bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTEH-9. scRNA sequencing of proneural GBM avatar model reveals acquisition of oncogenic transcriptional programming and infers a developmental path towards a genomically unstable state
Authors: Taylor Brett M , Chaim Isaac A , Koga Tomoyuki , Miki Shunichiro , Yee Brian E , Yeo Gene W , Furnari Frank B 
Published: July 2021

Abstract
Glioblastomas (GBMs) are the most common malignant primary brain tumors, and the paucity of novel treatments warrants an investigation of its origins and development into aggressive, lethal tumors. Koga & Chaim et al. have recently shown that human pluripotent stem cells (hiPSCs) with different combinations of driver mutations can be differentiated into neural progenitor cells (NPCs) and engrafted into mice to form high grade gliomas (iHGGs). In this work, scRNA seq analysis was used to investigate the development of TP53−/−;PDGFRAΔ8–9 iHGGs, an avatar model that has been shown to recapitulate the proneural subtype of GBM. After re-engrafting the primary avatar cultures (secondary tumor stage), the TP53−/−;PDGFRAΔ8–9 iHGGs developed diverse transcriptional programming and acquired a subpopulation of cells with high expression of known GBM oncogenes, such as MYC, CDK4, and PDGFRA. Notably, when all datasets were aggregated, this oncogene amplifying transcriptional program became the largest source of variation between all stages and replicates of the TP53−/−;PDGFRAΔ8–9 iHGGs. Indicated by a larger total copy number variation (CNV), this oncogene-amplifying program was associated with a genomically unstable developmental state. Trajectory inference could track the development of this population from the initial primary culture of TP53−/−;PDGFRAΔ8–9 iHGG. Differential gene expression analysis identified distinct divergences in clonal evolution––e.g., high expression of the S100 protein family in one cluster––following the acquisition of this genomically unstable state. Lastly, genomic PCR was used to ascertain whether these changes in transcriptional programming were reflected in changes in DNA copy number and identified DNA amplifications of MYC and CDK4. Our scRNA seq analysis of the GBM avatar model platform provides novel insight into how oncogenic states in GBM develop from a small number of driver mutations.
OTEH-10. Evolutionary trajectory of epigenomic of gliomas
Authors: Malta Tathiane , Sabedot Thais , Datta Indrani , Varn Frederick , Castro AnaValeria , Garofano Luciano ,   GLASS Consortium, Verhaak Roel , Iavarone Antonio , Poisson Laila , Noushmehr Houtan 
Published: July 2021

Abstract
Gliomas are the most common malignant brain tumor, have an aggressive behavior, and invariably relapse and progress. Despite the recent advancements, little is known about the role of the epigenome in glioma disease progression and recurrence. To investigate the molecular dynamics over time and in response to therapeutic pressures, the Glioma Longitudinal AnalySiS (GLASS) Consortium, a multinational collaboration, is investigating epigenome-wide molecular data from primary and recurrent matched pairs, including IDH mutant (IDHmut) and IDH wildtype (IDHwt) gliomas. We have compiled a total of 357 samples comprising 143 primary-recurrent pairs profiled by DNA methylation, of which 157 samples have genomic data (WXS/WGS) and 120 have transcriptomic data (RNAseq). IDHwt gliomas have a distinct epigenetic evolution compared to IDHmut after treatment. IDHwt gliomas are more epigenetically stable over time, while IDHmut gliomas display a loss of DNA methylation throughout disease progression. Next, we investigated the molecular drivers of longitudinal gliomas by integration of DNA methylation and gene expression data. We identified epigenetic activation of cell cycle pathways in recurrent IDHmut compared to initial tumors. Transcription factors musculin, ZNF367, and ZNF682 are enriched among recurrent IDHmut gliomas and potentially regulate IDHmut recurrence and/or progression. We next used a DNA methylation-based deconvolution approach to estimate the tumor microenvironment (TME) composition. We found that the TME among IDHmut subtypes (Codel, GCIMP-high, and GCIMP-low) presented less immune infiltration than IDHwt (Classic-like, Mesenchymal-like, and PA-like). Post-treatment, we found a decrease of CD4+T and an increase of CD8+T cells in IDHmut. In conclusion, IDHmut gliomas present a more unstable epigenome, while the epigenome of IDHwt gliomas seems relatively preserved after treatment. We identified potential master regulators of cell cycle deregulation of IDHmut recurrence. Finally, the TME differs across IDHmut and IDHwt gliomas and the cell composition changes over time.
OTME-3. Dissection of the role of stromal microenvironment and tumor-TME crosstalk in pediatric brain cancer
Authors: Federico Aniello , Kool Marcel 
Published: July 2021

