bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTEH-3. Targeted Gene-Expression analysis during malignant transformation in primary and secondary malignant meningioma
Authors: Maier Andrea Daniela , Meddis Alessandra , Haslund-Vinding Jeppe , Mirian Christian , Areskeviciute Ausrine , Nguyen Phuong , Westergaard Casper , Melchior Linea Cecilia , Munch Tina Nørgaard , Skjøth-Rasmussen Jane , Poulsgaard Lars , Ziebell Morten , Bartek Jiri , Broholm Helle , Poulsen Frantz Rom , Gerds Thomas Alexander , Scheie David , Mathiesen Tiit Illimar 
Published: July 2021

Abstract

Background
Malignant meningiomas comprise 2–5% of all meningiomas. The process of malignant transformation when benign meningiomas (WHO grade I-II) become malignant (WHO grade III) has not previously been investigated in sequential tumour surgeries. Upregulation of FOXM1 expression and DREAM-complex repression have shown phenotypical subgroups correlating with WHO grade and aggressiveness. We investigated the RNA expression of 30 genes central to meningioma biology and 770 genes involved in neuroinflammatory pathways in primary and secondary malignant meningioma patients who underwent one to several operations.

Methods
We identified a cohort of consecutive malignant meningioma patients treated at Rigshospitalet, Copenhagen from 2000–2020 (n=51) and gathered their malignant tumours and previous WHO grade I/II tumours. The malignant cohort (MC) was counter matched with a benign cohort (BC) where patients had no recurrences during follow-up. RNA expression signatures from 140 samples from the MC and 51 samples from the BC were analysed with the Nanostring Neuroinflammation panel customized with 30 genes known to be relevant in meningioma phenotypes.

Results
49% of MC patients had a previous grade I/II meningioma making them secondary malignant meningioma patients. Progression-free survival calculated from first malignant surgery to first recurrence or death showed no significant difference in the primary vs. secondary patients. Preliminary results of single-gene analysis of MC tumours showed FOXM1, MYBL2, TOP2A, BIRC5 expression was higher in WHO grade III samples. Gene-expression signatures in the individual patients and gene ontology enrichment analyses are in process.

Conclusions
FOXM1, MYBL2, TOP2A, BIRC5 RNA expression levels seem to rise during malignant progression across patients. Gene-expression analysis using the Nanostring technology is feasible and a potentially powerful tool to distinguish meningiomas prone to malignant transformation from truly benign meningiomas.
OTEH-12. Assessing Adaptive Responses to Loss of Extrachromosomal DNA Amplification
Authors: Berezovsky Artem , Datta Indrani , She Ruicong , Hasselbach Laura , Poisson Laila , deCarvalho Ana C 
Published: July 2021

Abstract

Background
Oncogene activation through somatic gene amplification happens frequently in GBM, with over 70% of these tumors presenting amplification of at least one putative driver gene, oftentimes in small extrachromosomal circular DNA segments composed of chromatin (ecDNA). A molecularly diverse and representative panel of GBM patient-derived cancer stem-like cells (CSC) and orthotopic mouse xenografts (PDX), which retain the original genomic abnormalities and ecDNA amplifications, was employed to assess adaptive response to the absence of ecDNA amplification.

Methods
We have isolated ecDNA negative cell populations from two patient-derived models. HF3035 harbors a MET amplification and HF3253 harbors a PDGFRA constitutively active genomic rearrangement and extrachromosomal amplification. We conducted paired, whole RNA-sequencing on 20 HF3253 populations (ecDNA+/-: 6 clones from 3 biological replicate PDXs and 4 clones from 4 in vitro technical replicates) and 12 HF3035 population (ecDNA+/-: 6 clones from 3 biological replicate PDXs).

