bluuebunny/crossref_metadata_2025_split huggingface dataset:
1236 Skull-Derived Myeloid Cells Augment T Cell Responses and Suppress Glioblastoma Growth
Authors: Lad Meeki , Young Jacob , Lui Austin , Salha Diana , Aghi Manish Kumar 
Published: March 2024

INTRODUCTION:
Recent studies have implicated skull marrow as a functional myeloid reservoir in CNS pathology. However, its contribution to malignancy remains unexplored.

METHODS:
Fluorescently labeled calvarial flaps were transplanted onto syngeneic glioblastoma-bearing mice, followed by flow cytometric profiling of tumor-infiltrative leukocytes. To assay SDMC function, tumor-bearing C57BL/6 mice were treated with preemptive calvarial ablation (13 Gy irradiation), or conversely intracalvarial AMD3100 to augment myeloid egress from marrow niches. Tumor burden was monitored via survival and bioluminescent imaging.

RESULTS:
72 h following CMFDA-stained calvarial transplantation into tumor-bearing Balb/C mice, 40.3% of tumor-infiltrative myeloid cells were fluorescent and thus skull-derived; transplantation in an alternative longitudinal model (GFP+ flaps, C57BL/6) validated that SDMCs were robust and viable at 3 weeks post-operatively. As MHCII+ cells were disproportionately enriched among SDMCs (87.9% vs 67.3%, p = 0.012), we interrogated the immunogenicity of these cells through targeted ablation. Indeed, skull-ablated mice had reduced aggregate infiltration by antigen-presenting cells than controls (cDCs: 1.1% vs 4.5%, p = 0.002; macrophages: 14.4% vs 36.6%, p < 0.001) and 6-fold greater necrosis (67.7% vs 13.5% apoptotic, p < 0.001), suggesting an impaired ability to mount a controlled, adaptive immune response. The stimulatory role of SDMCs was further demonstrated via intracalvarial AMD3100 administration, which through its promotion of myeloid precursor egress (0.26% vs 0.02%, p < 0.001) and cDC2 infiltration (10.4% vs 3.0%, p = 0.003) yielded robust CD4+ T cell activation and effector memory differentiation. These differences were clinically meaningful, as skull irradiation accelerated tumor growth and attenuated survival compared to controls, while the opposite was observed with AMD3100 treatment (median OS: 17d vs 22d, p < 0.001; 26.5 d vs 22 d, p = 0.006).

CONCLUSIONS:
The preferential polarization of SDMCs into immunostimulatory APCs warrants the continued exploration of local marrow-targeting agents (e.g., AMD3100) as therapeutic modalities.
1239 Trends in Geospatial Availability of Neuro-oncology Clinical Trials in the United States Over Two Decades
Authors: Naik Anant , Smith Emily Jean , Germano Isabelle M. 
Published: March 2024

INTRODUCTION:
Advances in brain tumors treatments rely on successful neuro-oncology (NO) clinical trials. To date, data on NO trials completion in the US is scarce. Understanding these factors could help improve access to and the design of future clinical trials.

METHODS:
NO clinical trials registered in the US were analyzed (2000-2019). Univariate and multivariate analysis were used to compare success rates among trials. Geospatial analysis was performed to determine the trial density and failure rates across different states. Trial density was estimated by the number of trials/state population.

RESULTS:
A total of 2,610 neuro-oncology clinical trials were registered in the US during the study period, of which 1,257 met a primary endpoint – completion or trial failure. North Dakota had the highest trial density (6.03 trials/100,000 residents), followed by South Dakota (5.83) and several Northeastern states (3.90-5.60). The change in trial failure rates did not correlate with trial density by state (p = 0.777). The states with the greatest increase in trial failure rates were Nevada (23.1%), West Virginia, Alaska, and Idaho (all three at 20.0%). Florida showed a trend towards a statistically significant increase in failure rates to 10.9% (p = 0.09).

