bluuebunny/crossref_metadata_2025_split huggingface dataset:
TBIO-01. SEX DIFFERENCES IN REDOX STATE UNDERLIE GLUTAMINE DEPENDENCY IN MALE GLIOBLASTOMA
Authors: Sponagel Jasmin , Zhang Shanshan , Chinnaiyan Prakash , Rubin Joshua , Ippolito Joseph 
Published: December 2020

Abstract
Glioblastoma (GBM) is an aggressive brain tumor in children and adults. It occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that males exhibit a significantly higher abundance of amino acid metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Furthermore, we found that male GBM cell cultures are significantly more sensitive to amino acid deprivation, which was almost entirely driven by amino acids involved in the synthesis of the antioxidant glutathione. Glutaminase 1 (GLS1) mediates the conversion from glutamine to glutamate, a crucial component of glutathione. We found that male GBM cells exhibited higher levels of GLS1, suggesting they are more dependent on glutamate. Indeed, we found that male GBM cells are more sensitive to pharmacological GLS1 inhibition with the clinical inhibitor CB-839. This correlated with significantly increased reactive oxygen species (ROS) in males compared to females. We further confirmed sex differences in redox state through pharmacological depletion of glutathione that resulted in a significant increase in ROS and cell death in male GBM. Together, these data indicate that male GBM cells are more dependent on glutamine to regulate ROS levels. This reveals novel sex-specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.
TBIO-02. IMMUNE PROFILING OF RARE EMBRYONAL BRAIN TUMORS REVEAL EVIDENCE OF DYSREGULATED INTERFERON SIGNALLING AS A POTENTIAL DETERMINANT OF IMMUNOLOGICAL HETEROGENEITY
Authors: Popovski Dean , Yao Fupan , Bondoc Andrew , Al-Karmi Salma , Ho Ben , Lindsay Holly , Li Xiao-Nan , Rutka James , Huang Annie 
Published: December 2020

Abstract
Embryonal brain tumors (EBTs) remain the most common malignant pediatric brain tumors. Despite recent advances and improved understanding of the molecular biology of EBTs, clinical outcomes remain poor for rare EBTs. Previous large-scale genomic studies of rare EBTs have shed light on distinct genomic, transcriptomic and epigenomic profiles. Interestingly, these studies have revealed prominent tumor heterogeneity that provides opportunity to develop novel treatment strategies to improve patient outcomes. To examine the tumor microenvironment and identify tumor- specific biological dependencies, we performed deconvolution analysis of bulk gene expression (171 RNA-seq, 236 microarrays) and 586 methylation arrays, which revealed significant intra and inter-tumoral heterogeneity and implicated interferon (IFN)-mediated signalling as a determinant of a distinct immunological profile in rare EBTs. To further elucidate the importance of IFN signalling, we performed scRNA-seq on 20 primary samples, which provided evidence of a spectrum of IFN-immunological responses that vary from immunosuppressive to immunologically exhaustive that occur in a host dependent manner. To further validate our findings, we utilised a genetically engineered murine model of Atypical Teratoid Rhabdoid Tumor and primary xenografts in humanised mice to corroborate our in-silico profiles in vivo. Through amalgamation of our in-silico data with our in vivo data, we have identified evidence that dysregulated IFN responses represent a core element of the immunological heterogeneity present within subsets of rare EBTs. An improved understanding of the immune milieu in rare EBTs will provide avenues to develop specific onco-immune targets to address this clinical need.
TBIO-09. IN SILICO ANALYSIS IDENTIFIES A PUTATIVE CELL-OF-ORIGIN FOR BRAF FUSION-POSITIVE CEREBELLAR PILOCYTIC ASTROCYTOMA
Authors: Younes Subhi Talal 
Published: December 2020

