bluuebunny/crossref_metadata_2025_split huggingface dataset:
OMRT-13. Delivery of Ubidecarenone (BPM 31510) to mitochondria effectuates metabolic reprogramming and redox activated apoptosis in Glioblastoma
Authors: Sarangarajan Rangaprasad , Nagpal Seema , Sun Jiaxin , Diers Anne , Shah Punit , Tolstikov Vladimir , Miller Gregory , Vishnudas Vivek , Gesta Stephane , Kiebish Michael , Granger Elder , Narain Niven , Recht Lawrence 
Published: July 2021

Abstract
GBM is a highly metabolic cancer phenotype that confers sustained growth and evasion of cell death mechanism via mitochondrial dysregulation. Efforts to re-engage mitochondrial metabolism via anti-cancer therapeutics has not been successful. BPM 31510 is a CoQ10-lipid conjugate nanodispersion for delivery of CoQ10 preferentially to mitochondria of human cells. BPM has demonstrated anti-cancer effects across multiple cancers, without adversely affecting normal tissue. The anti-cancer mechanism of CoQ10 was elucidated by Interrogative Biology, a data-driven approach to understand disease biology, identify targets and biomarkers of disease. Specifically, oncogenic and corresponding non-disease normal cell-based models (e.g. breast, liver, prostate, kidney) were subjected to cancer specific perturbations (e.g. hypoxia, metabolic stress). Comprehensive multi-omic (genome, proteome, lipidome, metabolome) and functional endpoints data were profiled. A Bayesian artificial intelligence analytics was used to generate network models in a data driven manner to identify BPM 31510 mechanism (i.e. shift in oxygen and glucose utilization, increase in oxidative stress and apoptosis in cancer cells). BPM 31510 re-capitulated its anti-cancer effect in GBM models, including LN-229 xenograft and C6 glioma allograft, both as monotherapy and in combination with temozolomide (TMZ)/radiation. The platform generated network maps from longitudinal pharmacodynamic samples (20 samples/28 days) collected from GBM patient refractory to TMZ/radiation/bevacizumab (Phase 1, NCT03020602, Stanford) identified alterations in intermediary metabolism as drivers of Progression Free Survival (PFS) and Overall Survival (OS) in response to BPM 31510 treatment. The platform supports the ongoing Phase 2 trial of adjuvant BPM 31510 plus TMZ/radiation in newly diagnosed GBM patients and potential accelerated approval.
OTEH-2. High-dimensional analysis of spatial immune cell heterogeneity in glioblastoma reveals differences between contrast-enhancing and non-contrast-enhancing tumor rims
Authors: Watson Dionysios C , Bayik Defne , Grabowski Matthew , Ahluwalia Manmeet , Mohammadi Alireza , Lathia Justin D 
Published: July 2021

Abstract

Background
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. GBM remains an incurable disease, with a median survival ~20 months. Complex intercellular interactions within the tumor microenvironment and spatial heterogeneity have challenged and impeded therapeutic efficacy. The non-contrast-enhancing (by T1-weighted MRI) rim of GBM is not always safely resectable and represents a major source of recurrence. We hypothesized that differential immune infiltration is an underlying factor of spatial heterogeneity in GBM, particularly in the non-contrast-enhancing tumor rim.

Methods
Five patients with newly diagnosed GBM (ages 53–84) were recruited to a device feasibility study (NCT04545177) utilizing an intraoperative high-resolution MRI-based navigation system coupled with the NICO Myriad (a non-ablative semi-automated resection tool) and a coupled automated biological Tissue Preservation System (NICO APS) to sample spatially mapped regions of tumors in a reproducible and minimally destructive manner. We obtained brain tumor tissue from: (a) tumor core, (b) contrast-enhancing tumor rim and (c) non-contrast-enhancing tumor rim. Downstream processing consisted of digestion of tumor tissue (Miltenyi human tumor digestion kit) for subsequent single-cell isolation, viability assessment and immediate staining for multiparametric flow cytometry for immune profiling.