CONCLUSIONS:
The results of this study highlight the variations in success rates and geographic distribution of neuro-oncology clinical trials in the United States. Factors beyond trial density may be critical to trial success. The significant geographic variations in trial density and failure rates across states emphasize the need for targeted efforts to improve access participation to trials in certain regions. Further studies aimed at identifying the factors contributing to the increase in trial failure rates are needed to develop strategies to improve trial enrollment.
1242 Metabologenomic Characterization Uncovers Heterogeneity Amongst IDH Mutant Gliomas
Authors: Ajisebutu Andrew A. , Mamatjan Yasin , Nassiri Farshad , Nejad Romina , Patil Vikas , Wang Justin Z. , Liu Jeff , Zadeh Gelareh 
Published: March 2024

INTRODUCTION:
Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas through the accumulation of oncometabolite R-2-hydroxyglutarate which drives the widespread restructuring of the DNA methylome; however, beyond R-2-hydroxyglutarate, a comprehensive metabologenomic characterization of IDH-mutant gliomas has yet to be performed.

METHODS:
Glioma samples from a cohort of 154 patients underwent multiplatform molecular analysis, including metabolomic studies, genome-wide DNA methylation profiling and bulk RNA sequencing. A integrative analysis was performed, including hierarchical clustering and principal component analysis of identified metabolites, differentially methylated probes, copy number alteration and bulk mRNA data. Survival analysis as well as multivariable hazard ratios for clinical variables were calculated by fitting Cox Proportional Hazards Models.

RESULTS:
We discovered a group of IDH-mutant gliomas whose metabolic profile highly resembled IDH wildtype tumors. Notably, these IDH-mutant gliomas with dysregulated metabolism were distinguished from their IDH-mutant counterparts by significantly shorter overall survival (median OS 118.9 months vs 173.6 months, p=0.048). The IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles. The prognostic relevance of dysregulated metabolism complements, but was not wholly explained by canonically recognized prognostic classifications in IDH-mutant gliomas including 1p/19q codeletion, glioma CpG Island Hypermethylator (GCIMP) status and CDKN2A homozygous deletion.

CONCLUSIONS:
Utilizing a cross-platform analysis we have uncovered a novel subtyping of IDH-mutant gliomas with dysregulated cellular metabolism with similar survival to IDH-wildtype tumors. The metabolic profile provides unique information on glioma phenotypes, which may facilitate a more comprehensive understanding of glioma biology, and provide a window to target novel dependencies.
1245 Malignant Meningioma Survival, Recurrence and Functional Outcomes in an International Multicenter Cohort
Authors: Rebchuk Alexander , Tosefsky Kira , Wang Justin Z. , Ellenbogen Yosef , Drexler Richard , Ricklefs Franz Lennard , Sauvigny Thomas , Schüller Ulrich , Cutler Christopher , Lucke-Wold Brandon , Mehkri Yusuf , Lama Sanju , Sutherland Garnette R. , Karsy Michael , Hoh Brian Lim , Westphal Manfred , Zadeh Gelareh , Yip Stephen , Makarenko Serge 
Published: March 2024

INTRODUCTION:
Meningiomas are the most common intracranial tumor. Grade 3 (malignant) meningiomas are the most aggressive subtype and represent 1-3% of all meningiomas cases.

METHODS:
Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated.

RESULTS:
We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227) and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). Older age (=65 years old) and male sex were independent predictors of worse OS and PFS in multivariate regression analysis. Postoperative radiotherapy was independently associated with improved OS in all patients and a sensitivity analysis including only patients =65 years old. Functional status, as measured by Karnofsky performance status, was stable between preoperative (median: 80 [IQR: 70, 90]), postoperative (median: 90 [IQR: 70, 98]) and 1-year postoperative (median: 70 [IQR: 50, 80]) timepoints.

