium for the augmentation of branch pulmonary arteries (PAs) in children.

METHODS

Between September 2016 and September 2019, Matrix Patch was used for the augmentation of branch PAs in 96 patients and implanted in 147 separate locations. The median age at implantation was 3.2 years (interquartile range: 0.9–8.4), and 33% of patients were infants. The patch was used mainly in redo surgeries (89.6%). Intra-procedural feasibility and reinterventions were analysed. Primary end points were death or patch-related reoperation/stent implantation. Explanted patches were stained for recellularization/calcification, or to reveal proliferation/inflammation.

RESULTS

A total of 81 patients, who received patches in 119 separate locations, were followed within a median of 20 months (interquartile range: 10.2–30.2). Patients with early reoperation/stent implantation were excluded from follow-up. No patch-related death was noted. Survival at last follow-up was 88% (95% CI: 78.8–93.7%). Overall probability of freedom from reoperation/stent implantation per location, 12 and 24 months after initial surgery was 85.8% (95% CI: 76.2–91.7%) and 78.7 (95% CI: 65.9–87.2%), respectively. At 20 months, superficial proliferation with discrete macrophage activity was seen in explants; however, no signs of calcification are observed.

CONCLUSIONS

The initial experience with the Matrix Patch in PAs showed comparable results to other xenogeneic patch materials. Long-term follow-up data are needed to prove the desired durability of the patch in different locations.
Poetry in Expanded Translation: Audre Lorde, Theresa Hak Kyung Cha, Harryette Mullen, Don Mee Choi
Authors: Ramayya Nisha
Published: March 2021

In this article, I discuss the politics and poetics of translation in the work of Audre Lorde, Theresa Hak Kyung Cha, Harryette Mullen, and Don Mee Choi, considering each poet's ideas about translation and translation practices, suggesting approaches to reading and thinking about their work in relation to translation and in relation to each other. I ask the following questions: in the selected poets' work, what are the relationships between the movement of people, the removal of dead bodies, and translation practices? How do the poets move between languages and literary forms, and what are the politics and poetics of their movements with regards to migration, dispossession, and death, as well as resistance, refusal, and rebirth? I select these poets because of the ways in which they confront relationships between the history of the English language and literature, imperialism and colonialism, racialisation and racism, gendered experiences and narratives, and their own poetic practices. These histories and experiences do not exist in isolation, nor do the poets attempt to circumscribe their approaches to language, representation, translation, and form from their lived experiences and everyday practices of survival and resistance. The selected poets’ work ranges in form, tone, and argument, but I argue that their refusal to circumscribe politics and poetics pertains to their subject positions and lived experiences as racialised and post/colonial women, and that this refusal is demonstrated in their diverse understandings of translation and translation practices.
Novel electrocardiographic criteria for short QT syndrome in children and adolescents
Authors: Suzuki Hiroshi , Horie Minoru , Ozawa Junichi , Sumitomo Naokata , Ohno Seiko , Hoshino Kenji , Ehara Eiji , Takahashi Kazuhiro , Maeda Yoshichika , Yoshinaga Masao , Tateno Shigeru , Takagi Junichi , Doi Shozaburo , Hoshina Satoshi , Sato Isamu , Ishikawa Taisuke , Makita Naomasa , Chinushi Masaomi , Akazawa Kohei , Nagashima Masami
Published: March 2021

Aims

Although shortening of the corrected QT interval (QTc) is a key finding in the diagnosis of short QT syndrome (SQTS), there may be overlap of the QTc between SQTS patients and normal subjects in childhood and adolescence. We aimed to investigate electrocardiographic findings for differentiation of SQTS patients.

Methods and results

The SQTS group comprised 34 SQTS patients <20 years old, including 9 from our institutions and 25 from previous reports. The control group comprised 61 apparently healthy subjects with an QTc of <360 ms who were selected from 13 314 participants in a school-based screening programme. We compared electrocardiographic findings, including QT and Jpoint-Tpeak intervals (QT and J-Tpeak, respectively), those corrected by using the Bazett’s and Fridericia’s formulae (cB and cF, respectively) and early repolarization (ER) between the groups. QT, QTc by using Bazett’s formula (QTcB), QTc by using Fridericia’s formula (QTcF), J-Tpeak, J-Tpeak cB, and J-Tpeak cF were significantly shorter in the SQTS group than in the control group. On receiver operating characteristic curve analysis, the area under the curve (AUC) was largest for QTcB (0.888) among QT, QTcB, and QTcF, with a cut-off value of 316 ms (sensitivity: 79.4% and specificity: 96.7%). The AUC was largest for J-Tpeak cB (0.848) among J-Tpeak, J-Tpeak cB, and J-Tpeak cF, with a cut-off value of 181 ms (sensitivity: 80.8% and specificity: 91.8%). Early repolarization was found more frequently in the SQTS group than in the control group (67% vs. 23%, P = 0.001).

