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Ryan T. Mott, Kristi C. Turner, Darell D. Bigner and Roger E. McLendon

Object

DIFFUSELY infiltrating astrocytomas are the most common primary brain tumors. As a group, they demonstrate an inherent tendency toward malignant progression. Histological grading using the guidelines of the World Health Organization (WHO) remains the gold standard for predicting the biological behavior of these tumors. Although useful, this grading system is often limited due to small sample sizes and the subjectivity in interpretation. Given the important roles for EGFR and PTEN in the malignant progression of astrocytomas, the authors hypothesized that the fraction of tumor cells with aberrations in these genetic loci would correlate with the histological grade.

Methods

The authors evaluated 217 consecutive diffusely infiltrating astrocytomas that were graded using the WHO guidelines, including 16 diffuse astrocytomas (WHO Grade II), 72 anaplastic astrocytomas ([AAs] WHO Grade III), and 129 glioblastomas multiforme ([GBMs] WHO Grade IV). Cases were evaluated quantitatively using dual-color fluorescence in situ hybridization with probes for the EGFR and PTEN loci and the centromeres of chromosomes 7 and 10.

Results

The population of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus correlated significantly with histological grade. In particular, high-grade astrocytomas (that is, AAs and GBMs) had elevated fractions of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus. Using these findings, the authors generated a mathematical model capable of subcategorizing high-grade astrocytomas. The successful model incorporated only the percentage of tumor cells with polysomy of EGFR and monosomy of PTEN, as well as patient age. The predictions of this model correlated with survival in a manner similar to histopathological grading.

Conclusions

The findings presented in this study emphasize the utility of combining histological interpretation and molecular testing in the evaluation of infiltrating astrocytomas. These results underscore the utility of building a grading framework that combines histopathological and molecular analysis.

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Ryan C. Turner, Sean C. Dodson, Charles L. Rosen and Jason D. Huber

Ischemic stroke remains a leading cause of morbidity and death for which few therapeutic options are available. The development of neuroprotective agents, a once promising field of investigation, has failed to translate from bench to bedside successfully. This work reviews the ischemic cascade, agents targeting steps within the cascade, and potential reasons for lack of translation. Additional therapeutic targets are highlighted and areas requiring further investigation are discussed. It is clear that alternative targets need to be pursued, such as the role glia play in neurological injury and recovery, particularly the interactions between neurons, astrocytes, microglia, and the vasculature. Similarly, the biphasic nature of many signaling molecules such as matrix metalloproteinases and high-mobility group box 1 protein must be further investigated to elucidate periods of detrimental versus beneficial activity.

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Gennadiy A. Katsevman, Ryan C. Turner, Ogaga Urhie, Joseph L. Voelker and Sanjay Bhatia

OBJECTIVE

It is commonly reported that achieving gross-total resection of contrast-enhancing areas in patients with glioblastoma (GBM) improves overall survival. Efforts to achieve an improved resection have included the use of both imaging and pharmacological adjuvants. The authors sought to investigate the role of sodium fluorescein in improving the rates of gross-total resection of GBM and to assess whether patients undergoing resection with fluorescein have improved survival compared to patients undergoing resection without fluorescein.

METHODS

A retrospective chart review was performed on 57 consecutive patients undergoing 64 surgeries with sodium fluorescein to treat newly diagnosed or recurrent GBMs from May 2014 to June 2017 at a teaching institution. Outcomes were compared to those in patients with GBMs who underwent resection without fluorescein.

RESULTS

Complete or near-total (≥ 98%) resection was achieved in 73% (47/64) of fluorescein cases. Of 42 cases thought not to be amenable to complete resection, 10 procedures (24%) resulted in gross-total resection and 15 (36%) resulted in near-total resection following the use of sodium fluorescein. No patients developed any local or systemic side effects after fluorescein injection. Patients undergoing resection with sodium fluorescein, compared to the non–fluorescein-treated group, had increased rates of gross- or near-total resection (73% vs 53%, respectively; p < 0.05) as well as improved median survival (78 weeks vs 60 weeks, respectively; p < 0.360).

CONCLUSIONS

This study is the largest case series to date demonstrating the beneficial effect of utilizing sodium fluorescein as an adjunct in GBM resection. Sodium fluorescein facilitated resection in cases in which it was employed, including dominant-side resections particularly near speech and motor regions. The cohort of patients in which sodium fluorescein was utilized had statistically significantly increased rates of gross- or near-total resection. Additionally, the fluorescein group demonstrated prolonged median survival, although this was not statistically significant. This work demonstrates the promise of an affordable and easy-to-implement strategy for improving rates of total resection of contrast-enhancing areas in patients with GBM.