CONCLUSIONS:
This study provides robust survival, recurrence, and functional outcome data for malignant meningiomas in North America and Europe over a 30-year period. We demonstrate that older age and male sex are associated with worse survival and recurrence outcomes. We further affirm that adjuvant radiotherapy confers a survival benefit in the treatment of malignant meningiomas, including in patients older than 65 years. Despite concerns around surgical and radiotherapy treatment complications, functional status remains stable in the first year following treatment of malignant meningiomas.
141 Motor and Somatosensory Applications for Nerve Cuff Electrodes in Clinical Neuroprosthesis and Neurorehabilitation
Authors: Abraham Mickey Ellis , Beyer Ryan , Brown Nolan James , Zomalan Brolyn , Lee Gold Justin , Sahyouni Ronald , Khalessi Alexander A. , Murthy Nikhil Krishna 
Published: March 2024

INTRODUCTION:
Surgically implanted neuroprosthetics aim to restore motor and somatosensory function by delivering controlled electrical impulses to paralyzed nerves. Recently, nerve cuff electrodes (NCEs) have been increasingly studied and may eventually offer the potential to recover somatomotor function in patients with neurologic injury.

METHODS:
The PubMed, Google Scholar, and Web of Science databases were searched to identify relevant articles published between 2012 – 2022 describing use of neuroprosthetic NCEs for clinical somatomotor rehabilitation. Data from all relevant articles retrieved were collected and summarized.

RESULTS:
NCE-neural interfaces can restore both upper and lower extremity motor function in spinal cord injury patients and may provide a treatment modality superior to that of muscle-based electrodes. The search yielded 137 studies, and of those reviewed, 18 were original research articles that used peripheral nerve stimulation to elicit motor actions and/or somatosensory perceptions through NCEs. 10 studies looked at restoring motor function in patients with spinal cord injuries or stroke-related paralysis and 7 studies looked at somatosensory applications of NCEs in patients with amputations. Currently, sensory NCE interfacing can restore and improve multiple aspects of sensation in amputees. While there is room for further study in various applications, technological improvements and wider clinical adoption, NCEs have been demonstrated to provide a clinically acceptable option in reducing intraoperative duration and morbidity, while preserving long-term functional stability, threshold charge maintenance, and acceptable mechanical failure rates.

CONCLUSIONS:
NCEs appear to be a promising avenue for future research in the field of neuroprosthetics. As the translational avenue continues to mature and more clinical studies become avaiable, the utility of NCEs will be better understood.
145 Encoding Brain Dynamics: Neuropsychological Test Scores as Predictors of iEEG Spectral Features in Epilepsy
Authors: Hattab Tariq , Krieg Jordan , Kawtharani Sarah , Koenig Seth , Waldron Eric , Herman Alexander , Darrow David P. 
Published: March 2024

INTRODUCTION:
Intracranial EEG is a valuable tool for investigating the neural mechanisms underlying medically refractory epilepsy (MRE). Despite the advances made in understanding the condition, there is a lack of research exploring the relationship between iEEG data and neuropsychological test performance in MRE patients.

METHODS:
We performed a retrospective analysis of resting-state iEEG data from 70 MRE patients, extracting spectral features from 4.4 million 10-second time windows across 5201 electrodes. Using MATLAB and FieldTrip toolbox, we processed the data and used two brain atlases for probabilistic electrode assignment. Neuropsychological test scores were corrected for demographic factors. Relationships between preoperative neuropsychological test scores and spectral features were explored using nested hierarchical generalized linear mixed effects (GLME) models, focusing on the hippocampus.

RESULTS:
We found significant associations between neuropsychological tests and hippocampal power spectral densities (PSDs). Rey Auditory verbal learning test (RAVLT) recognition correct and short-term retention percentages were significantly associated with relative power (RP) in the beta-range (p < 0.05, FDR-corrected). The Boston naming test and Trail Making Test (TMT)-A finishing time showed significant associations with high-beta/low-gamma PSD (p < 0.05, FDR-corrected). TMT-B errors are positively correlated with delta/theta RP (p < 0.05, FDR-corrected).

CONCLUSIONS:
Our study provides novel insights into the relationship between iEEG spectral features and neuropsychological test performance in MRE patients. The findings suggest that the heterogeneity in spectral features may explain relevant cognitive performance, highlighting the biological basis and circuits of neuropsychological testing.
146 Intracranial Correlates of Fear Memory in Freely Moving Humans During Virtual Reality
Authors: Gill Jay , Langevi Jean-Philippe , Suthana Nanthia 
Published: March 2024

INTRODUCTION:
Distressing reactions to perceived threats in safe environments is a hallmark feature of anxiety-related disorders such as post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD). The development of targeted neural circuit therapies requires an understanding of how neurophysiological activity relates to behavior and subjective emotional experience.