Conclusion

A QTcB <316 ms, J-Tpeak cB < 181 ms, and the presence of ER may indicate SQTS patients in childhood and adolescence.
On the de Rham–Witt Complex over Perfectoid Rings
Authors: Davis Christopher , Patchkoria Irakli
Published: March 2021

Fix an odd prime $p$. The results in this paper are modeled after work of Hesselholt and Hesselholt–Madsen on the $p$-typical absolute de Rham–Witt complex in mixed characteristic. We have two primary results. The 1st result is an exact sequence that describes the kernel of the restriction map on the de Rham–Witt complex over $A$, where $A$ is the ring of integers in an algebraic extension of $\textbf{Q}_p$ or where $A$ is a $p$-torsion-free perfectoid ring. The 2nd result is a description of the $p$-power torsion (and related objects) in the de Rham–Witt complex over $A$, where $A$ is a $p$-torsion-free perfectoid ring containing a compatible system of $p$-power roots of unity. Both of these results are analogous to the results of Hesselholt and Madsen. Our main contribution is the extension of their results to certain perfectoid rings. We also provide algebraic proofs of these results, whereas the proofs of Hesselholt and Madsen used techniques from topology.
Knowledge, practices and perceived barriers of physiotherapists involved in disaster management: a cross-sectional survey of Nigeria-based and trained physiotherapists
Authors: Ojukwu Chidiebele P , Eze Obumneke G , Uduonu Ekezie M , Okemuo Adaora J , Umunnah Joseph O , Ede Stephen S , Onuchukwu Chioma L , Anekwu Emelie M , Ezeigwe Anne U
Published: March 2021

Background

Disasters represent substantial health risks to the human population. Proper interventions at all stages of disaster management (DM) are essential for human-related outcomes. The role of physiotherapy in DM should not be underestimated, but unfortunately information on the involvement of physiotherapists in DM is limited in sub-Saharan Africa.

Methods

One hundred and fifty Nigeria-based and trained physiotherapists were recruited to complete a questionnaire investigating the knowledge, practices and perceived barriers of the role of physiotherapists in DM.

Results

Physiotherapists had moderate knowledge of their role at every stage of DM. However, their involvement in specific DM-related activities during various stages of DM in the country was low. Major barriers to the involvement of physiotherapists in DM included a lack of established government policies on the integration of physiotherapists in DM (90.0%) and a lack of specialty clinical practice areas in DM (89.3%). For improved involvement of physiotherapists in DM in Nigeria, respondents recommended creating an awareness of the role of physiotherapists in DM (91.3%), providing continuous education programmes on DM (90.6%) and inclusion of DM in physiotherapy training programmes in Nigeria (90.0%).

Conclusion

Physiotherapists perceived that they are not adequately involved in DM in Nigeria, despite their moderate knowledge of their role during DM.
Calling for “IR as Becoming-Rhizomatic”
Authors: Eun Yong-Soo
Published: March 2021

This article takes reflexive stock on the current state of the discipline of international relations (IR) in order to catalyze a robust debate on diversity in IR knowledge and knowledge production. IR has witnessed a theoretical explosion and proliferation since the 1980s, and pluralism is acknowledged as a legitimate position for producing IR knowledge and theory. As a result, we have now arrived at “a plural, and pluralist,” field, and several IR scholars have observed that the discipline is much healthier as a result. On closer inspection, however, what we find in IR is quantitative (i.e., representational) diversity and closed territoriality, as opposed to qualitative (i.e., ontological) diversity and open territoriality. By reviewing what defines the nature of diversity in artifacts, including the field of knowledge we know as IR, this article shows that territories and codes of knowledge production in IR remain narrowly confined within a few lines of articulation and strata. Furthermore, although IR is often regarded as a plural, and pluralist, field, the article demonstrates that this is true only in terms of actualized knowledge assemblages (e.g., approaches, theories, or research programs), and not the kinds and movement of territories and codes of knowledge production through which those assemblages are actualized. How can we ensure qualitative diversity and open territoriality in the production of IR knowledge? This article takes preliminary steps in addressing this question by calling for IR as “becoming-rhizomatic.”
Development and validation of high definition phenotype-based mortality prediction in critical care units
Authors: Sun Yao , Kaur Ravneet , Gupta Shubham , Paul Rahul , Das Ritu , Cho Su Jin , Anand Saket , Boutilier Justin J , Saria Suchi , Palma Jonathan , Saluja Satish , McAdams Ryan M , Kaur Avneet , Yadav Gautam , Singh Harpreet
Published: March 2021

Objectives

The objectives of this study are to construct the high definition phenotype (HDP), a novel time-series data structure composed of both primary and derived parameters, using heterogeneous clinical sources and to determine whether different predictive models can utilize the HDP in the neonatal intensive care unit (NICU) to improve neonatal mortality prediction in clinical settings.