Results
Viability varied across sampled regions (median 85%, range 52–100%). With the exception of 1 sample, viability was &gt;70% in all specimens. High-dimensional analysis with 26 marker flow cytometry revealed spatial heterogeneity in the frequency of myeloid-derived suppressor cell subsets, regulatory T cells, CD8+ T cells, as well as expression of T cell activation and exhaustion markers.

Conclusions
Semi-automated, spatially mapped intraoperative sampling of GBM with high viability of specimens is feasible and reproducible with the NICO Myriad and APS devices. High-dimensional analysis of immune cells in the GBM microenvironment captured the spatial heterogeneity of GBM. Future studies will expand on these observations by analyzing more patient specimens in combination with multiple omics assays.
OTME-11. Characterizing the immunologic context of pediatric brain tumors
Authors: Galvin Robert , Maeser Danielle , Gruener Robert , Huang R Stephanie 
Published: July 2021

Abstract
Therapy for pediatric central nervous system (CNS) malignancies can be toxic, and outcomes are suboptimal. Immunotherapy holds promise as a therapeutic avenue, but the poorly understood microenvironment limits its application. The Children’s Brain Tumor Network (CBTN) released the Pediatric Brain Tumor Atlas, containing expression profiles of nearly 700 primary CNS tumors. To study the immune microenvironment, a classification from The Cancer Genome Atlas project is applied. High-grade lesions are predominantly lymphocyte deplete (C4, 81%) or immunologically quiet (C5, 11%). Low-grade lesions are more mixed with 46% C4, 21% C5, and a higher proportion of inflammatory subtype (C3, 31%). For survival parameters, adjusting for tumor grade and extent of resection, the hazard ratio is 2.2 (0.78 – 6.3), p = 0.13) and 2.4 (0.6 – 10.0, p = 0.24) for C4 and C5, respectively. With no events among low-grade tumors, progression-free survival will be another useful metric and released by CBTN in April. Deconvolution of immune cell gene signatures among C4 samples reveals decreased abundance of T cells (OR 0.26, 0.1 – 0.5) yet increasing T-cell abundance is associated with decreased survival time in high-grade samples (HR 3.7, 1.4 – 10.1). Additionally, there are increased macrophage and decreased microglia signatures among high-grade samples and the C4 and C5 subtypes. It is hypothesized that expression of inhibitory immunomodulators contributes to a pro-tumorigenic microenvironment and represent potential therapeutic targets. In lieu of normal tissue in the data set, differential gene expression experiments between disease states reveals upregulated immunomodulators. Conventional immunomodulators, e.g. PDL1 and CTLA4, are expressed in low-grade samples with C3 subtype, which is abundant in craniopharyngioma. Alternative inhibitory immunomodulators, e.g. KDM1A, EZH2, CD276, are significantly expressed in high-grade samples including diffuse midline glioma. Overall, our analysis contributes to the understanding of the immune microenvironment and identifies potential mechanisms of immune escape among pediatric CNS tumors.
OTME-12. Role of the transsulfuration pathway in glioblastoma invasion
Authors: Garcia Joseph H , Jain Saket , Akins Erin A , Spatz Jordan M , Beniwal Angad S , Gill Sabraj A , Wolfe Kayla J , Cha Junghwa , Cha Junghwa , Kumar Sanjay , Aghi Manish K 
Published: July 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 the tumor’s cellular metabolism. Though studies have investigated links between GBM’s metabolic profile and its invasive capability, these studies have had two notable limitations. First, while infiltrating GBM cells extending beyond the tumor edge utilize adaptive cellular machinery to overcome stressors in their microenvironment, these cells at the invasive front have not been the ones sampled in invasive studies, which have used cell lines or banked tumor 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 has developed two parallel approaches: acquisition of site-directed biopsies from patient GBMs to define regional heterogeneity in invasiveness, and engineering of 3D platforms to study invasion in vitro. Through utilization of these platforms, and by taking advantage of the system-wide, unbiased screens of metabolite profile and gene expression available, our team looks to identify targetable metabolic factors which drive cellular invasion in GBM. Untargeted metabolomics revealed cystathionine to be selectively enriched in the invasive tumor front of both site directed biopsies (fold change 5.8), and 3D organoid models (fold change 14.2). RNA sequencing revealed 7/30(23%) metabolic genes upregulated in the invasive tumor front were involved in cysteine or glutathione metabolism. These results highlight a clear role of the transsulfuration pathway in GBM invasion that our team looks to investigate with further targeted assays.
OTME-22. Bioinformatic evaluation of ECM molecules and angiogenic associate genes in diffuse midline glioma (DMG): mapping the tumour microenvironment
Authors: Kozhushko Nikita , Jedrysik Malwina , Fillmore Helen 
Published: July 2021