Abstract
Brain tumors are the deadliest malignancies that occur during childhood and strong efforts are required to develop innovative therapeutic strategies. The intrinsic capacity of malignant cells to organize, shape and exploit the surrounding environment where they develop (tumor microenvironment, TME), has not been fully elucidated for pediatric brain cancers yet. Here, we exploited a multi-omic approach to define the TME cell populations and their contributions in the most common pediatric brain tumor entities, such as medulloblastomas and ependymomas. Analysis of single-cell RNA sequencing data of human tumors resulted in the identification of heterogeneous populations of non-malignant cells present in the TME. In particular, re-clustering and marker-based cell type assignment strategies allowed to define a broad range of immune and stromal subclasses showing distinctive expression signatures reflecting variegated functional roles. By cross-matching the tumor data with normal brain expression atlases, we could further refine the annotation of the newly identified stromal functional subpopulations and define the “tumor-associated” marker signatures of genes exclusively enriched in stromal cells within the TME, linked to immune activation, cell adhesion and cytokine regulation pathways. Bulk transcriptomic data of human tumors and matching patient-derived xenografts (PDXs) showed that a group of secreted stromal factors acting as regulators of tumorigenic mechanisms, such as IGF2 and COL4A1, are lost after xenografting and replaced by the host murine microenvironment, suggesting that tumor cells are involved in paracrine and bivalent crosstalk with TME cells, impacting on tumor cell growth and progression. Finally, bulk deconvolution and cell-cell communication analysis were exploited to define, respectively, the stromal cell proportions and the key factors involved in the tumor-TME crosstalk; this latter can be considered as possible targets for tailored and more specific anti-tumor therapeutic strategies.
OTME-17. Single cell characterization of the immune microenvironment of melanoma brain and leptomeningeal metastases
Authors: Smalley Inna , Chen Zhihua , Phadke Manali , Li Jiannong , Yu Xiaoqing , Wyatt Clayton , Evernden Brittany , Messina Jane , Sarnaik Amod , Sondak Vernon , Zhang Chaomei , Law Vincent , Tran Nam , Etame Arnold , Macaulay Robert , Eroglu Zeynep , Forsyth Peter , Rodriguez Paulo , Chen Ann , Smalley Keiran 
Published: July 2021

Abstract
Melanoma brain metastases (MBM) and leptomeningeal metastases (LMM) are two manifestations of melanoma dissemination to the CNS with vastly different survival outcomes. Analysis of single cell RNA-Seq data from 43 clinical specimens has uncovered a distinct, immune-suppressed T cell landscape in the LMM microenvironment that is distinct to those of the brain and skin metastases. An LMM patient with an extraordinarily long survival and documented response to therapy demonstrated an immune repertoire that was distinct from those of typical poor survivors and more similar to CSF from non-LMM donors. Analysis of serial specimens over the course of therapy demonstrated reductions in melanoma cells and macrophages, coupled with increased levels of T cells and dendritic cells in the CSF of the extraordinary responder, whereas poor survivors showed no improvement in T cell responses. In MBM patients, targeted therapy and immunotherapy was associated with increased immune infiltrate, with similar T cell transcriptional diversity noted between skin metastases and MBM - suggestive of immune cell trafficking into the brain. Treatment with targeted therapy was associated with an enrichment of CD8 T cells. Immunotherapy was associated with a more diverse lymphocyte landscape and higher numbers of antibody-producing cells. These findings were confirmed by multiplexed staining of patient specimens and using an immune-competent mouse model of MBM. Correlation analysis across the entire immune landscape identified the presence of a rare, novel population of dendritic cells (DC3s) to be correlated with increased overall survival, regardless of disease site/treatment. The presence of DC3s positively regulated the immune environment of both patient samples and preclinical melanoma models through modulation of activated T cells and MHC expression in the tumor. Our study provides the first comprehensive atlas of two distinct sites of melanoma CNS metastases and identifies rare populations of cells that underlie the biology of this devastating disease.
OTME-21. The role of Glioblastoma associated mesenchymal stem cells in immune suppression
Authors: Dharma Sanam Sahjram , Barone Tara , Figel Sheila , Birkemeier Meaghan , Zhang Yali , Fenstermaker Robert , Ciesielski Michael 
Published: July 2021