Abstract
Childhood cancers are increasingly recognized as disorders of cellular development. This study sought to identify the cellular and developmental origins of cerebellar pilocytic astrocytoma, the most common brain tumor of childhood. By leveraging publicly available gene expression data from such tumors and controlling for driver mutations, a set of eight known neuro-developmental genes were identified as being upregulated in cerebellar pilocytic astrocytoma. Mapping those genes onto mouse neuro-developmental atlases identified significant overlap in their expression within the ventricular zone of the cerebellar anlage. Further analysis with a single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at the division point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor cells and their progeny exhibited evidence of MAPK pathway activation, the paradigmatic oncogenic cascade known to be active in cerebellar pilocytic astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories as those found in mice. Taken together, these data suggest this population of ventricular zone progenitor cells as the cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.
TBIO-21. Lnc-TALC PROMOTES O6-METHYLGUANINE-DNA METHYLTRANSFERASE EXPRESSION VIA REGULATING THE C-MET PATHWAY BY COMPETITIVELY BINDING WITH miR-20b-3p
Authors: Wu Pengfei , Cai Jinquan , Chen Qun 
Published: December 2020

Abstract
Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.
TBIO-26. NON-CANONICAL OPEN READING FRAMES ENCODE FUNCTIONAL PROTEINS ESSENTIAL FOR CANCER CELL SURVIVAL
Authors: Prensner John , Enache Oana , Luria Victor , Krug Karsten , Clauser Karl , Dempster Joshua , Karger Amir , Wang Li , Stumbraite Karolina , Wang Vickie , Botta Ginevra , Lyons Nicholas , Goodale Amy , Kalani Zohra , Fritchman Briana , Brown Adam , Alan Douglas , Green Thomas , Yang Xiaoping , Jaffe Jacob , Roth Jennifer , Piccioni Federica , Kirschner Marc , Ji Zhe , Root David , Golub Todd 
Published: December 2020

Abstract
The brain is the foremost non-gonadal tissue for expression of non-coding RNAs of unclear function. Yet, whether such transcripts are truly non-coding or rather the source of non-canonical protein translation is unknown. Here, we used functional genomic screens to establish the cellular bioactivity of non-canonical proteins located in putative non-coding RNAs or untranslated regions of protein-coding genes. We experimentally interrogated 553 open reading frames (ORFs) identified by ribosome profiling for three major phenotypes: 257 (46%) demonstrated protein translation when ectopically expressed in HEK293T cells, 401 (73%) induced gene expression changes following ectopic expression across 4 cancer cell types, and 57 (10%) induced a viability defect when the endogenous ORF was knocked out using CRISPR/Cas9 in 8 human cancer cell lines. CRISPR tiling and start codon mutagenesis indicated that the biological impact of these non-canonical ORFs required their translation as opposed to RNA-mediated effects. We functionally characterized one of these ORFs, G029442—renamed GREP1 (Glycine-Rich Extracellular Protein-1)—as a cancer-implicated gene with high expression in multiple cancer types, such as gliomas. GREP1 knockout in &gt;200 cancer cell lines reduced cell viability in multiple cancer types, including glioblastoma, in a cell-autonomous manner and produced cell cycle arrest via single-cell RNA sequencing. Analysis of the secretome of GREP1-expressing cells showed increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth inhibitory effect of GREP1 knock-out. Taken together, these experiments suggest that the non-canonical ORFeome is surprisingly rich in biologically active proteins and potential cancer therapeutic targets deserving of further study.
THER-04. IS THERE A ROLE FOR CANNABIDIOL IN THE TREATMENT OF CHILDHOOD BRAIN TUMOURS?
Authors: Lockwood George , Hatfield Amelia , Mabrouk Mohamed , O’Sullivan Saoirse E , Grundy Richard G , Storer Lisa C D 
Published: December 2020