Abstract
Paediatric Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating cancer of an extremely aggressive nature, located in the pontine area of the brain. DIPG primarily affects children, with the average age of diagnosis between 6 and 7 years. Unfortunately, the outlook and overall survival remains bleak. While there has been impressive progress in identifying genes that are central to and drive DIPG growth; there remains several gaps in documenting the DIPG microenvironment landscape. The focus of this study is to begin to examine mRNA expression of genes associated with blood vessel development, angiogenesis, and extracellular matrix molecules (ECM) in normal brain development and DIPG by utilizing publicly available genomic datasets. In-depth bioinformatics from GSE26576 dataset included differential expression and gene ontology (GO) with KEGG pathway analyses using Gene Expression Omnibus (GEO) and DAVID, which have revealed a number of significantly upregulated genes that may affect DIPG angiogenic processes (p&lt;0.05). 38 of such genes from 9 different GO terms were then included in a protein-to-protein interaction network that revealed a surprising connection between MMP16, CSPG4 and COL11A1. Subsequently, using R2 genomic visualisation platform from publicly available single cell RNAseq data we showcased the difference in their individual expression based on the molecular subtypes of DIPG histone 3 (H3) mutation (K27M, wild type and G34R) with a strong statistical significance (p&lt;0.05). Interestingly, during normal paediatric development such genes showed consistent expression, suggesting their potential complications in DIPG angiogenesis. Overall, this bioinformatic approach has led to the identification of a set of interacting genes that will inform our in vitro and in vivo studies. This information will add to the documentation of the host/tumour microenvironment landscape and our plan is to continue to explore this area to map the spatial and temporal expression of these genes.
Cost-Effectiveness of Amphotericin B Deoxycholate Versus Itraconazole for Induction Therapy of Talaromycosis in Human Immunodeficiency Virus–Infected Adults in Vietnam
Authors: Buchanan James , Altunkaya James , Van Kinh Nguyen , Van Vinh Chau Nguyen , Trieu Ly Vo , Thi Thanh Thuy Pham , Hai Vinh Vu , Thi Hong Hanh Doan , Thuy Hang Nguyen , Phuong Thuy Tran , van Doorn Rogier , Thwaites Guy , Gray Alastair , Le Thuy 
Published: July 2021

Abstract

Background
Talaromycosis (penicilliosis) is an invasive fungal infection and a major cause of human immunodeficiency virus (HIV)–related deaths in Southeast Asia. Guidelines recommend induction therapy with amphotericin B deoxycholate; however, treatment with itraconazole has fewer toxic effects, is easier to administer, and is less expensive. Our recent randomized controlled trial in Vietnam found that amphotericin B was superior to itraconazole with respect to 6-month mortality. We undertook an economic evaluation alongside this trial to determine whether the more effective treatment is cost-effective.

Methods
Resource use, direct and indirect costs, and health and quality-of-life outcomes (measured using quality-adjusted life-years [QALYs]) were evaluated for 405 trial participants from 2012 to 2016. Both a Vietnamese health service and a broader societal costing perspective were considered. Mean costs and QALYs were combined to calculate the within-trial cost-effectiveness of amphotericin vs itraconazole from both perspectives.

Results
From a Vietnamese health service perspective, amphotericin increases costs but improves health outcomes compared to itraconazole, at a cost of $3013/QALY gained. The probability that amphotericin is cost-effective at a conventional (World Health Organization CHOICE) threshold of value for money is 46%. From a societal perspective, amphotericin is cost-reducing and improves outcomes compared to itraconazole, and is likely to be a cost-effective strategy at any value for money threshold greater than $0.

