bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential perceptions of and reactions to incivil and intolerant user comments
Authors: Kümpel Anna Sophie , Unkel Julian 
Published: June 2023

AbstractBuilding on recent research that challenges the notion that norm violations in online discussions are inherently detrimental, this study relies on a distinction between incivil and intolerant user comments and investigates how online users perceive and react to these distinct forms of antinormative discourse online. Conducting a preregistered factorial survey experiment with a nationally representative sample of n = 964 German online users, we presented participants with manipulated user comments that included statements associated with incivil (profanity; attacks toward arguments) and intolerant discourse (offensive stereotyping; violent threats). The results show that intolerant statements consistently lead to higher perceptions of offensiveness and harm to society as well as an increased intention to delete the comment containing the statement, whereas incivil statements do not. An exploratory multiverse analysis further suggests that these effects remain robust across a variety of analytical decisions.
Can lipid mediators and free fatty acids guide acute coronary syndrome diagnosis and treatment?
Authors: Uzun Gulbahar , Unal Aslihan , Basarici Ibrahim , Kucuk Murathan , Donmez Levent , Nacitarhan Cahit , Özdem Sebahat 
Published: June 2023

AbstractObjectiveThe aim of this study was to investigate fatty acids, lipid mediator levels, and the desaturase index rates on different acute coronary syndrome types and their possible relationship with routine lipid parameters.MethodsThe study included 81 patients with myocardial infarction (MI), 20 patients with unstable angina pectoris, and 31 healthy people. Fatty acids, CD59, lipoxin A4, 8-isoprostane, serum lipids, albumin, C-reactive protein (CRP), and high sensitive troponin levels were measured in all participants.ResultsWhen the fatty acid groups were evaluated as a ratio of albumin, MUFA/albumin and SFA/albumin ratios were significantly higher in the MI group compared to the control group. Although CD59 and lipoxin A4 levels were higher in the control group, there was no significant differences between the groups. When lipoxin A4/CRP and CD59/CRP ratios were evaluated, the results were significantly lower than those in the control group. ConclusionLipid mediators may be useful in treating atherosclerosis by contributing to the resolution of inflammation.
Gap opening in protoplanetary discs: gas dynamics from global axisymmetric non-ideal MHD simulations with consistent thermochemistry
Authors: Hu Xiao , Li Zhi-Yun , Wang Lile , Zhu Zhaohuan , Bae Jaehan 
Published: June 2023

ABSTRACT
Recent high angular resolution ALMA observations have revealed numerous gaps in protoplanetary discs. A popular interpretation has been that planets open them. Most previous investigations of planet gap-opening have concentrated on viscous discs. Here, we carry out 2D (axisymmetric) global simulations of gap opening by a planet in a wind-launching non-ideal MHD disc with consistent thermochemistry. We find a strong concentration of poloidal magnetic flux in the planet-opened gap, where the gas dynamics are magnetically dominated. The magnetic field also drives a fast (nearly sonic) meridional gas circulation in the denser disc regions near the inner and outer edges of the gap, which may be observable through high-resolution molecular line observations. The gap is more ionized than its denser surrounding regions, with a better magnetic field–matter coupling. In particular, it has a much higher abundance of molecular ion HCO+, consistent with ALMA observations of the well-studied AS 209 protoplanetary disc that has prominent gaps and fast meridional motions reaching the local sound speed. Finally, we provide fitting formulae for the ambipolar and Ohmic diffusivities as a function of the disc local density, which can be used for future 3D simulations of planet gap-opening in non-ideal MHD discs where thermochemistry is too computationally expensive to evolve self-consistently with the magneto-hydrodynamics.
A new method to constrain annihilating dark matter
Authors: Chan Man Ho , Lee Chak Man 
Published: June 2023