Abstract
Brain tumours are the leading cause of cancer related death in children with limited treatment options and high recurrence rates. Recent evidence suggests there may be anti-tumoral properties of cannabinoids, and of cannabidiol (CBD) in particular. We evaluated the effect of CBD on paediatric brain tumour cell lines in 2D and 3D spheroids; pHGG (SF188), ependymoma (BxD-1425EPN) and human astrocytes. At the CBD EC50 concentration, astrocytic cell death was insignificant. 3D spheroids decreased in size by approximately 20% when cultured in CBD compared to cells only after 5-day exposure. Cell death increased with time after a single dose of CBD. Western Blot showed an increase in Lc3b expression (autophagy) after 24 hours incubation (early cell death) with CBD in both BxD-1425EPN and SF188 with PARP expression (apoptosis) increased after 5 days incubation (late cell death). Cell cycle analysis showed a decrease of cells in G1 and no change in G2 indicating cell cycle arrest. In hypoxia, SF188 and BxD-1425EPN cells showed decreased cell death after 24 hours and 5 days when compared to normoxia and an EC50 within acceptable limits could not be achieved. SF188 cells pre-treated with receptor antagonists indicate that CBD was not acting through CB1, CB2, GPR18, PPARα or PPARγ receptors but may act as a partial agonist of the TRPV1 and 5-HT1A receptors and a full agonist of the GPR55 receptor (resazurin assay). This provides evidence that CBD is effective at killing paediatric brain tumour cells and does not have a significant effect on normal astrocytes.
THER-05. GENETICALLY STABLE POLIOVIRUS VECTOR CARRYING H3.3K27M ANTIGEN FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA BY INTRAMUSCULAR INJECTION
Authors: Mosaheb Mubeen , Landi Daniel , Dobrikova Elena , Brown Michael , Yang Yuanfan , Cable Jana , Okada Hideho , Nair Smita , Bigner Darell , Ashley David , Gromeier Matthias 
Published: December 2020

Abstract

BACKGROUND
H3 K27M-mutant diffuse midline glioma (DMG) is invariably lethal. Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses, in particular, are uniquely tropic for dendritic cells (DC) and potently activate DC, inducing Th1-dominant cytokine profiles, CD8 T cell immunity, and enhanced epitope presentation. Thus, poliovirus is ideally suited for vectored delivery of signature tumor neoantigens, e.g. the H3 K27M feature of DMG. However, poliovirus vector design is inherently limited by genetic instability and the underlying neuropathogenicity of poliovirus.

METHODS
We created a genetically stable, polio:rhinovirus chimera vector devoid of neuropathogenicity and modified for stable expression of the HLA-A2 restricted H3.3 K27M antigen (RIPO (H3.3)).

RESULTS
RIPO(H3.3) infects, activates, and induces H3.3K27M antigen presentation in DCs in vitro. Given intramuscularly in vivo, RIPO(H3.3) recruits and activates DCs with Th1-dominant cytokine profiles, efficiently primes H3.3K27M-specific CD8 T cells, induces antigen-specific CD8 T cell migration to the tumor site, delays tumor growth, and enhances survival in murine tumor models.

CONCLUSION
This novel approach leverages the unique ability of polioviruses to activate DCs while simultaneously introducing the H3.3 K27M antigen. In this way, DCs are activated optimally in situ, while being simultaneously infected to express/present tumor antigen. RIPO(H3.3), given by intramuscular injection, will be evaluated in a clinical trial for children with H3 K27M-mutant diffuse midline glioma.
THER-09. ONCOLYTIC ADENOVIRUS, DNX-2401, FOR NAIVE DIFFUSE INTRINSIC PONTINE GLIOMAS: A PHASE I CLINICAL TRIAL
Authors: Iñigo-Marco Ignacio , Gonzalez-Huarriz Marisol , García-Moure Marc , Tamayo Ibon , Hervas Sandra , Hernandez Ruben , Buñales Maria , DeAndrea Carlos , Villalba Maria , Jones Chris , MacKay Alan , Hulleman Esther , Van der Lugt Jasper , Aldave Guillermo , Lopez-Ibor Blanca , Patiño-Garcia Ana , Diez-Valle Ricardo , Fueyo Juan , Gomez-Manzano Candelaria , de Larraya Jaime Gallego Perez , Tejada Sonia , Alonso Marta M 
Published: December 2020

Abstract
The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in newly diagnosed DIPG patients (NCT03178032) followed by radiotherapy. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with 1x1010vp and given the lack of toxicity we escalated to 5x1010vp. The procedure was well tolerated and reduced tumor volume was demonstrated in all patients after combined treatment (virus + radiotherapy). We performed molecular studies (RNAseq and the Oncomine Childhood Research Panel from Thermo Fisher). The immune cell composition of the biopsies pre-virus injection was assessed using multiplexed quantitative immunofluorescence. T cells were hardly detectable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with the virus. We also measured pre and post treatment neutralizing antibodies and their relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). In summary, the virus has shown safety and efficacy in some patients. The information obtained in this clinical study would aid understanding the response of DIPG patients to viral therapies and, therefore, to better tailor this strategy to improve the survival of these patients.
Regulation of Root Nutrient Transporters by CIPK23: ‘One Kinase to Rule Them All’
Authors: Ródenas Reyes , Vert Grégory 
Published: December 2020