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Ryan C. Turner, Zachary J. Naser, Julian E. Bailes, David W. Smith, Joseph A. Fisher and Charles L. Rosen

Object

Helmets successfully prevent most cranial fractures and skull traumas, but traumatic brain injury (TBI) and concussions continue to occur with frightening frequency despite the widespread use of helmets on the athletic field and battlefield. Protection against such injury is needed. The object of this study was to determine if slosh mitigation reduces neural degeneration, gliosis, and neuroinflammation.

Methods

Two groups of 10 adult male Sprague-Dawley rats were subjected to impact-acceleration TBI. One group of animals was fitted with a collar inducing internal jugular vein (IJV) compression prior to injury, whereas the second group received no such collar prior to injury. All rats were killed 7 days postinjury, and the brains were fixed and embedded in paraffin. Tissue sections were processed and stained for markers of neural degeneration (Fluoro-Jade B), gliosis (glial fibrillary acidic protein), and neuroinflammation (ionized calcium binding adapter molecule 1).

Results

Compared with the controls, animals that had undergone IJV compression had a 48.7%–59.1% reduction in degenerative neurons, a 36.8%–45.7% decrease in reactive astrocytes, and a 44.1%–65.3% reduction in microglial activation.

Conclusions

The authors concluded that IJV compression, a form of slosh mitigation, markedly reduces markers of neurological injury in a common model of TBI. Based on findings in this and other studies, slosh mitigation may have potential for preventing TBI in the clinical population.

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Ryan C. Turner, Michael J. Seminerio, Zachary J. Naser, J. Neal Ford, Samantha J. Martin, Rae R. Matsumoto, Charles L. Rosen and Jason D. Huber

Object

Despite the role of aging in development of neurological and neurodegenerative diseases, the effects of age are often disregarded in experimental design of preclinical studies. Functional assessment increases the clinical relevance of animal models of neurological disease and adds value beyond traditional histological measures. However, the relationship between age and functional impairment has not been systematically assessed through a battery of functional tests.

Methods

In this study, various sensorimotor and behavioral tests were used to evaluate effects of aging on functional performance in naive animals. Sensorimotor measures included locomotor activity; Rotarod, inclined plane, and grip-strength testing; and modified Neurological Severity Score. The Morris water maze was used to examine differences in learning and memory, and the elevated plus maze and forced swim test were used to assess anxiety-like and depressive-like behaviors, respectively.

Results

Older Sprague-Dawley rats (18–20 months) were found to perform significantly worse on the inclined plane tests, and they exhibited alterations in elevated-plus maze and forced swim test compared with young adult rats (3–4 months). Specifically, older rats exhibited reduced exploration of open arms in elevated plus maze and higher immobility time in forced swim test. Spatial acquisition and reference memory were diminished in older rats compared with those in young adult rats.

Conclusions

This study demonstrates clear differences between naive young adult and older animals, which may have implications in functional assessment for preclinical models of neurological disease.

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Brandon P. Lucke-Wold, Ryan C. Turner, Aric F. Logsdon, Linda Nguyen, Julian E. Bailes, John M. Lee, Matthew J. Robson, Bennet I. Omalu, Jason D. Huber and Charles L. Rosen

OBJECT

Chronic traumatic encephalopathy is a progressive neurodegenerative disease characterized by neurofibrillary tau tangles following repetitive neurotrauma. The underlying mechanism linking traumatic brain injury to chronic traumatic encephalopathy has not been elucidated. The authors investigate the role of endoplasmic reticulum stress as a link between acute neurotrauma and chronic neurodegeneration.

METHODS

The authors used pharmacological, biochemical, and behavioral tools to assess the role of endoplasmic reticulum stress in linking acute repetitive traumatic brain injury to the development of chronic neurodegeneration. Data from the authors’ clinically relevant and validated rodent blast model were compared with those obtained from postmortem human chronic traumatic encephalopathy specimens from a National Football League player and World Wrestling Entertainment wrestler.

RESULTS

The results demonstrated strong correlation of endoplasmic reticulum stress activation with subsequent tau hyperphosphorylation. Various endoplasmic reticulum stress markers were increased in human chronic traumatic encephalopathy specimens, and the endoplasmic reticulum stress response was associated with an increase in the tau kinase, glycogen synthase kinase–3β. Docosahexaenoic acid, an endoplasmic reticulum stress inhibitor, improved cognitive performance in the rat model 3 weeks after repetitive blast exposure. The data showed that docosahexaenoic acid administration substantially reduced tau hyperphosphorylation (t = 4.111, p < 0.05), improved cognition (t = 6.532, p < 0.001), and inhibited C/EBP homology protein activation (t = 5.631, p < 0.01). Additionally the data showed, for the first time, that endoplasmic reticulum stress is involved in the pathophysiology of chronic traumatic encephalopathy.

CONCLUSIONS

Docosahexaenoic acid therefore warrants further investigation as a potential therapeutic agent for the prevention of chronic traumatic encephalopathy.