Results
Nonparametric differentially expressed gene (DEG) analysis using NOISeqBio (R/Bioconductor), identified 564 differentially expressed genes (482 upregulated in ecDNA(-)) employing a stringent false discovery rate of 0.05. Genes significantly associated with PDGF stimulation, central carbon metabolism, and H3K27me3 were downregulated in ecDNA(-), while genes significantly associated with astrocytic processes, neuronal differentiation, and EGFR signaling were upregulated in ecDNA(-) (EnrichR). We employed an additive linear model with PDX serving as a blocking factor to compare ecDNA+ and ecDNA- populations in both models (R/edgeR). 2071 genes were upregulated in ecDNA+ PDX specimens and 2365 genes were downregulated. Specifically, E2F targets were highly enriched in ecDNA+ populations, in addition to mRNA pre-processing. ecDNA loss primarily targeted glycogen metabolism, NTRK signaling, and inositol phosphate catabolism.

Conclusions
We have identified PDX-specific and non-specific features to an adaptive response to the loss of ecDNA amplification. Notably, a signature adaptation is an upregulation of seemingly redundant receptor tyrosine kinases.
OTME-2. Regulation of chromatin accessibility in the hypoxic tumor microenvironment of glioblastoma
Authors: Dzwigonska Monika , Mieczkowski Jakub , Pilanc Paulina , Cyranowski Salwador , Kominek Agata , Piwocka Katarzyna , Kaminska Bozena , Leszczynska Katarzyna B 
Published: July 2021

Abstract
Chromatin structure is often dysregulated in cancers, including glioblastoma (GBM), the most common primary brain tumor in adults. GBM has the poorest prognosis and no efficient cure to date due to diffusive growth into the surrounding brain, preventing complete surgical resection and leading to inevitable tumor relapse. Tumor microenvironment (TME) of GBM contains brain-residing microglia and bone-marrow derived macrophages (collectively known as glioma-associated microglia/macrophages, GAMs) that constitute up to 30% of the tumor mass and promote tumor invasion. Hypoxia (a shortage of oxygen) is a key factor in tumor progression of GBM as it can globally and rapidly alter the gene expression, induce cancer cell invasiveness, stemness and lead to therapy resistance. Hypoxia can enhance the pro-tumorigenic function of GAMs, e.g. by inducing expression of cytokines and cell surface receptors both in GAMs and glioma cells, but little is known about chromatin alterations of GBM under hypoxia. Since regulation of expression of such molecules could depend on the epigenetic alterations, we hypothesize that hypoxia may potently alter the chromatin accessibility and functions of GAMs and glioma cells.
We determine the genome-wide changes in chromatin accessibility in GAMs and glioma cells in response to hypoxic stress using single-cell Pi-ATAC-seq (Protein-indexed Assay of Transposase Accessible Chromatin with sequencing), which allows simultaneous genome-wide assessment of chromatin accessibility and expression of intracellular protein markers in single cells, allowing faithful selection of hypoxic and non-hypoxic cells. Secondly, we are employing an oxygen-dependent co-culture model in vitro to study the mechanisms of chromatin alterations in GAMs and glioma cells under controlled hypoxic conditions and test how these changes depend on the glioma - GAMs cross-communication. In summary, we characterize the interactions between innate immune cells and glioma cells by looking at their chromatin alterations under hypoxia.
Supported by the National Science Center grant (Poland) 2019/33/B/NZ1/01556 (KBL).
OTME-4. IDH mutated gliomas promote epileptogenesis via D-2-hydroxyglutarate dependent mTOR hyperactivation
Authors: Mortazavi Armin , Fayed Islam , Bachani Muzna , Maric Dragan , Dowdy Tyrone , Larion Mioara , Ksendzovsky Alexander , Zaghloul Kareem 
Published: July 2021