ABSTRACT
Recent indirect searches of dark matter using gamma-ray, radio, and cosmic ray data have provided some stringent constraints on annihilating dark matter. In this article, we propose a new indirect method to constrain annihilating dark matter. By using the data of the G2 cloud near the Galactic supermassive black hole Sgr A*, we can get stringent constraints on the parameter space of dark matter mass and the annihilation cross-section, especially for the non-leptophilic annihilation channels $b\bar{b}$ and W±. For the thermal annihilation cross-section, the lower bounds of dark matter mass can be constrained up to TeV order for the non-leptophilic channels with the standard spike index γsp = 7/3.
ATRT-04. TARGETING THE COREST COMPLEX HELPS REPROGRAM AT/RT’S ABNORMAL EPIGENETIC LANDSCAPE TOWARD A DIFFERENTIATION PHENOTYPE
Authors: Geethadevi Anupa , Collard Marianne , Vaidya Nikhil , Findlay Tyler , Malebranche Kristen , Eberhart Charles , Raabe Eric , Cole Philip , Alani Rhoda , Rubens Jeffrey 
Published: June 2023

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are deadly infantile brain tumors. Their aggressive phenotype results from a single recurring biallelic loss-of-function mutation in genes encoding components of the SWI/SNF chromatin-remodeling complex - mainly SMARCB1 and SMARCA4 in remaining tumors. Residual SWI/SNF activity continues to inhibit EZH2 methyltransferase except at promoter regions colocalized to REST, which associates with neuronal differentiation and tumor suppressor genes. At these sites, EZH2 increases repressive H3K27me3 marks, helping maintain AT/RT in a stem cell-like state, and driving its aggressive growth and therapy resistance.
We study the consequences of disrupting SWI/SNF inhibition at sites of EZH2/REST co-localization to target AT/RT precisely. The repressive action of REST is carried out mainly by the CoREST complex, consisting of LSD1, HDAC1/2 and RCOR. Lentiviral knockdown of RCOR2 reversed AT/RT’s stem cell-like state and induced differentiation along the glial and neuronal lineage. A decrease in the H3K27Me3 further confirmed the absence of COREST complex assembly at these sites.
We used a bifunctional LSD1 and HDAC1/2 inhibitor, Corin, to pharmacologically target the CoREST complex in AT/RT cells. Corin also induced neuronal differentiation in AT/RT with increased expression of neuronal differentiation markers and decreased expression of stem cell markers. Further, Corin reduced AT/RT cell viability and proliferation (p&lt;0.05) and increased apoptosis (p&lt;0.05). In mice bearing orthotopic CHLA06 tumors, convection-enhanced delivery of a single dose of Corin increased H3K27ac, demonstrating that Corin engaged its target in vivo and induced apoptosis (western blot, cPARP).
These studies demonstrate that targeting the CoREST complex disrupts AT/RT epigenetic abnormalities, reversing their stem cell-like state, slowing tumor cell growth, and inducing apoptosis. Targeting the CoREST complex with Corin is a promising new strategy that may translate into the clinical setting to help improve AT/RT’s dismal survival.
ATRT-08. THE SINGLE-CELL LANDSCAPE OF PINEOBLASTOMA IDENTIFIES DEVELOPMENTAL ORIGINS AND EXPOSES TUMORIGENIC DEPENDENCIES
Authors: Gudenas Brian , Englinger Bernhard , Liu Anthony P Y , Ahmad Sheikh Tanveer , Meredith David , Pfaff Elke , Paul Leena , Hadley Jennifer , Batts Melissa , Klimo Jr. Paul , Boop Frederick A , Gajjar Amar , Robinson Giles W , Orr Brent A , Lin Hong , Alexandrescu Sanda , Jones David T W , Filbin Mariella G , Northcott Paul A 
Published: June 2023