Abstract
Protein kinases constitute essential regulatory components in the majority of cellular processes in eukaryotic cells. The CBL-INTERACTING PROTEIN KINASE (CIPK) family of plant protein kinases functions in calcium (Ca2+)-related signaling pathways and is therefore involved in the response to a wide variety of signals in plants. By covalently linking phosphate groups to their target proteins, CIPKs regulate the activity of downstream targets, their localization, their stability and their ability to interact with other proteins. In Arabidopsis, the CIPK23 kinase has emerged as a major hub driving root responses to diverse environmental stresses, including drought, salinity and nutrient imbalances, such as potassium, nitrate and iron deficiencies, as well as ammonium, magnesium and non-iron metal toxicities. This review will chiefly report on the prominent roles of CIPK23 in the regulation of plant nutrient transporters and on the underlying molecular mechanisms. We will also discuss the different scenarios explaining how a single promiscuous kinase, such as CIPK23, may convey specific responses to a myriad of signals.
An ER–Golgi Tethering Factor SLOH4/MIP3 Is Involved in Long-Term Heat Tolerance of Arabidopsis
Authors: Isono Kazuho , Tsukimoto Ryo , Iuchi Satoshi , Shinozawa Akihisa , Yotsui Izumi , Sakata Yoichi , Taji Teruaki 
Published: December 2020

Abstract
Plants are often exposed not only to short-term (S-) heat stress but also to diurnal long-term (L-) heat stress over several consecutive days. To reveal the mechanisms underlying L-heat stress tolerance, we here used a forward genetic screen for sensitive to long-term heat (sloh) mutants and isolated sloh4. The mutant was hypersensitive to L-heat stress but not to S-heat stress. The causal gene of sloh4 was identical to MIP3 encoding a member of the MAIGO2 (MAG2) tethering complex, which is composed of the MAG2, MIP1, MIP2 and MIP3 subunits and is localized at the endoplasmic reticulum (ER) membrane. Although sloh4/mip3 was hypersensitive to L-heat stress, the sensitivity of the mag2-3 and mip1–1 mutants was similar to that of the wild type (WT). Under L-heat stress, the ER stress and the following unfolded protein response (UPR) were more pronounced in sloh4 than in the WT. Transcript levels of bZIP60-regulated UPR genes were strongly increased in sloh4 under L-heat stress. Two processes known to be mediated by INOSITOL REQUIRING ENZYME1 (IRE1) — accumulation of the spliced bZIP60 transcript and a decrease in the transcript levels of PR4 and PRX34, encoding secretory proteins — were observed in sloh4 in response to L-heat stress. These findings suggest that misfolded proteins generated in sloh4 under L-heat stress may be recognized by IRE1 but not by bZIP28, resulting in the initiation of the UPR via activated bZIP60. Therefore, it would be possible that only MIP3 in the MAG2 complex has an additional function in L-heat tolerance, which is not related to the ER–Golgi vesicle tethering.
Lipid accumulation product is a reliable indicator for identifying metabolic syndrome: the China Multi-Ethnic Cohort (CMEC) Study
Authors: Zhang X , Hong F , Liu L , Nie F , Du L , Guan H , Wang Z , Zeng Q , Yang J , Wang J , Li X , Zhang J , Luo P 
Published: December 2020

