Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models

BACKGROUND: Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations. METHODS: C57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC. RESULTS: The combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity. CONCLUSION: These data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy

Toward Improving Safety in Neurosurgery with an Active Handheld Instrument

Microsurgical procedures, such as petroclival meningioma resection, require careful surgical actions in order to remove tumor tissue, while avoiding brain and vessel damaging. Such procedures are currently performed under microscope magnification. Robotic tools are emerging in order to filter surgeons’ unintended movements and prevent tools from entering forbidden regions such as vascular structures. The present work investigates the use of a handheld robotic tool (Micron) to automate vessel avoidance in microsurgery. In particular, we focused on vessel segmentation, implementing a deep-learning-based segmentation strategy in microscopy images, and its integration with a feature-based passive 3D reconstruction algorithm to obtain accurate and robust vessel position. We then implemented a virtual-fixture-based strategy to control the handheld robotic tool and perform vessel avoidance. Clay vascular phantoms, lying on a background obtained from microscopy images recorded during petroclival meningioma surgery, were used for testing the segmentation and control algorithms. When testing the segmentation algorithm on 100 different phantom images, a median Dice similarity coefficient equal to 0.96 was achieved. A set of 25 Micron trials of 80 s in duration, each involving the interaction of Micron with a different vascular phantom, were recorded, with a safety distance equal to 2 mm, which was comparable to the median vessel diameter. Micron’s tip entered the forbidden region 24% of the time when the control algorithm was active. However, the median penetration depth was 16.9 μm, which was two orders of magnitude lower than median vessel diameter. Results suggest the system can assist surgeons in performing safe vessel avoidance during neurosurgical procedures

The influence of suturectomy on age-related changes in cerebral blood flow in rabbits with familial bicoronal suture craniosynostosis: A quantitative analysis.

BACKGROUND:Coronal suture synostosis is a condition which can have deleterious physical and cognitive sequelae in humans if not corrected. A well-established animal model has previously demonstrated disruptions in intracranial pressure and developmental abnormalities in rabbits with congenital craniosynostosis compared to wild type rabbits. OBJECTIVE:The current study aimed to measure the cerebral blood flow (CBF) in developing rabbits with craniosynostosis who underwent suturectomy compared to those with no intervention and compared to wild type rabbits. METHODS:Rabbits with early onset coronal suture synostosis were assigned to have suturectomy at 10 days of age (EOCS-SU, n = 15) or no intervention (EOCS, n = 18). A subset of each group was randomly selected for measurement at 10 days of age, 25 days of age, and 42 days of age. Wild type rabbits (WT, n = 18) were also randomly assigned to measurement at each time point as controls. Cerebral blood flow at the bilateral hemispheres, cortices, thalami, and superficial cortices was measured in each group using arterial spin-labeling MRI. RESULTS:At 25 days of age, CBF at the superficial cortex was significantly higher in EOCS rabbits (192.6 ± 10.1 mL/100 mg/min on the left and 195 ± 9.5 mL/100 mg/min on the right) compared to WT rabbits (99.2 ± 29.1 mL/100 mg/min on the left and 96.2 ± 21.4 mL/100 mg/min on the right), but there was no significant difference in CBF between EOCS-SU (97.6 ± 11.3 mL/100 mg/min on the left and 99 ± 7.4 mL/100 mg/min on the right) and WT rabbits. By 42 days of age the CBF in EOCS rabbits was not significantly different than that of WT rabbits. CONCLUSION:Suturectomy eliminated the abnormally increased CBF at the superficial cortex seen in EOCS rabbits at 25 days of age. This finding contributes to the evidence that suturectomy limits abnormalities of ICP and CBF associated with craniosynostosis

Resveratrol Attenuates Behavioral Impairments and Reduces Cortical and Hippocampal Loss in a Rat Controlled Cortical Impact Model of Traumatic Brain Injury

Resveratrol (3,5,4′-trihydroxystilbene) is a plant-derived small molecule that is protective against multiple neurological and systemic insults. To date, no studies have explored the potential for resveratrol to provide behavioral protection in adult animals in the setting of traumatic brain injury (TBI). Using 50 male Sprague-Dawley rats, we employed the controlled cortical impact (CCI) model to ascertain whether post-injury administration of resveratrol would reduce the severity of the well-described cognitive and motor deficits associated with the model. Contusion volumes and hippocampal neuronal numbers were also measured to characterize the tissue and neuronal-sparing properties, respectively, of resveratrol. We found that 100 mg/kg, but not 10 mg/kg, of intraperitoneal resveratrol administered after injury provides significant behavioral protection in rats sustaining CCI. Specifically, rodents treated with 100 mg/kg of resveratrol showed improvements in motor performance (beam balance and beam walking) and testing of visuospatial memory (Morris water maze). Behavioral protection was correlated with significantly reduced contusion volumes, preservation of CA1 and CA3 hippocampal neurons, and protection from overt hippocampal loss as a result of incorporation into the overlying cortical contusion in resveratrol-treated animals. Although the mechanisms by which resveratrol mediates its neuroprotection is unclear, the current study adds to the growing literature identifying resveratrol as a potential therapy for human brain injury