Abstract
Pineoblastoma (PB), a rare and aggressive brain tumor affecting children, presents with a highly variable age distribution and treatment outcome. Our recent bulk tumor analyses of DNA methylation and mutational landscapes uncovered four discrete PB molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB), providing a major advance in our understanding of biological and clinical heterogeneity. However, developmental origins of PB subgroup heterogeneity and mechanisms governing how specific genetic alterations promote malignancy remain unknown. We conducted single-nucleus RNA sequencing of 38 primary tumors, including cases from all subgroups, to uncover intra-tumoral heterogeneity, developmental origins and expose selective dependencies. Transcriptional programs driving intra-tumoral heterogeneity showed subgroup-specific patterns such as mRNA splicing associated with PB-miRNA1/2 and phototransduction in PB-RB and PB-MYC/FOXR2. Next, we created a single-cell transcriptional atlas of the murine pineal gland across 11 developmental stages and found significant associations between PB subgroups and specific differentiation states of the pinealocyte lineage, suggesting subgroup-specific developmental origins. Characterization of pineal development informed generation of biologically faithful disease models, including a novel genetically engineered mouse model of the PB-RB subgroup. PB-Rb1 mouse tumors were histologically and molecularly validated for their fidelity to human tumor counterparts, exhibiting up-regulation of key pinealocyte lineage markers that are diagnostic in patients. Using cell lines derived from our PB-Rb1 mouse model we identified several transcription factor dependencies we believe are high-jacked during normal pinealocyte development. Our findings inform the developmental origins of pineoblastoma as well as provides candidates for potential therapeutic targets.
ATRT-09. COMBINATION OF THE PI3K INHIBITOR PAXALISIB WITH THE NUCLEOSIDE ANALOG GEMCITABINE ACTIVATES THE INTEGRATED STRESS RESPONSE AND EXTENDS SURVIVAL IN ORTHOTOPIC MODELS OF ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Findlay Tyler , Malebranche Kristen , Geethadevi Anupa , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: June 2023

Abstract
Relapsed atypical teratoid/rhabdoid tumors (AT/RT) are a deadly disease without a known cure. The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is looking for effective combination therapies for an upcoming clinical trial to better treat relapsed AT/RT. We have previously identified that AT/RT are dependent on activation of mTORC1 and mTORC2 for growth and survival. Paxalisib is a highly brain penetrant PI3k inhibitor which acts upstream of mTOR to simultaneously inhibit mTORC1/2. In murine orthotopic xenograft models of AT/RT, Paxalisib significantly extends survival as a single agent therapy (CHLA-06: 40 to 54 days, p=0.001; BT12: 21 to 35 days, p=0.02). However, to improve the durability of this single agent therapy, we evaluated the efficacy of rational therapeutic partners. Analysis of RNAseq following mTOR inhibition (mTORi) showed an upregulation of genes associated with the integrated stress response (ISR) (ATF4, CHOP, PPP1R15A; t-test p&lt;0.05). Gemcitabine is a pyrimidine nucleoside prodrug, which inhibits DNA synthesis and induces DNA damage, also leading to ISR activation. While the ISR can be protective, intense or prolonged activation leads to cell death. We therefore hypothesized that Paxalisib would combine with Gemcitabine to over-activate the ISR and drive AT/RT cell death. Through protein analyses, we demonstrate that combination therapy further activates the ISR compared to DMSO control (Western Blot: phospho-eIF2α, ATF4, and CHOP). Combination therapy also increases apoptosis (Western blot cPARP, MUSE Annexin V Assay) and synergizes to decrease AT/RT cell growth (SynergyFinder BLISS score CHLA-06: 16.8, BT12: 14.3, CHLA-266: 13.9). In mice bearing CHLA-06 orthotopic tumors, Paxalisib/Gemcitabine combination therapy slows tumor growth (Bioluminescent imaging) and extends median survival from 22 to 82.5 days (p&lt;0.0001) compared to vehicle control treated mice. We aim to translate these results in this upcoming PNOC clinical trial to treat relapsed AT/RT.
ATRT-15. ATRTS HIJACK EPIGENETIC MECHANISMS TO PROMOTE IMMUNOSUPPRESSION AND ESCAPE FROM NK CELL THERAPY
Authors: Swaminathan Jyothishmathi , Ho Ben , Maegawa Shinji , Guo Lei , Laureano Alvaro , Brugmann Ben , Kennis Bridget , Dobson Tara , Shaik Shavali , Ravikumar Visweswaran , Sandberg David , Cooper Laurence , Zaky Wafik , Khatua Soumen , Silla Lucia , Lee Dean , Rao Arvind , Harmanci Arif , Xu Lin , Huang Annie , Gopalakrishnan Vidya 
Published: June 2023