Abstract
Glioblastoma (GBM) is an aggressive brain cancer, with an overall survival of 14.6 months. The tumor microenvironment in GBM plays major roles in immunosuppression and modulation of the response to therapies. GBM patients with higher levels of mesenchymal stem like cells (G-MSC) show poor overall survival as compared to patients with no/lower G-MSC levels. Our lab found that levels of G-MSC corelate with CD4+ T cells in humans and murine models of GBM, and with immunosuppressive molecules like PTGS2, the gene for cyclooxygenase 2. To investigate the mechanism by which G-MSCs promote immunosuppression, we isolated G-MSCs from an orthotopic mouse model of GBM and subjected them to RNASeq analysis to obtain an unbiased picture of transcriptomic changes occurring upon activation. We identified changes in multiple immune modulating pathways involving antigen presentation, leukocyte migration and activation, and immune checkpoints. Our findings indicate that G-MSCs represent a key immune modulating faction in the microenvironment. Further dissection of the role of these cells in immune modulation will aid us in understanding the biology of the brain tumor microenvironment and identifying potential combination therapies.
De-democratization and the Politics of Knowledge: Unpacking the Cultural Marxism Narrative
Authors: Paternotte David , Verloo Mieke 
Published: July 2021

AbstractThe politics of knowledge matter to the current wave of de-democratization in Europe. Building on Walby’s social complexity theory, this article highlights the dynamics between epistemic configurations and contemporary politics. Focusing on academic institutions, and taking gender studies as an illustration, this article shows that actors opposing (social) sciences and academia not only aim to dismantle existing institutions of knowledge production but also promote a new politics of truth. In this, the Cultural Marxism master frame operates as a diagnosis and a prognosis frame, providing the base for attacks on academia and for a strategy of profound transformation of the realm of knowledge in Europe.
Factors associated with new persistent opioid use after ankle sprain: a cross-sectional analysis
Authors: Gossett Timothy D. , Finney Fred T. , Hu Hsou Mei , Waljee Jennifer F. , Brummett Chad M. , Walton David M. , Talusan Paul G. , Holmes James R. 
Published: July 2021

Background:
Chronic opioid use is a growing crisis in the United States. The authors examined the risk factors associated with new persistent opioid use in patients who had nonoperatively treated ankle sprains and offer evidence-based treatment recommendations for practitioners.

Methods:
A United States insurance claims database was used to select patients who underwent nonoperative treatment of an ankle sprain between January 2008 and December 2016. The authors examined opioid prescribing 1 yr before diagnosis and 6 mo after and defined new persistent opioid use as prescription fulfillment between 91 and 180 days after injury. We evaluated the effect of patient factors and amount prescribed on the likelihood of new persistent opioid use and the probability of refill within 30 days using logistical regression analysis.

Results:
A total opioid dose of 150 mg oral morphine equivalents (OMEs) prescribed within 7 days of diagnosis was the greatest modifiable risk factor for new persistent opioid use [adjusted odds ratio (aOR) 1.38, 95% confidence interval (CI), 1.28 to 1.49, P<0.001] and for likelihood of refill within 30 days (aOR, 2.22, 95% CI, 2.10 to 2.35, P<0.001). Additional factors included tobacco use, medical comorbidities, and certain pain and mental health disorders.

Conclusions:
New persistent opioid use is common in patients who had nonoperatively treated acute ankle sprains and is linked to identifiable patient and prescribing factors. Factors associated with new persistent opioid use include high initial prescribed dose, tobacco use, medical comorbidities, and certain pain and mental health disorders. These factors were also associated with a higher probability of refill. There is strong evidence-based support for the treatment of these injuries without opioids.