Materials and Methods

A total of 49 primary data parameters were collected from July 2018 to May 2020 from eight level-III NICUs. From a total of 1546 patients, 757 patients were found to contain sufficient fixed, intermittent, and continuous data to create HDPs. Two different predictive models utilizing the HDP, one a logistic regression model (LRM) and the other a deep learning long–short-term memory (LSTM) model, were constructed to predict neonatal mortality at multiple time points during the patient hospitalization. The results were compared with previous illness severity scores, including SNAPPE, SNAPPE-II, CRIB, and CRIB-II.

Results

A HDP matrix, including 12 221 536 minutes of patient stay in NICU, was constructed. The LRM model and the LSTM model performed better than existing neonatal illness severity scores in predicting mortality using the area under the receiver operating characteristic curve (AUC) metric. An ablation study showed that utilizing continuous parameters alone results in an AUC score of >80% for both LRM and LSTM, but combining fixed, intermittent, and continuous parameters in the HDP results in scores >85%. The probability of mortality predictive score has recall and precision of 0.88 and 0.77 for the LRM and 0.97 and 0.85 for the LSTM.

Conclusions and Relevance

The HDP data structure supports multiple analytic techniques, including the statistical LRM approach and the machine learning LSTM approach used in this study. LRM and LSTM predictive models of neonatal mortality utilizing the HDP performed better than existing neonatal illness severity scores. Further research is necessary to create HDP–based clinical decision tools to detect the early onset of neonatal morbidities.
Tracing the Roots of Samādhi Burial Practice
Authors: McLaughlin Mark
Published: March 2021

A Hindu samādhi is a shrine that marks the final resting-place of a realised guru’s body and reflects the traditional understanding that the realised sage’s perfected body should not be cremated but rather should be preserved as a localised instantiation of sacred power. While some scholars speculate that the Hindu samādhi shrine tradition is borrowed from the Sufi dargāh (tomb-shrine) tradition, I argue that the Hindu samādhi burial practice has pre-dargāh roots resonant with the Buddhist stūpa and relic worship tradition. This article charts the development of this samādhi burial practice in regard to three important considerations: the act of taking samādhi, burying the body, and marking the burial site. It is this long-established burial practice that eventually blossoms into a full-fledged worship tradition in part by coming into contact with the Sufi dargāh tradition.
Semantic change and knowledge transmission: Some case studies in the distribution of words in ECCO
Authors: Regan John
Published: March 2021

This article attempts to make good on the affordances of lexical co-association to investigate semantic change in the British eighteenth-century corpus, mindful of the theories of knowledge that have been presented in an adumbrated state above. Pulling back to enquire into the whole of the eighteenth-century printed corpus, and designing tools fit for apprehending and making sense of such a large, impersonal, non-individual view, will result in a complementary picture of how knowledge was structured and transmitted in the eighteenth century compared with individualistic or ‘great man’ narratives of the history of ideas. Taking the eighteenth-century corpus as a field of enquiry (even in light of its various well-known limitations and inherent biases) results of course in a virtually total loss of granularity at the level of close reading, and a consequent turn away from individual texts written by individual people. But what replaces this is the ability to reconstitute structures of semantic expression from that time that are unexaminable at the level of the sentence and the paragraph, the chapter, and the book. As will be demonstrated, we may now make visible the printed, common, and possibly ‘public’ or social structures of meaning. This article’s field of enquiry is the vast common printed semantic storehouse, as opposed to what is laid down by single authors in clauses, sentences, and chapters.
Machine learning the fates of dark matter subhaloes: a fuzzy crystal ball
Authors: Petulante Abigail , Berlind Andreas A , Holley-Bockelmann J Kelly , Sinha Manodeep
Published: March 2021

The evolution of a dark matter halo in a dark matter only simulation is governed purely by Newtonian gravity, making a clean testbed to determine what halo properties drive its fate. Using machine learning, we predict the survival, mass loss, final position, and merging time of subhaloes within a cosmological N-body simulation, focusing on what instantaneous initial features of the halo, interaction, and environment matter most. Survival is well predicted, with our model achieving 94.25 per cent out-of-bag accuracy using only three model inputs (redshift, subhalo-to-host-halo mass ratio, and the impact angle of the subhalo into its host) taken at the time immediately before the subhalo enters its host. However, the mass loss, final location, and merging times are much more stochastic processes, with significant errors between true and predicted quantities for much of our sample. Only five inputs (redshift, impact angle, relative velocity, and the masses of the host and subhalo) determine almost all of the subhalo evolution learned by our models. Generally, subhaloes that enter their hosts at a mid-range of redshifts (z = 0.67–0.43) are the most challenging to make predictions for, across all of our final outcomes. Subhalo orbits that come in more perpendicular to the host are easier to predict, except for in the case of predicting disruption, where the opposite appears to be true. We conclude that the detailed evolution of individual subhaloes within N-body simulations is difficult to predict, pointing to a stochasticity in the merging process. We discuss implications for both simulations and observations.
DNA polymerase D temporarily connects primase to the CMG-like helicase before interacting with proliferating cell nuclear antigen
Authors: Oki Keisuke , Yamagami Takeshi , Nagata Mariko , Mayanagi Kouta , Shirai Tsuyoshi , Adachi Naruhiko , Numata Tomoyuki , Ishino Sonoko , Ishino Yoshizumi
Published: March 2021