Abstract
Atypical Teratoid/Rhabdoid Tumors (ATRTs) are malignant tumors of the central nervous system in children. They are almost universally characterized by genetic loss of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator of Chromatin Subfamily member B1 (SMARCB1) - a core subunit of the ATP-dependent SWI/SNF chromatin remodeling complex, and dysregulation of lineage restricted enhancers. Here, we show that tumor subgroup-specific upregulation of a distant member of the transforming growth factor-β (TGF-β), bone morphogenic factor (BMF) family of proteins drives insensitivity to NK-mediated cytolysis in vitro and in vivo. Mechanistically, subgroup-specific loss of chromatin occupancy by the RE1 Silencing Transcription Factor (REST) to its consensus RE1 motif, allowed deposition of enhancer-specific histone H3 lysine4 (K4) mono-methylation and histone H3K27 acetylation marks to activate an enhancer-promoter interaction. Restoration of REST binding or BET-domain inhibition resulted in a significant reduction in the enhancer marks and enhancer-promoter interaction and involved histone H3K27me3 deposition at the REST binding site, to facilitate gene silencing and sensitization of ATRTs to NK-mediated cytolysis. Thus, our study has identified a novel function for REST as a modulator of tumor-intrinsic enhancer activity and tumor-extrinsic immune microenvironment. Of equal significance, we highlight a role of REST in recruiting the polycomb repressive complex-2 (PRC2) in gene silencing in ATRTs.
BIOL-05. IDENTIFICATION AND VALIDATION OF PA2G4 AS A POTENTIAL THERAPEUTIC TARGET IN PEDIATRIC DIFFUSE GLIOMAS
Authors: Sirhan Zaid , Sells Blake E , Fleming Jessica , Manring Heather R , Graham Richard T , McElroy Joseph P , Haque Saikh J , Boué Daniel R , Becker Aline P , Bell Erica H , Finlay Jonathan , Chakravarti Arnab 
Published: June 2023

Abstract
Brain tumors are the second most common pediatric malignancy after leukemia. High grade gliomas have a significantly high morbidity and mortality in children, with a 5-year survival rate under 20%. This study aims to identify important biological mechanisms and proteins as prognostic biomarkers and novel therapeutic targets. We hypothesize that higher grade pediatric diffuse gliomas can be effectively targeted by knocking down expression of the proliferation associated protein 2G4 (PA2G4) that binds to MYCN and prevents its ubiquitination. LC-MS/MS proteomic profiling was performed on 28 formalin-fixed paraffin embedded primary diffuse glioma samples from Nationwide Children’s Hospital (Columbus, OH). Cox proportional hazard models were used to correlate individual proteins with progression-free survival (PFS) and overall survival (OS). Differences in fold change were calculated for each protein between low grade (LGG, grade 2) and high-grade glioma (HGG, grades 3-4) patients. Ingenuity Pathway Analysis was performed considering only proteins with p-values &lt;0.05. In vitro studies were performed to evaluate the roles of PA2G4 in the SF188 glioma cell line. In comparing high- and low-grade tumors, 471 proteins were found to be significantly differentially expressed. Eighty-six and 121 proteins were significantly associated with OS and PFS, respectively. PA2G4 was expressed 2.0-fold higher in HGG vs LGG (p=0.015). Additionally, high expression of PA2G4 protein was associated with significantly worse PFS (p=0.041) and OS (p=0.035) and selected for further studies. Preliminary in vitro results showed that knocking-down PA2G4 decreased AKT phosphorylation/activation and levels of MYCN protein. Given that activated MYCN plays critical oncogenic roles in patients with poor survival PA2G4 may serve as a novel therapeutic target in higher grade pediatric diffuse gliomas. Studies are underway to unfold how PA2G4 affects treatment resistance and tumor recurrence in pediatric patients.
BIOL-14. FROM NON-MALIGNANT TO MALIGNANT: GENERATING AND TARGETING DIFFUSE MIDLINE GLIOMA IN A NOVEL HUMAN PONTINE ORGANOID MODEL
Authors: Bessler Nils , Moreno Cristian Ruiz , Wezenaar Amber , Dommann Noëlle , Keramati Farid , Ariese Hendrikus C R , Honhoff Celina , de Blank Sam , Román Mario Barrera , Collot Raphaël , van Ineveld Ravian , Krashennikova Maria Alieva , Kranendonk Mariette E G , Wehrens Ellen J , Alemany Anna , Stunnenberg Henk G , Rios Anne C 
Published: June 2023