Abstract
Epilepsy in the context of brain tumors provides a great burden in these patients, yet mechanisms underlying this process are poorly understood. It has been demonstrated that isocitrate dehydrogenase (IDH) mutations are an independent factor in epileptogenesis in patients with low grade gliomas. Here, using electrographically sorted human cortical tissue from patients with IDH mutated tumor related epilepsy and in vitro cortical cultures, we explore a metabolic paradigm and its impact on increased neuronal excitability. We hypothesize the IDH mutation promotes epileptogenesis through its neomorphic activity of D-2-hydroxyglutarate (D-2-HG) production in turn interrupts surrounding normal neuronal circuitry potentially through metabolic perturbations. We demonstrate D-2-HG increases neuronal spiking activity, promotes distinct metabolic profiles independent of neuronal spiking activity, as well as increases neuronal mTOR signaling, which is reflected in human peritumoral epileptic cortex. Increased mTOR signaling is sufficient to upregulate neuronal spiking activity and, reciprocally, inhibition of mTOR corrects neuronal activity as well as partially corrects metabolic reprogramming. Our results suggest D-2-HG can lead to mTOR activation within the peritumoral neurons, thereby suggesting an additional possible mechanism of epileptogenesis in patients with IDH mutated low grade gliomas. Ultimately, our results raise the possibility of mTOR inhibition may be a promising treatment of seizures in patients with these tumors.
OTME-6. Deep sequencing reveals heterogeneity of brain metastasis-associated macrophages and microglia and uncovers their cell type-specific functions within the tumor microenvironment
Authors: Schulz Michael , Alekseeva Tijna , Anthes Julian , Macas Jandranka , Michels Birgitta , Möckl Aylin , Niesel Katja , Salamero-Boix Anna , Stein Stefan , Farin Henner , Plate Karl H , Reiss Yvonne , Rödel Franz , Sevenich Lisa 
Published: July 2021

Abstract
Macrophages represent a highly plastic cell type,indispensable for tissue and organ homeostasis, as well as innate immunity. Basic and translational research attributed tumor-promoting functions to macrophages, and their presence is often associated to poor patient prognosis and therapy resistance. While brain-resident macrophages, the so-called microglia (MG), represent the major immune cell type in the parenchyma under normal conditions, primary and metastatic brain tumors induce the recruitment of different immune cell types from the periphery, including monocyte-derived macrophages (MDM). Controversy remained about the redundancy of disease-associated molecular signatures and functions. The identification of markers that reliably distinguish brain-resident from blood-borne tumor-associated macrophages (TAMs) allowed the interrogation of molecular traits of different TAM populations in mouse and human brain tumors.
Using RNA-Seq, we demonstrated that TAMs rapidly acquire disease-associated transcriptional programs upon initial tumor infiltration, while gene expression remained stable during different stages of BrM progression. Across different BrM models, disease-associated transcriptional changes revealed lineage-specific, non-redundant functions of TAM populations, which was further reflected by cell type-specific occupation of different niches within the BrM microenvironment. Furthermore, we observed dose- and cell type-specific immune modulatory effects of whole brain radiotherapy on myeloid cells in BrM leading to a transient loss of disease-associated transcriptional programs predominately in blood-borne myeloid populations. This effect can at least in part be attributed to a replenishment of the recruited macrophage pool. This observation was further supported by scRNA-Seq analyses revealing higher heterogeneity of TAM-MDM compared to TAM-MG under treatment-naïve conditions and in response to radiotherapy.
Together, our results point towards the phenotypic plasticity of TAMs, especially MDMs, and the contribution of each compartment in instigating cancer-associated inflammation or the establishment of an immuno-suppressive TME. While TAM-MG exert functions related to pro-inflammatory responses, TAM-MDM are rather involved in tissue repair and regulation of adaptive immune cell functions.
OTME-20. Chitinase-3-like-1(CHI3L1) Protein Complexes Regulate the immunosuppressive Microenvironment in Glioblastoma
Authors: Chen Apeng , Jiang Yinan , Li Zhengwei , Xiao Xiangwei , Yimlamai Dean , Pollack Ian , Camacho Carlos , Hu Baoli 
Published: July 2021

Abstract
Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.
LDIP cooperates with SEIPIN and LDAP to facilitate lipid droplet biogenesis in Arabidopsis
Authors: Pyc Michal , Gidda Satinder K. , Seay Damien , Esnay Nicolas , Kretzschmar Franziska K. , Cai Yingqi , Doner Nathan M. , Greer Michael S. , Hull J. Joe , Coulon Denis , Bréhélin Claire , Yurchenko Olga , de Vries Jan , Valerius Oliver , Braus Gerhard H. , Ischebeck Till , Chapman Kent D. , Dyer John M. , Mullen Robert T. 
Published: July 2021