Level of Evidence:
Level III.
Efficacy of Intraoperative Neuromonitoring Using Transcranial Motor-Evoked Potentials for Degenerative Cervical Myelopathy
Authors: Funaba Masahiro , Kanchiku Tsukasa , Yoshida Go , Imagama Shiro , Kawabata Shigenori , Fujiwara Yasushi , Ando Muneharu , Yamada Kei , Taniguchi Shinichirou , Iwasaki Hiroshi , Tadokoro Nobuaki , Takahashi Masahito , Wada Kanichiro , Yamamoto Naoya , Shigematsu Hideki , Kobayashi Kazuyoshi , Yasuda Akimasa , Ushirozako Hiroki , Ando Kei , Hashimoto Jun , Morito Shinji , Takatani Tsunenori , Tani Toshikazu , Matsuyama Yukihiro 
Published: July 2021

Study Design.
A prospective multicenter observational study.

Objective.
To elucidate the efficacy of transcranial motor-evoked potentials (Tc(E)-MEPs) in degenerative cervical myelopathy (DCM) surgery by comparing cervical spondylotic myelopathy (CSM) to cervical ossification of the posterior longitudinal ligament (OPLL) and investigate the timing of Tc(E)-MEPs alerts and types of interventions affecting surgical outcomes.

Summary of Background Data.
Although CSM and OPLL are the most commonly encountered diseases of DCM, the benefits of Tc(E)-MEPs for DCM remain unclear and comparisons of these two diseases have not yet been conducted.

Methods.
We examined the results of Tc(E)-MEPs from 1176 DCM cases (840 CSM /336 OPLL) and compared patients background by disease, preoperative motor deficits, and the type of surgical procedure. We also assessed the efficacy of interventions based on Tc(E)-MEPs alerts. Tc(E)-MEPs alerts were defined as an amplitude reduction of more than 70% below the control waveform. Rescue cases were defined as those in which waveform recovery was achieved after interventions in response to alerts and no postoperative paralysis.

Results.
Overall sensitivity was 57.1%, and sensitivity was higher with OPLL (71.4%) than with CSM (42.9%). The sensitivity of acute onset segmental palsy including C5 palsy was 40% (OPLL/CSM: 66.7%/0%) whereas that of lower limb palsy was 100%. The most common timing of Tc(E)-MEPs alerts was during decompression (63.16%), followed by screw insertion (15.79%). The overall rescue rate was 57.9% (OPLL/CSM: 58.3%/57.1%).

Conclusion.
Since Tc(E)-MEPs are excellent for detecting long tract injuries, surgeons need to consider appropriate interventions in response to alerts. The detection of acute onset segmental palsy by Tc(E)-MEPs was partially possible with OPLL, but may still be difficult with CSM. The rescue rate was higher than 50% and appropriate interventions may have prevented postoperative neurological complications.

Level of Evidence: 3
Stratification for Identification of Prognostic Categories In the Acute RESpiratory Distress Syndrome (SPIRES) Score
Authors: Villar Jesús , González-Martín Jesús M. , Ambrós Alfonso , Mosteiro Fernando , Martínez Domingo , Fernández Lorena , Soler Juan A. , Parra Laura , Solano Rosario , Soro Marina , del Campo Rafael , González-Luengo Raúl I. , Civantos Belén , Montiel Raquel , Pita-García Lidia , Vidal Anxela , Añón José M. , Ferrando Carlos , Díaz-Domínguez Francisco J. , Mora-Ordoñez Juan M. , Fernández M. Mar , Fernández Cristina , Fernández Rosa L. , Rodríguez-Suárez Pedro , Steyerberg Ewout W. , Kacmarek Robert M. 
Published: July 2021

OBJECTIVES:
To develop a scoring model for stratifying patients with acute respiratory distress syndrome into risk categories (Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score) for early prediction of death in the ICU, independent of the underlying disease and cause of death.

DESIGN:
A development and validation study using clinical data from four prospective, multicenter, observational cohorts.