Abstract
Diffuse Midline Glioma (DMG) is a rare and aggressive pediatric cancer with no chance of survival, demonstrating a critical need for therapy development. Predictive preclinical models that take into account the unique developmental background and anatomical environment of DMG, are so far lacking. We developed a new regionally patterned brain organoid protocol based on a timely regulated sequence of morphogens. The patterned organoids give rise to pontine and medulla oblongata identity, as confirmed by transcriptomic profiling and immunofluorescence imaging. As the tissue matures, the complexity inherently takes shape and gives rise to pons-specific neurons and glial cells, offering the first human in vitro model for this region of the brain. Introducing H3K27M, including its partner mutations P53 and PDGFRA-D842V via electroporation forms de novo H3K27M diffuse midline glioma with a similar genetic make-up as found in patients. Indeed, contrary to common cell lines or PDX models, single cell sequencing and 3D imaging reveal that Organoid-DMG resembles WHO-defined primary patient cancer, including its diverse cell population heterogeneity and invasive nature. Utilizing barcode-based lineage tracing allows us to unravel and track the cancerous developmental evolution. Thus, we can now model early emerging populations and identify their transcriptomic signatures, which is conceptually impossible to conduct with patient-derived tumor tissue. In summary, we generated a bona fide DMG in vitro model which will give insights into tumorigenesis of DMG and ultimately contribute to pre-clinical drug- and immunotherapy development.
BIOL-24. USING NEEDLE WASH SPECIMEN AFTER STEREOTACTIC BIOPSY TO DEVELOP PDOX MODELS OF DIPG AND DIFFUSE MIDLINE GLIOMAS
Authors: Abdallah Aalaa , DuCuypere Michael , Xiao Sophie , Suarez Milagros , Wadhwani Nitin , Du Yuchen , Lam Sandi , Li Xiao-Nan 
Published: June 2023

Abstract
Obtaining viable tissue remains a major barrier for lab-based studies, especially in brain tumors deemed surgically unresectable such as diffuse midline gliomas. Surgical biopsy is performed for those tumors invested in deep and vital brain structures however, biopsied specimens are usually of small volume without additional tissue for research after clinical testing. To overcome the barrier of limited surgical specimen volume, we partnered with neurosurgeons to develop a protocol which procures viable cells from discarded biopsy needle after stereotactic biopsies to develop patient-derived orthotopic xenograft (PDOX) models. After procurement of surgical specimen and prior to disposal of biopsy needle, each stereotactic biopsy needle was washed with FBS media twice. Wash solution was collected and immediately transported on ice to the research lab. Cell number was counted for in vitro culture and for orthotropic in vivo tumor implantation. To date, 29 samples of biopsy needle washes have been obtained including 12 diffuse midline gliomas of the brain stem, 8 supratentorial diffuse midline gliomas, and 3 pineal region tumors with harvested cell number from no visible cells to 5.3 million cells (median 1 million). 14 tumors have been orthotopically implanted into matched locations of immunodeficient mouse brains. Tumor formation was confirmed in 4 out of 15 (28.5%), including 2 brain stem tumors, 1 infiltrating astrocytoma, and 1 midline glioma, after implantation of cell numbers as low as 12,500. 3 models were successfully sub-transplanted to passages II and III. Histological examination confirmed the replication of key pathological features of the originating patient tumors. In conclusion, we have developed a novel protocol to procure clinical specimen by using wash solution of stereotactic brain tumor biopsy needles for surgically unresectable tumors. Our work demonstrates a new possibility for clinical sample acquisition and tumor modeling, opening new frontiers in the field of pediatric brain tumor research.
CNSC-01. GABAERGIC NEURON-TO-GLIOMA SYNAPSES IN DIFFUSE MIDLINE GLIOMAS
Authors: Barron Tara , Yalçın Belgin , Mochizuki Aaron , Cantor Evan , Shamardani Kiarash , Tlais Dana , Franson Andrea , Lyons Samantha , Mehta Vilina , Jahan Samin Maleki , Taylor Kathryn , Keough Michael , Xu Haojun , Su Minhui , Quezada Michael , Woo Pamelyn , Fisher Paul , Campen Cynthia , Partap Sonia , Koschmann Carl , Monje Michelle 
Published: June 2023

Abstract
High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling and direct neuron-to-glioma synapses. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric and adult high-grade gliomas, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation, we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam – a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety - increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and DMG cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.