AbstractBackgroundPrevious studies have shown that lipid accumulation product (LAP) was associated with the risk of cardiometabolic disease. It is not clear whether LAP could be used as a marker to identify metabolic syndrome (MetS) among Chinese ethnic groups.AimTo assess the reliability of LAP as a maker to identify MetS among Dong adults.DesignPopulation-based cross-sectional study.MethodWe included 6494 Dong individuals (1403 patients) aged 30–79 years from southwest China. MetS was established by Chinese Diabetes Society. Logistic regression model was utilized to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Receiver operating characteristic (ROC) curve was utilized to calculate area under the ROC curve (AUC) and 95% CIs to obtain the identification ability for MetS.ResultsThe risk of MetS was increased with per 5 units increase of LAP (OR 1.37 [95% CI, 1.34–1.39]). Similar results were found in subgroup analyses and sensitivity analyses. Clustered metabolic risk associated with per 5 units increase of LAP was observed for people with 1 (OR 1.59 [95% CI, 1.53–1.65]), 2 (2.15 [2.06–2.24]), 3 (2.59 [2.48–2.71]), 4 (2.81 [2.69–2.95]) and 5 (3.03 [2.87–3.21]) MetS components. LAP presented higher AUC (0.915 [95% CI, 0.907–0.923]) than other included obesity indices (P &lt; 0.05).ConclusionThese data support evidence that LAP was related to the risk of MetS, had a high AUC and could be a reliable index for identifying MetS patients among Dong adults in Chinese.
Climate Change Policy: Can New Actors Affect Japan’s Policy-Making in the Paris Agreement Era?
Authors: KAMEYAMA Yasuko 
Published: December 2020

AbstractThis article examines changes in Japan’s policies related to climate change, focusing on three notable events that could have significantly altered Japan’s decisions on climate change: (a) the hosting of the Third Conference of the Parties (COP3) to the United Nations Framework Convention on Climate Change (UNFCCC) and the adoption of the Kyoto Protocol in December 1997, (b) the Fukushima Daiichi nuclear power plant accident in March 2011, and (c) the adoption of the Paris Agreement in December 2015 and its early enforcement in November 2016. The study shows that the Japanese government’s position remained fundamentally the same throughout these events. It called for emission reduction targets that would not harm the Japanese economy, considered nuclear power to be the least costly way to reduce carbon dioxide emissions, and avoided any mention of a 2°C mean global temperature rise as the long-term target. Meanwhile, after the Paris Agreement came into effect in 2016, an increasing number of Japanese private companies and local governments started taking voluntary actions to reduce their respective emissions, independent of national policy. These changes by sub/non-state actors have begun to alter decision-making at the national government level and could be a sign of transformational changes in Japan, wherein these new actors’ voices have a greater influence on Japan’s climate change policy than those of the traditional state-based actors.
‘Unconscionability’ and the case against lumping: three case studies
Authors: Liew Ying Khai 
Published: December 2020

Abstract
This article argues that unconscionability provides no good basis for arguments in favour of lumping equitable doctrines in English law. It explores three areas of equity where unconscionability has most strongly divided lumpers and splitters: undue influence and unconscionable bargains; proprietary estoppel and constructive trusts; and the ‘rule in Re Rose’ and the decision in Pennington v Waine. In relation to each discussion, the paper explains how lumpers rely on the idea of unconscionability to argue in favour of merging or expanding those established doctrines, and argues against lumping, by explaining how this distorts a proper understanding of the law.
Effects of myricetin against cadmium-induced neurotoxicity in PC12 cells
Authors: Aminzadeh Azadeh , Salarinejad Ayda 
Published: December 2020

Abstract
Cadmium (Cd) is one of the most prevalent toxic metals widely found in the environment. Cd induces toxicity and apoptosis in various organs and cells. The nervous system is one of the primary organs targeted by Cd. Cd toxicity is correlated with induction of severe oxidative stress. Myricetin, a natural product, has been found to exert protective effects against various disease conditions. The present study aimed to evaluate the potential protective effects of myricetin on Cd-induced neurotoxicity in PC12 cells. The cells were pretreated with myricetin in the absence and presence of Cd. The viability of cells was assessed using the MTT assay. Markers of oxidative stress were investigated by the lipid peroxidation (LPO), glutathione (GSH) content, and total antioxidant capacity (TAC). Moreover, activation of caspase 3 was examined by Western blot analysis. Myricetin could significantly enhance the viability of PC12 cells. Pretreatment of the cells with myricetin, prior to Cd exposure, showed a significant decrease in the levels of LPO whereas GSH and TAC levels were increased. In addition, the activity of caspase-3 was notably prevented by myricetin. These findings revealed that myricetin has protective effects on Cd-induced neurotoxicity in PC12 cells, which can be linked to its antioxidant potential, inhibition of LPO, and prevention of caspase-3 activation.