The eukaryotic replisome is comprised of three family-B DNA polymerases (Polα, δ and ϵ). Polα forms a stable complex with primase to synthesize short RNA-DNA primers, which are subsequently elongated by Polδ and Polϵ in concert with proliferating cell nuclear antigen (PCNA). In some species of archaea, family-D DNA polymerase (PolD) is the only DNA polymerase essential for cell viability, raising the question of how it alone conducts the bulk of DNA synthesis. We used a hyperthermophilic archaeon, Thermococcus kodakarensis, to demonstrate that PolD connects primase to the archaeal replisome before interacting with PCNA. Whereas PolD stably connects primase to GINS, a component of CMG helicase, cryo-EM analysis indicated a highly flexible PolD–primase complex. A conserved hydrophobic motif at the C-terminus of the DP2 subunit of PolD, a PIP (PCNA-Interacting Peptide) motif, was critical for the interaction with primase. The dissociation of primase was induced by DNA-dependent binding of PCNA to PolD. Point mutations in the alternative PIP-motif of DP2 abrogated the molecular switching that converts the archaeal replicase from de novo to processive synthesis mode.
Jonckheere–Terpstra–Kendall-based non-parametric analysis of temporal differential gene expression
Authors: Iuchi Hitoshi , Hamada Michiaki
Published: March 2021

Time-course experiments using parallel sequencers have the potential to uncover gradual changes in cells over time that cannot be observed in a two-point comparison. An essential step in time-series data analysis is the identification of temporal differentially expressed genes (TEGs) under two conditions (e.g. control versus case). Model-based approaches, which are typical TEG detection methods, often set one parameter (e.g. degree or degree of freedom) for one dataset. This approach risks modeling of linearly increasing genes with higher-order functions, or fitting of cyclic gene expression with linear functions, thereby leading to false positives/negatives. Here, we present a Jonckheere–Terpstra–Kendall (JTK)-based non-parametric algorithm for TEG detection. Benchmarks, using simulation data, show that the JTK-based approach outperforms existing methods, especially in long time-series experiments. Additionally, application of JTK in the analysis of time-series RNA-seq data from seven tissue types, across developmental stages in mouse and rat, suggested that the wave pattern contributes to the TEG identification of JTK, not the difference in expression levels. This result suggests that JTK is a suitable algorithm when focusing on expression patterns over time rather than expression levels, such as comparisons between different species. These results show that JTK is an excellent candidate for TEG detection.
Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy
Authors: Caravaca-Fontán Fernando , Díaz-Encarnación Montserrat , Cabello Virginia , Ariceta Gema , Quintana Luis F , Marco Helena , Barros Xoana , Ramos Natalia , Rodríguez-Mendiola Nuria , Cruz Sonia , Fernández-Juárez Gema , Rodríguez Adela , Pérez de José Ana , Rabasco Cristina , Rodado Raquel , Fernández Loreto , Pérez Gómez Vanessa , Ávila Ana , Bravo Luis , Espinosa Natalia , Allende Natalia , Sanchez de la Nieta Maria Dolores , Rodríguez Eva , Olea Teresa , Melgosa Marta , Huerta Ana , Miquel Rosa , Mon Carmen , Fraga Gloria , de Lorenzo Alberto , Draibe Juliana , Cano-Megías Marta , González Fayna , Shabaka Amir , López-Rubio Maria Esperanza , Fenollosa María Ángeles , Martín-Penagos Luis , Da Silva Iara , Alonso Titos Juana , Rodríguez de Córdoba Santiago , Goicoechea de Jorge Elena , Praga Manuel
Published: March 2021

Introduction

The association between a change in proteinuria over time and its impact on kidney prognosis has not been analysed in complement component 3 (C3) glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.

Methods

This was a retrospective, multicentre observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases. Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modelling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure.

Results

The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13–41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (hazard ratio 0.79; 95% confidence interval 0.56–0.97; P < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up.

Conclusions

The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.
BIMG-03. MOLECULAR IMAGING OF GLUCOSE METABOLISM FOR INTRAOPERATIVE FLUORESCENCE GUIDANCE DURING GLIOMA SURGERY
Authors: Belykh Evgenii , Jubran Jubran , George Laeth , Bardonova Liudmila , Healey Deborah , Georges Joseph , Quarles Chad , Eschbacher Jennifer , Mehta Shwetal , Scheck Adrienne , Nakaji Peter , Lawton Michael , Preul Mark
Published: March 2021

PURPOSE

This study evaluated the utility of using molecular imaging of fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) as a discriminatory marker for intraoperative tumor border identification in a mouse glioma model.

PROCEDURES

2-NBDG and were assessed in GL261 and U251 orthotopic tumor bearing mice. Intraoperative fluorescence of 2-NBDG administered topical and intravenous in normal and tumor regions was assessed with operating microscope, handheld confocal laser scanning endomicroscope (CLE) and benchtop confocal laser scanning microscope (LSM). Additionally, 2-NBDG fluorescence in tumors was compared to 5-aminolevulinic acid-induced protoporphyrin IX fluorescence.