AbstractCytoplasmic lipid droplets (LDs) are evolutionarily conserved organelles that store neutral lipids and play critical roles in plant growth, development, and stress responses. However, the molecular mechanisms underlying their biogenesis at the endoplasmic reticulum (ER) remain obscure. Here we show that a recently identified protein termed LD-associated protein [LDAP]-interacting protein (LDIP) works together with both endoplasmic reticulum-localized SEIPIN and the LD-coat protein LDAP to facilitate LD formation in Arabidopsis thaliana. Heterologous expression in insect cells demonstrated that LDAP is required for the targeting of LDIP to the LD surface, and both proteins are required for the production of normal numbers and sizes of LDs in plant cells. LDIP also interacts with SEIPIN via a conserved hydrophobic helix in SEIPIN and LDIP functions together with SEIPIN to modulate LD numbers and sizes in plants. Further, the co-expression of both proteins is required to restore normal LD production in SEIPIN-deficient yeast cells. These data, combined with the analogous function of LDIP to a mammalian protein called LD Assembly Factor 1, are discussed in the context of a new model for LD biogenesis in plant cells with evolutionary connections to LD biogenesis in other eukaryotes.
’t Hooft expansion of multi-boundary correlators in 2D topological gravity
Authors: Okuyama Kazumi , Sakai Kazuhiro 
Published: July 2021

AbstractWe study multi-boundary correlators of Witten–Kontsevich topological gravity in two dimensions. We present a method of computing an open string like expansion, which we call the ’t Hooft expansion, of the $n$-boundary correlator for any $n$ up to any order by directly solving the Korteweg–De Vries equation. We first explain how to compute the ’t Hooft expansion of the one-boundary correlator. The algorithm is very similar to that for the genus expansion of the open free energy. We next show that the ’t Hooft expansion of correlators with more than one boundary can be computed algebraically from the correlators with a lower number of boundaries. We explicitly compute the ’t Hooft expansion of the $n$-boundary correlators for $n=1, 2, 3$. Our results reproduce previously obtained results for Jackiw–Teitelboim gravity and also the ’t Hooft expansion of the exact result of the three-boundary correlator which we calculate independently in the Airy case.
Functional Reach Test, Single-Leg Stance Test, and Tinetti Performance-Oriented Mobility Assessment for the Prediction of Falls in Older Adults: A Systematic Review
Authors: Omaña Humberto , Bezaire Kari , Brady Kyla , Davies Jayme , Louwagie Nancy , Power Sean , Santin Sydney , Hunter Susan W 
Published: July 2021

AbstractObjectiveThe authors sought to systematically review the existing literature on the falls-related diagnostic test properties of the Functional Reach Test (FRT), single-leg stance test (SLST), and Tinetti Performance-Oriented Mobility Assessment (POMA) in older adults across settings and patient populations.MethodsThe PubMed, EMBASE, and CINAHL databases were searched (inception–July 2020). Inclusion criteria were participants aged 60 years or more, prospectively recorded falls, and the reporting of falls-related predictive validity. Manuscripts not published in English were excluded. Methodological quality of reporting was assessed using the Tooth Scale.ResultsOf 1071 studies reviewed, 21 met the inclusion criteria (12 POMA, 8 FRT, 6 SLST). Seven studies (58.3%) used a modified version of the POMA, and 3 (37.5%) used a modified FRT. For the outcome of any fall, the respective ranges of sensitivity and specificity were 0.076 to 0.615 and 0.695 to 0.97 for the POMA, 0.27 to 0.70 and 0.52 to 0.83 for the modified POMA, 0.73 and 0.88 for the FRT, 0.47 to 0.682 and 0.59 to 0.788 for the modified FRT, and 0.51 and 0.61 for the SLST in community-dwelling older adults. For the SLST, the sensitivity and specificity for recurrent falls in the community-dwelling setting were 0.33 and 0.712, respectively.ConclusionAll the clinical tests of balance demonstrated an overall low diagnostic accuracy and a consistent inability to correctly identify fallers. None of these tests individually are able to predict future falls in older adults. Future research should develop a better understanding of the role that clinical tests of balance play in the comprehensive assessment of falls risk in older adults.ImpactNeither the FRT, SLST, nor POMA alone shows consistent evidence of being able to correctly identify fallers across fall types, settings, or older adult subpopulations. These clinical tests of balance cannot substitute a comprehensive falls risk assessment and thus should be incorporated in practice solely to identify and track balance impairment in older adults.
Medication decision-making and adherence in lupus: patient–physician discordance and the impact of previous ‘adverse medical experiences’
Authors: Sloan Melanie , Lever Elliott , Gordon Caroline , Harwood Rupert , Georgopoulou Sofia , Naughton Felix , Wincup Chris , Sutton Stephen , D’Cruz David 
Published: July 2021