METHODS:
The task induced memories fear memories, a critical component of anxiety-related disorders etiology, using a novel virtual reality platform. Here, participants freely explored a virtual reality environment via walking or joystick. Participants were instructed to stop movement following color change of the room. When the room turned green (CS+), a noxious virtual reality stimulus (insect) attacked the participant (US) 6 seconds following color change onset. When the room turned blue (CS-), no noxious VR stimulus occurred. In addition to intracranial electroencephalography (iEEG) activity, we recorded physiological and behavioral metrics of fear.

RESULTS:
We found that the same neural signature indicative of fear memory retrieval in rodents (increased amygdala theta oscillations) was significantly elevated for the fear compared to the neutral cue in freely behaving humans.

CONCLUSIONS:
These findings represent an important step in translating decades of research in rodents to humans and provide putative electrophysiological signatures of fear behavior that can be used as putative targets for treatment with closed loop brain stimulation therapies. We believe that this combined collection of simultaneous autonomic responses to subjective emotional (fear ratings and physiology), clinical symptoms (anxiety scales) and neural activity has immense transdiagnostic clinical potential for anxiety-related disorders and can inform neurosurgical approaches to treating severe psychopathology.
152 Integrated Clinical Genomic Analysis Reveals Xenobiotic Metabolic Genes are Downregulated in Meningiomas of Current Smokers
Authors: Basit Khan A. Basit , Patel Rajan , McDonald Malcolm F. , Goethe Eric , English Collin , Gadot Ron , Shetty Arya , Harmanci Arif , Harmanci Akdes , Klisch Tiemo , Patel Akash J. 
Published: March 2024

INTRODUCTION:
Meningiomas are the most common primary intracranial tumor. We sought to identify clinical drivers of different molecular changes in meningioma. As such, clinical and genomic consequences of smoking in patients with meningiomas remain unexplored.

METHODS:
88 tumor samples were analyzed. Whole exome sequencing (WES) was used to assess somatic mutation burden. RNA sequencing data was used to identify differentially expressed genes (DEG) and genes sets (GSEA).

RESULTS:
Fifty-seven patients had no history of smoking, thirty-one patients had history of ever smoking. Smokers were less likely to present with headache (p = 0.045) or have incidentally discovered meningiomas (p = 0.049). WES revealed no difference in canonical mutation burden. Smokers had increased mutation rate in KRTAP1-3, RECQL4, PTPRT, and PLB1 compared to never smokers (p < 0.05). Mutational signature from smokers showed disrupted DNA mismatch repair (cosine-similarity = .784). DEG analysis of current smokers as compared to past or never smokers revealed the xenobiotic metabolic genes UGT2A1 and UGT2A2 were both significantly downregulated in current smokers compared to past (Log2FC = -3.97, padj = 0.0347 and Log2FC = -4.18, padj = 0.0304) and never smokers (Log2FC = -3.86, padj = 0.0235 and Log2FC = -4.20, padj = 0.0149). GSEA analysis of current smokers showed downregulation of xenobiotic metabolism and enrichment for G2M checkpoint, E2F targets, and mitotic spindle compared to past and never smokers (FDR <25% each).

CONCLUSIONS:
There are limited differences in the clinical course of meningioma patients who smoke. There is no difference in burden of canonical mutations in meningiomas from patients who smoke, but differential mutation in several novel meningioma genes is identified. Mutational signatures in meningiomas from smokers show disrupted DNA mismatch repair. Meningiomas from current smokers demonstrate downregulation of xenobiotic metabolic enzymes UGT2A1 and UGT2A2, which are downregulated in other smoking related cancers. Taken together, our demonstrate novel alterations in meningioma molecular biology in response to systemic carcinogens.
179 Stem Progenitor Cell Proliferation in the Brainstem After Spinal Cord Injury: A Potential Target for Therapeutic Intervention Distant From the Site of Injury
Authors: Carmichael Marc , Hayes Nancy , Nowakowski Richard 
Published: March 2024

INTRODUCTION:
Though there has been an increasing number of clinical trials focused on modulating stem/progenitor cell proliferation in the spinal cord after spinal cord injury (SCI), little is known about the acute response of stem/progenitor cells in supraspinal structures. We hypothesized that the signals stimulating stem/progenitor cell proliferation in the spinal cord after SCI activate similar responses in supraspinal regions because pathways injured in the spinal cord have their targets or sources in the brain.