RESULTS

Intravenously administered 2-NBDG was detectable in brain tumor and absent in contralateral normal brain parenchyma on wide field operating microscopy imaging. Intraoperative and benchtop CLE showed preferential 2-NBDG accumulation in the cytoplasm of glioma cells (tumor-background ratio of 2.76±0.43). Topically administered 2-NBDG did not create a sufficient tumor-background contrast for white field operating microscopy imaging, or under benchtop LSM (tumor-background ratio 1.42 ± 0.72). However, topical 2-NBDG did create sufficient contrast to evaluate cellular tissue architecture and differentiate tumor cells from normal brain parenchyma. PpIX imaging resulted in a more specific delineation of gross tumor margins than IV or topical 2-NBDG, and a significantly higher tumor-normal brain fluorescence intensity ratio.

CONCLUSION

After intravenous administration, 2-NBDG selectively accumulated in the experimental brain tumors and provided bright contrast under wide field fluorescence imaging with a clinical grade operating microscope. Topical 2-NBDG was able to create a sufficient contrast to differentiate tumor from normal brain cells based on visualization of cellular architecture with CLE. 5-ALA demonstrated superior specificity in outlining tumor margins and significantly higher tumor-background contrast. Given its non-toxicity, using 2-NBDG as a topical molecular marker for noninvasive in vivo intraoperative microscopy is encouraging, and warrants further clinical evaluation.
DDRE-08. NRF2/GLUTATHIONE METABOLISM AS A NOVEL THERAPEUTIC TARGET FOR IDH1-MUTATED GLIOMA
Authors: Liu Yang , Yu Di , Celiku Orieta , Li Aiguo , Larion Mioara , Yang Chunzhang
Published: March 2021

BACKGROUND

IDH1-mutated glioma is a recently defined disease entity with distinctive patterns of tumor cell biology, metabolism, and resistance to therapy. Although IDH1 mutations are highly prevalent in patients with WHO II/III glioma, curative molecular targeting approaches remain unavailable for this disease cluster.

METHODS

In the present study, we investigated the glutathione de novo synthesis pathway through the TCGA patient cohort and patient-derived cell lines with IDH1 mutation. The biologic function of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed by biochemistry and cell biology assays. Finally, NRF2 inhibitors were evaluated in IDH1-mutated cell lines and preclinical models as an experimental therapy.

RESULTS

IDH1 mutant neomorphic activity depletes the cellular pools of enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The limitation of NAD(P) not only affects the anabolic reactions, but also results in oxidative stress and damages on DNA and protein. Further, we showed that the reprogrammed redox landscape results in constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1. NRF2 mediated the transcriptional activation of GCLC, GCLM, and SLC7A11, which not only strengthens the glutathione de novo synthesis, but also relieves the metabolic burden in IDH1-mutated cells. The importance of the glutathione synthesis is further confirmed through COX regression analysis on lower-grade glioma. Blockade of the NRF2/glutathione metabolic pathway synergizes with the elevated intrinsic oxidative stress, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion.

CONCLUSION

We report that the NRF2-guided cytoprotective pathways play pivotal roles in the disease progression of IDH1-mutated glioma. Targeting NRF2 and glutathione metabolism could be novel targeting strategies for IDH1-mutated glioma.
DDRE-09. THERAPEUTIC TARGETING OF PURINE METABOLISM IN DIPG
Authors: Mersich Ian , Dasgupta Biplab
Published: March 2021

Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem malignancy in children with median survival less than 1 year and 5-year overall survival only 2 percent. Little progress has been made in treating this deadly disease due to its inoperable location and treatments aimed at targets defined in adult gliomas. Despite recent advances in genetic characterization of DIPGs there are still no targeted therapies that significantly improve overall survival. We recently generated a metabolic profile for patient-derived DIPG cell lines by integrating an untargeted metabolomics analysis with RNA-sequencing data from the same lines which demonstrated dysregulated purine metabolism in these cells. Furthermore, we have identified putative driver mutations common to DIPG patients as the direct cause for this metabolic alteration. Purine metabolism provides the basic components of nucleotides needed for tumor proliferation and thus considered a high-priority target in cancer treatment. De novo purine biosynthesis (DNPS) is a sequential ten step enzymatic process resulting in the production of inosine monophosphate. The DNPS enzymes co-localize into a metabolon known as the purinosome and our preliminary data demonstrates DIPG cell lines are selectively sensitive to pharmacological and genetic disruption of purinosome formation. Interestingly, antifolate compounds that inhibit DNPS, but do not disrupt purinosome assembly, are cytotoxic to both DIPG cells and normal cell types. Strikingly, cell viability could be rescued by purine supplementation when inhibiting this pathway with antifolates, however inhibition of DNPS by disruption of purinosome assembly could not be rescued. Metabolomics analysis showed DIPGs have a preference for generating GMP over AMP which is exacerbated when purinosome assembly is disrupted. This is likely due to the duel-role of the DNPS enzyme ADSL which is required for AMP production.
DDRE-21. THE FUNCTION OF MITOCHONDRIAL OSMR IN GLIOMA STEM CELL RESPIRATION AND GLIOBLASTOMA PATHOGENESIS
Authors: Jahani-Asl Arezu , Sharanek Ahmad
Published: March 2021