Abstract

Objectives
Medication adherence is critical in the successful management of lupus. There is very limited existing literature on reasons why non-adherence is not reported. This study explores the impact of current and previous medical experiences on patient satisfaction, adherence and reporting of non-adherence.

Methods
Mixed methodology involved thematic analysis of in-depth interviews (n = 23) to further explore the statistically analysed quantitative survey findings (n = 186).

Results
This study identified five themes: (i) physician-patient discordance and a ‘hierarchy of evidence’ in medication decisions; (ii) the association of adherence with satisfaction with care; (iii) the persisting impact of past adverse medical experiences (AMEs); (iv) the dynamic balance of patient-physician control; and (v) holistic care, beyond a purely medication-based focus. Improving quality of life (43% of participants) and a supportive medical relationship (24%) were the main reasons for adherence. Patient-priorities and self-reported symptoms were perceived as less important to physicians than organ-protection and blood results. Non-reporters of non-adherence, non-adherers and those with past AMEs (e.g. psychosomatic misdiagnoses) had statistically significant lower satisfaction with care. The importance of listening to patients was a key component of every theme, and associated with patient satisfaction and adherence. The mean rating for rheumatologist’s listening skills was 2.88 for non-adherers compared with 3.53 for other participants (mean difference 0.65, P = 0.003).

Conclusion
Patients would like more weight and discussion given to self-reported symptoms and quality of life in medication decisions. Greater understanding and interventions are required to alleviate the persisting impact of past AMEs on some patients’ wellbeing, behaviour and current medical relationships.
Species Tree Inference Methods Intended to Deal with Incomplete Lineage Sorting Are Robust to the Presence of Paralogs
Authors: Yan Zhi , Smith Megan L , Du Peng , Hahn Matthew W , Nakhleh Luay 
Published: July 2021

Abstract
Many recent phylogenetic methods have focused on accurately inferring species trees when there is gene tree discordance due to incomplete lineage sorting (ILS). For almost all of these methods, and for phylogenetic methods in general, the data for each locus are assumed to consist of orthologous, single-copy sequences. Loci that are present in more than a single copy in any of the studied genomes are excluded from the data. These steps greatly reduce the number of loci available for analysis. The question we seek to answer in this study is: what happens if one runs such species tree inference methods on data where paralogy is present, in addition to or without ILS being present? Through simulation studies and analyses of two large biological data sets, we show that running such methods on data with paralogs can still provide accurate results. We use multiple different methods, some of which are based directly on the multispecies coalescent model, and some of which have been proven to be statistically consistent under it. We also treat the paralogous loci in multiple ways: from explicitly denoting them as paralogs, to randomly selecting one copy per species. In all cases, the inferred species trees are as accurate as equivalent analyses using single-copy orthologs. Our results have significant implications for the use of ILS-aware phylogenomic analyses, demonstrating that they do not have to be restricted to single-copy loci. This will greatly increase the amount of data that can be used for phylogenetic inference.[Gene duplication and loss; incomplete lineage sorting; multispecies coalescent; orthology; paralogy.]