Conclusions
Our analysis indicates that induction therapy with amphotericin is a cost-effective treatment strategy for HIV-infected adults diagnosed with talaromycosis in Vietnam. These results provide the evidence base for health care providers and policy makers to improve access to and use of amphotericin.
Autism and the Right to a Hypersensitivity-Friendly Workspace
Authors: de Vries Bouke 
Published: July 2021

AbstractMany individuals on the autism spectrum are hypersensitive to certain sensory stimuli. For this group, as well as for non-autistic individuals with sensory processing disorders, being exposed to e.g. fluorescent lights, perfume odours, and various sounds and noises can be real torment. In this article, I consider the normative implications of such offence for the design of office spaces, which is a topic that has not received any attention from philosophers. After identifying different ways in which the senses of hypersensitive workers might be protected within these spaces, I show that many of such accommodations can be made at reasonable cost, before arguing that doing so ought to be a legal requirement.
‘Take the Pill, It Is Only Fair’! Contributory Fairness as an Answer to Rose’s Prevention Paradox
Authors: Zameska Jay A 
Published: July 2021

Abstract
One proposal to significantly reduce cardiovascular disease is the idea of administering a ‘polypill’—a combination of drugs that reduce the risk of heart disease and carry few side effects—to everyone over the age of 55. Despite their promise, population strategies like the polypill have not been well-accepted. In this article, I defend the polypill (and consequently, other similar population strategies) by appealing to fairness. The argument focuses on the need to fairly distribute the costs to individuals. While the fact that population strategies like the polypill impose minor costs on everyone has primarily been used to criticize such strategies, I argue that it gives us a reason to support them. I argue that implementing a population strategy with the polypill contributes to the public good of ‘health system capacity’. I then explain that public goods have widely accepted obligations: they carry an obligation to fairly distribute the costs of the goods and prevent free-riding. Thus, we have at least one pro tanto moral reason to implement the polypill. As such, this article challenges the current literature on the topic, which has largely held adopting population strategies like the polypill to be unjustifiable.
Development of convolutional neural networks for an electron-tracking Compton camera
Authors: Ikeda Tomonori , Takada Atsushi , Abe Mitsuru , Yoshikawa Kei , Tsuda Masaya , Ogio Shingo , Sonoda Shinya , Mizumura Yoshitaka , Yoshida Yura , Tanimori Toru 
Published: July 2021

Abstract
The Electron-Tracking Compton Camera (ETCC), which is a complete Compton camera that tracks Compton scattering electrons with a gas micro time projection chamber, is expected to open up MeV gamma-ray astronomy. The technical challenge for achieving several degrees of the point-spread function is precise determination of the electron recoil direction and the scattering position from track images. We attempted to reconstruct these parameters using convolutional neural networks. Two network models were designed to predict the recoil direction and the scattering position. These models marked 41$^\circ$ of angular resolution and 2.1 mm of position resolution for 75 keV electron simulation data in argon-based gas at 2 atm pressure. In addition, the point-spread function of the ETCC was improved to 15$^\circ$ from 22$^\circ$ for experimental data from a 662 keV gamma-ray source. The performance greatly surpassed that using traditional analysis.
National Blockchain Laws as a Threat to Capital Markets Integration
Authors: Lehmann Matthias 
Published: July 2021