Glioblastoma contains a rare population of self-renewing brain tumor stem cells (BTSCs) which are endowed with properties to proliferate, spur the growth of new tumors, and at the same time, evade ionizing radiation (IR) and chemotherapy. However, the drivers of BTSC resistance to therapy remain unknown. The cytokine receptor for oncostatin M (OSMR) regulates BTSC proliferation and glioblastoma tumorigenesis. We have discovered that OSMR translocates to the mitochondria and regulates oxidative phosphorylation, independent of its role in cell proliferation. Mechanistically, OSMR is targeted to the mitochondrial matrix via the presequence translocase-associated motor complex components, mtHSP70 and TIM44. OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I and promotes mitochondrial respiration. Deletion of OSMR impairs spare respiratory capacity, increases reactive oxygen species, and sensitizes BTSCs to IR-induced cell death. Importantly, suppression of OSMR improves glioblastoma response to IR and prolongs lifespan.
DDRE-23. A COMPREHENSIVE CHARACTERIZATION OF THE GBM LIPIDOME REVEALS A MOLECULARLY-DEFINED SUB-GROUP WITH HEIGHTENED SENSITIVITY TO LIPID PEROXIDATION INDUCED CELL DEATH
Authors: Morrow Danielle , Minami Jenna , Bayley Nicholas , Williams Kevin , Bensinger Steven , Prins Robert , Liau Linda , Cloughesy Timothy , Nathanson David
Published: March 2021

Cancers, including the universally lethal glioblastoma (GBM), have reprogrammed lipid metabolism to fuel tumor growth and promote survival. However, the full extent to which lipid content is altered across molecularly heterogeneous patient tumors has yet to be fully elucidated. Additionally, the molecular alterations responsible for aberrant lipid metabolism, and the potential for identifying new therapeutic opportunities are not fully understood. To systematically investigate the GBM lipidome, we performed integrated transcriptomic, genomic and shotgun lipidomic analysis of an extensive library of molecularly diverse patient-derived GBM tumors across tumor microenvironments both in vivo (n=23) and in vitro (n=30). Using this comprehensive approach, we discovered two GBM sub-groups defined by their combined molecular and lipidomic profile. Triacylglycerides (TAGs) enriched in polyunsaturated fatty acids (PUFAs) were among the most significantly altered lipids between the two groups of GBM tumors. TAGs are the main components of lipid droplets, which have been shown to sequester PUFAs away from membrane phospholipids where their sensitivity to peroxidation leads to cell death. The GBM subgroup with a depletion of PUFA TAGs showed heightened sensitivity to lipid peroxidation both under basal conditions and in response to pro-oxidant compounds in vitro. Our findings suggest a novel association between specific molecular signatures of GBM, lipid metabolism and lipid peroxidation-induced cell death. This relationship may present a new therapeutic opportunity to target reprogrammed lipid metabolism in a molecularly-defined subset of GBMs.
DDRE-31. FEASIBILITY AND BIOLOGIC ACTIVITY OF A KETOGENIC / INTERMITTENT FASTING DIET IN GLIOMA PATIENTS
Authors: Schreck Karisa , Hsu Fang-Chi , Berrington Adam , Henry-Barron Bobbie , Vizthum Diane , Blair Lindsay , Kossoff Eric , Easter Linda , Whitlow Christopher , Cervenka Mackenzie , Barker Peter , Blakeley Jaishri , Strowd Roy
Published: March 2021

BACKGROUND

There has been increasing interest in exploring ketogenic diet therapies (KDT) in patients with glioma given the poor prognosis. The purpose of this single-arm, open label phase 2 study was to rigorously examine the feasibility, safety, systemic biological activity, and cerebral activity of a KDT in patients with glioma.

METHODS

25 patients with biopsy-confirmed WHO Grade 2–4 astrocytoma with stable disease following adjuvant chemotherapy were enrolled in an 8-week GLioma Atkins-based Diet (GLAD). GLAD consisted of 2 fasting days (calories<20% calculated estimated needs) interleaved between 5 modified Atkins diet days (net carbohydrates≤20 gm/day) each week. The primary outcome was dietary adherence by food records. Markers of systemic and cerebral activity included weekly urine ketones, serum insulin, glucose, hemoglobin A1c, IGF-1, and MR spectroscopy at baseline and week 8.