SETTING:
A network of multidisciplinary ICUs.

PATIENTS:
One-thousand three-hundred one patients with moderate-to-severe acute respiratory distress syndrome managed with lung-protective ventilation.

INTERVENTIONS:
None.

MEASUREMENTS AND MAIN RESULTS:
The study followed Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis guidelines for prediction models. We performed logistic regression analysis, bootstrapping, and internal-external validation of prediction models with variables collected within 24 hours of acute respiratory distress syndrome diagnosis in 1,000 patients for model development. Primary outcome was ICU death. The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score was based on patient’s age, number of extrapulmonary organ failures, values of end-inspiratory plateau pressure, and ratio of Pao
2 to Fio
2 assessed at 24 hours of acute respiratory distress syndrome diagnosis. The pooled area under the receiver operating characteristic curve across internal-external validations was 0.860 (95% CI, 0.831–0.890). External validation in a new cohort of 301 acute respiratory distress syndrome patients confirmed the accuracy and robustness of the scoring model (area under the receiver operating characteristic curve = 0.870; 95% CI, 0.829–0.911). The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score stratified patients in three distinct prognostic classes and achieved better prediction of ICU death than ratio of Pao
2 to Fio
2 at acute respiratory distress syndrome onset or at 24 hours, Acute Physiology and Chronic Health Evaluation II score, or Sequential Organ Failure Assessment scale.

CONCLUSIONS:
The Stratification for identification of Prognostic categories In the acute RESpiratory distress syndrome score represents a novel strategy for early stratification of acute respiratory distress syndrome patients into prognostic categories and for selecting patients for therapeutic trials.
Phospholipid Screening Postcardiac Arrest Detects Decreased Plasma Lysophosphatidylcholine: Supplementation as a New Therapeutic Approach
Authors: Nishikimi Mitsuaki , Yagi Tsukasa , Shoaib Muhammad , Takegawa Ryosuke , Rasul Rehana , Hayashida Kei , Okuma Yu , Yin Tai , Choudhary Rishabh C. , Becker Lance B. , Kim Junhwan 
Published: July 2021

OBJECTIVES:
Cardiac arrest and subsequent resuscitation have been shown to deplete plasma phospholipids. This depletion of phospholipids in circulating plasma may contribute to organ damage postresuscitation. Our aim was to identify the diminishment of essential phospholipids in postresuscitation plasma and develop a novel therapeutic approach of supplementing these depleted phospholipids that are required to prevent organ dysfunction postcardiac arrest, which may lead to improved survival.

DESIGN:
Clinical case control study followed by translational laboratory study.

SETTING:
Research institution.

PATIENTS/SUBJECTS:
Adult cardiac arrest patients and male Sprague-Dawley rats.

INTERVENTIONS:
Resuscitated rats after 10-minute asphyxial cardiac arrest were randomized to be treated with lysophosphatidylcholine specie or vehicle.

MEASUREMENTS AND MAIN RESULTS:
We first performed a phospholipid survey on human cardiac arrest and control plasma. Using mass spectrometry analysis followed by multivariable regression analyses, we found that plasma lysophosphatidylcholine levels were an independent discriminator of cardiac arrest. We also found that decreased plasma lysophosphatidylcholine was associated with poor patient outcomes. A similar association was observed in our rat model, with significantly greater depletion of plasma lysophosphatidylcholine with increased cardiac arrest time, suggesting an association of lysophosphatidylcholine levels with injury severity. Using a 10-minute cardiac arrest rat model, we tested supplementation of depleted lysophosphatidylcholine species, lysophosphatidylcholine(18:1), and lysophosphatidylcholine(22:6), which resulted in significantly increased survival compared with control. Furthermore, the survived rats treated with these lysophosphatidylcholine species exhibited significantly improved brain function. However, supplementing lysophosphatidylcholine(18:0), which did not decrease in the plasma after 10-minute cardiac arrest, had no beneficial effect.

CONCLUSIONS:
Our data suggest that decreased plasma lysophosphatidylcholine is a major contributor to mortality and brain damage postcardiac arrest, and its supplementation may be a novel therapeutic approach.