METHODS:
We employed a mouse model of SCI, bromodeoxyuridine (BrdU) labeling of cells in S-phase, and co-labeling of markers of astrocytes, microglia, glial/oligodendrocyte precursor cells, and neuronal lineages to characterize the proliferative response within the brainstem of C57BL/6J mice 96 hours after a thoracic SCI. The extent of SCI and white matter (WM) spared was quantified by labeling of beta amyloid precursor protein and eriochrome cyanine R staining, respectively.

RESULTS:
Compared to sham-operated mice, there was a significant increase (3-fold; p < 0.01) in BrdU-labeled cells in the ventral-caudal medulla of injured mice. This response was consistent with the extent of SCI and primarily in WM tracts (57%) and the inferior olive (41%; IO). Co-labeling with cell-specific markers indicated that this response is glial (i.e., NG-2+ glial/oligodendrocyte precursor cells and GFAP+ astrocytes) with the largest increase in the number of BrdU-labeled cells occurring in the IO (6-fold increase; p < 0.01). Notably, there were no BrdU-labeled cells that co-labeled with markers of microglia or neuronal lineages.

CONCLUSIONS:
Our results demonstrate a stem/progenitor cell response within days of SCI that occurs distant from the injury site, notably in brainstem structures involved in motor learning and coordination. These findings highlight an acute response of glial/oligodendrocyte precursor cells in the brainstem as a potential target for future studies and therapeutic intervention after SCI.
180 The Impact of Brain Tissue Oxygen Monitoring With Intracranial Pressure Monitoring on Patients With Severe TBI: A National Trauma Bank Data Analysis
Authors: Nosova Kristin , Jukic Alma , Bauer Isabel L. , Deaver Courtney , Pico Annemarie Campbell , Bates Bryan , He Jack , Keric Natasha , Nakaji Peter , Bina Robert Wagner 
Published: March 2024

INTRODUCTION:
While numerous studies have demonstrated the importance of ICP monitoring in improving the mortality rate for severe traumatic brain injuries (TBI), the benefits of brain oxygenation monitoring (PbO2) in combination with ICP monitoring are still currently under investigation as part of the BOOST III trial.

METHODS:
Patients with severe TBI based on the Glascow Coma Scale were identified using National Trauma Bank data from 2019-2021. Patients who died in the ED, had ED disposition inconsistent with severe TBI, or were transferred to another hospital were excluded. Summary statistics, t-tests, chi-square tests, non-parametric tests, multivariate logistic models, and log-log regression models were used to evaluate and model the data.

RESULTS:
13,139 patients with severe TBI who underwent ICP monitoring were identified, with 709 (5%) undergoing PbO2 monitoring. Patients with PbO2 monitors had longer ICU length of stay (17.3 days vs. 14.3 days p < .05) and a longer duration of ventilation (14.5 days vs. 12 days p < .05). Additionally, patients with PbO2 monitors experienced increased rates of deep vein thrombosis and pulmonary embolism (OR 1.57 95% CI; 1.22-2.01). There was no significant difference in mortality rate with PbO2 monitoring after controlling for severity (4.5% vs. 4%, p = 0.07).

CONCLUSIONS:
PbO2 monitoring was associated with longer ICU length of stay and days ventilated, consistent with prior studies. Patients with PbO2 monitoring experienced higher rates of deep vein thrombosis and pulmonary embolism. Different from previous studies, our results indicate PbO2 monitoring does not impact mortality outcomes. Data about functional outcomes are not yet available. Further studies are needed to address this discrepancy; the ongoing BOOST III trial may provide a better understanding on the proper use of PbO2 monitoring.