RESULTS

21 patients completed the study. 80% of patients reached ≥40 mg/dL urine acetoacetate during the study. 48% of patients were adherent by food record. The diet was well-tolerated with two grade 3 adverse events (neutropenia, seizure). Measures of systemic activity including hemoglobin A1c, insulin, and fat body mass decreased significantly, while lean body mass increased. MR spectroscopy demonstrated increased ketone concentrations (β-hydroxybutyrate (bHB) and acetone (Ace)) in both lesional and contralateral brain, compared to baseline. Higher total choline (tCho) and glutamine (Gln) levels were observed in lesional as compared to contralateral brain at baseline, and both decreased following intervention. Average ketonuria correlated with cerebral ketones in lesional (tumor) and contralateral brain (bHB Rs0.52, p=0.05). There were no differences in cerebral metabolites in IDH-mutant glioma after controlling for ketonuria.

CONCLUSIONS

The GLAD dietary intervention, while demanding, produced meaningful ketonuria, and significant systemic and cerebral metabolic changes in participants. Participant ketonuria correlated with cerebral ketone concentration and appears to be a better indicator of systemic activity than patient-reported food records.
ETMM-04. AURKA INHIBITION REPROGRAMS METABOLISM AND IS SYNTHETICALLY LETHAL WITH FATTY ACID OXIDATION INHIBITION IN GLIOBLASTOMA MODEL SYSTEMS
Authors: Nguyen Trang , Shu Chang , Shang Enyuan , Mela Angeliki , Humala Nelson , Mahajan Aayushi , Akman Hasan , Quinzii Catarina , Zhang Guoan , Westhof Mike-Andrew , Karpel-Massler Georg , Bruce Jeffrey , Canoll Peter , Siegelin Markus
Published: March 2021

Aurora kinase A (AURKA) has emerged as a viable drug target for glioblastoma (GBM), the most common malignant primary brain tumor in adults with a life expectancy of 12–15 months. However, resistance to therapy remains a critical issue, which partially may be driven by reprogramming of metabolism. By integration of transcriptome, chromatin immunoprecipitation with sequencing (CHIP-seq.), assay for transposase-accessible chromatin with sequencing (ATAC-seq.), proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1A, a master regulator of oxidative metabolism. Silencing of PGC1A reversed AURKAi mediated metabolic reprogramming and sensitized GBM cells to AURKAi driven reduction of cellular viability. Chromatin immunoprecipitation experiments showed binding of c-Myc to the promoter region of PGC1A, which is abrogated by AURKA inhibition and in turn unleashed PGC1A expression. Consistently, ATAC-seq. confirmed higher accessibility of a MYC binding region within the PGC1A promoter, suggesting that MYC acts as a repressor of PGC1A. Combining alisertib with inhibitors of FAO or the electron transport chain exerted substantial synergistic growth inhibition in PDX lines in vitro and extension of overall survival in orthotopic GBM PDX models without induction of toxicity in normal tissue. In summary, these findings support that simultaneous targeting of oxidative energy metabolism and AURKAi might be a potential novel therapy against GBM.
FSMP-07. CYSTATHIONINE-Γ-LYASE DRIVES ANTIOXIDANT DEFENSE IN CYSTEINE-RESTRICTED IDH1 MUTANT ASTROCYTOMAS
Authors: Cano-Galiano Andrés , Oudin Anais , Fack Fred , Allega Maria-Francesca , Sumpton David , Martinez-Garcia Elena , Dittmar Gunnar , Hau Ann-Christin , Herold-Mende Christel , Bjerkvig Rolf , Meiser Johannes , Tardito Saverio , Niclou Simone P
Published: March 2021

Mutations in isocitrate dehydrogenase 1 or 2 (IDH1/2) define glioma subtypes and are considered primary events in gliomagenesis, impacting tumor epigenetics and metabolism. IDH enzymes are crucial for the generation of reducing potential, yet the impact of the mutation on the cellular antioxidant system is not understood. Here, we investigate how glutathione (GSH) levels are maintained in IDH1 mutant gliomas, despite an altered NADPH/NADP balance. We find that IDH1 mutant astrocytomas specifically upregulate cystathionine γ-lyase (CSE), the enzyme responsible for cysteine production upstream of GSH biosynthesis. Genetic and chemical interference with CSE in patient-derived glioma cells carrying the endogenous IDH1 mutation, sensitized tumor cells to cysteine depletion, an effect not observed in IDH1 wild-type gliomas. This correlated with reduced GSH synthesis as shown by in vitro and in vivo serine tracing and led to delayed tumor growth in mice. Thus we show that IDH1 mutant astrocytic gliomas critically rely on NADPH-independent de novo GSH synthesis to maintain the antioxidant defense, which uncovers a novel metabolic vulnerability in this dismal disease.
FSMP-09. FORMATE PROMOTES CANCER CELL INVASION AND METASTASIS VIA CALCIUM SIGNALING
Authors: Delbrouck Catherine , Pozdeev Vitaly I , Oudin Anais , Grzyb Kamil , Neises Laura , Kiweler Nicole , Skupin Alexander , Letellier Elisabeth , Niclou Simone P , Meiser Johannes
Published: March 2021