Abstract
Various states have started providing private law frameworks for blockchain transfers and crypto assets. France and Liechtenstein have adopted the first acts, while a commission of the British government sees no difficulties in extending property protection under the common law to crypto assets. In the USA, an amendment to the Uniform Commercial Code has been suggested, which has not stopped some states going their own, different way. The aim in all cases is to promote the use of modern distributed ledger technology and enhance investor protection. While these initiatives will increase legal certainty, they differ significantly. This has an important downside: there is a strong risk that the blockchain will be made subject to diverging legal rules. Similar to the world of intermediated securities, various national laws will need to be consulted to determine the rights and privileges of investors. This may increase transaction costs, thwart interoperability, and produce thorny conflict-of-laws problems. Markets risk being fragmented into national segments, with an inevitable diminution of their depth and liquidity. As a remedy, this article suggests developing uniform rules for the blockchain. Before national legislators and judges once again divide the world through idiosyncratic rules, the private law of crypto assets should be harmonized to the highest degree possible. Uniform rules should ideally be forged at the global level, by fora like the International Institute for the Unification of Private Law (Unidroit), the United Nations Commission on International Trade Law (UNCITRAL), and the Hague Conference on Private International Law. In the absence of worldwide rules, uniformization of private law should take place at the regional level—for instance, by the European Union. The article makes specific suggestions as to how this can be achieved and what the content of those rules should be.
Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool
Authors: O’Toole Áine , Scher Emily , Underwood Anthony , Jackson Ben , Hill Verity , McCrone John T , Colquhoun Rachel , Ruis Chris , Abu-Dahab Khalil , Taylor Ben , Yeats Corin , du Plessis Louis , Maloney Daniel , Medd Nathan , Attwood Stephen W , Aanensen David M , Holmes Edward C , Pybus Oliver G , Rambaut Andrew 
Published: July 2021

Abstract
The response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the ‘real-time’ generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic’s transmission lineages.
Noble gases and neuroprotection: summary of current evidence
Authors: Höllig Anke , Coburn Mark 
Published: July 2021

Purpose of review
To summarize the current data on neuroprotection derived by noble gas treatment focusing on xenon and argon.

Recent findings
Both xenon and argon have demonstrated neuroprotective properties in an array of disease models. However, current data for argon after traumatic brain injury (TBI) is conflicting. Recent human data is only available for xenon showing some beneficial aspects (fewer adverse events) but no effect on outcomes, such as incidence of postoperative delirium.

Summary
Promising results are available for neuroprotection derived by noble gas treatment. Results for xenon are more consistent than those for argon. The mechanism of action of xenon (noncompetitive NMDA-receptor inhibition) is also better understood compared with that of argon. The evidence for argon's neuroprotective actions (particularly after TBI) remains uncertain.
Five-Year Longitudinal Cohort Study Determines the Critical Intervals for Periodic Audiometric Testing Based on 5070 Tests of Metallurgical Workers Exposed and Nonexposed to Noise
Authors: Silva Vagner Antonio Rodrigues , Guimarães Alexandre Caixeta , Lavinsky Joel , Pauna Henrique Furlan , Duarte Alexandre Scalli Mathias , Castilho Arthur Menino , Chone Carlos Takahiro , Crespo Agrício Nubiato 
Published: July 2021

Objectives:
To compare the progression of 3-, 4-, and 6-kHz thresholds (pure-tone average) over 5 years and determine the most critical period for occupational risk among workers exposed and nonexposed to noise.

Design:
Metallurgical workers were divided into 2 groups: noise-exposed and non–noise-exposed groups. The 6 initial audiometric tests of each worker were analyzed as baseline test and annual tests 1 to 5.

Results:
A total of 845 workers were included, 748 in the noise-exposed group and 97 in the non–noise-exposed group, resulting in 5070 tests analyzed. The nonexposed group showed no significant difference in the mean pure-tone averages between any of the annual tests in either ear. In the exposed group, a significant difference was observed in mean pure-tone averages between baseline and Test1 (p = 0.001 right ear; p = 0.001 left ear), between Test3 and Test4 (p = 0.002 right ear; p = 0.005 left ear), and between Test4 and Test5 (p = 0.003 right ear; p = 0.001 left ear). There was no difference between Test1 and Test2 or between Test2 and Test3 in either ear.

Conclusions:
The progression of pure-tone averages at 3, 4, and 6 kHz differed between workers exposed and nonexposed to noise. Noise-exposed workers had a significant progressive worsening of audiometric thresholds after 3 years of employment. This study identified, in an unprecedented way, two critical periods of noise exposure: in the first year and after the third year of employment in a noisy environment.