Serine catabolism via the folate cycle provides formate that is essential for nucleotide synthesis in proliferating cells. In addition to this canonical function to support biomass production in anabolic cells, we have recently demonstrated in vitro and in vivo that formate production in cancer cells is often in excess of the anabolic demand. This excess formate production is characterized by formate overflow and thus, net formate excretion into the tumor microenvironment. Interestingly, we observe increased rates of formate overflow upon different chemical perturbations that induce growth arrest. Thus, stressed cancer cells that encounter growth restriction such as upon chemotherapy, are often characterized by increased formate release rates. We demonstrated that such high formate levels in the extracellular space promote invasion of glioblastoma cells. Using ex vivo brain slice cultures and an orthotopic brain tumor model, we demonstrate that silencing MTHFD1L, the essential enzyme to enable formate overflow, results in decreased invasiveness of the tumor. Embarking from this observation, we investigated the underlying mechanism and now provide evidence that the formate-dependent increase of cell motility is mediated by an activation of Ca2+ signaling. Activation of Ca2+ signaling triggers integrin and matrix metallopeptidase (MMP) responses enabling the invasion process. Targeting either the Ca2+ response or MMP release can suppress the formate dependent increase in invasion. Finally, we tested the effect of formate also in context of breast cancer where we were able to recapitulate our observation of increased invasiveness and, in this case, formate also promoted the metastatic potential. We conclude that excreted formate might serve as a cellular stress signal that represents a promotive trigger to support tumor escape mechanisms.
TBMT-01. HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE MONITORS TERT-INDUCED ELEVATION IN PENTOSE PHOSPHATE PATHWAY FLUX IN BRAIN TUMORS IN VIVO
Authors: Batsios Georgios , Viswanath Pavithra , Taglang Celine , Flavell Robert , Costello Joseph , Pieper Russell O , Larson Peder , Ronen Sabrina
Published: March 2021

Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is an attractive therapeutic target for gliomas. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway (PPP) in low grade gliomas expressing TERT. Hyperpolarized δ-[1-13C]gluconolactone has been used to detect flux via the PPP by monitoring its conversion to 6-phospho-[1-13C]gluconate (6PG) in isolated perfused liver. The goal of our study was to evaluate whether hyperpolarized δ-[1-13C]gluconolactone can be used to monitor elevated PPP flux induced by TERT expression in low grade gliomas, thereby providing a non-invasive method of assessing TERT expression in vivo. Immortalized normal human astrocytes without (NHApre) and with TERT expression (NHApost) were used in cell bioreactor experiments. In vivo experiment with rats bearing orthotopic NHApost or patient-derived low-grade oligodendroglioma (SF10417) tumors were contacted. Dynamic 13C MR spectra were acquired at 14T (cells) or 3T (rats) following injection of hyperpolarized δ-[1-13C]gluconolactone. NHApost cells showed significantly higher flux through the PPP compared to NHApre. This finding was in agreement with previous results indicating that TERT expression elevates PPP flux. In all rats δ-[1-13C]gluconolactone and 6PG were observed indicating that δ-[1-13C]gluconolactone crosses the blood-brain barrier and is rapidly metabolized. Furthermore, both models presented homogeneous distribution of δ-[1-13C]gluconolactone in the brain and higher ratio of 6PG-to-δ-[1-13C]gluconolactone in the tumor area. In summary we show in vivo that hyperpolarized δ-[1-13C]gluconolactone metabolism to 6-phospho-[1-13C]gluconate is significantly higher in tumor compared to contralateral normal brain in TERT-expressing genetically-engineered and patient-derived low-grade oligodendrogliomas. Due to its fundamental role in tumor proliferation, TERT is both a tumor biomarker and a therapeutic target. Monitoring HP δ-[1-13C]gluconolactone metabolism, therefore, has the potential to inform on tumor burden and response to therapy in the clinic.
Article 36 TFEU
Authors: Klamert Marcus , Moustakali Maria , Tomkin Jonathan
Published: March 2021

Article 30 EC The provisions of Articles 34 and 35 shall not preclude prohibitions or restrictions on imports, exports or goods in transit justified on grounds of public morality, public policy or public security; the protection of health and life of humans, animals or plants; the protection of national treasures possessing artistic, historic or archaeological value; or the protection of industrial and commercial property. Such prohibitions or restrictions shall not, however, constitute a means of arbitrary discrimination or a disguised restriction on trade between Member States.
The Politics of Economic and Monetary Union
Authors: Jones Erik
Published: March 2021

The purpose of this chapter is to explain why so many experts were surprised by the politics that surrounded Europe’s economic and monetary union (EMU) both during and after the financial crisis that dominated the first two decades of the twenty-first century. This question is important because it has changed fundamentally the relationship between the euro as a single currency and the European Union (EU) as a larger project. Before the crisis, it was fair to say that the euro existed to serve the EU, as one of the many important building blocks in the wider project of European integration. During and after the crisis, it became more common to assert that an end of the euro would entail the end of the European project. That inversion of priorities was unexpected–and it explains, more than anything else, why the politics of economic and monetary union can no longer be ignored.