Background and Purpose-Hypoxic/ischemic (HI) brain injury affects 1 to 6 per 1000 live human births, with a mortality of 15% to 20%. A quarter of survivors have permanent disabilities. Hypothermia is the only intervention that improves outcome; however, further improvements might be obtained by combining hypothermia with additional treatments. Xenon is a noble anesthetic gas with an excellent safety profile, showing great promise in vitro and in vivo as a neuroprotectant. We investigated combinations of 50% xenon (Xe 50% ) and hypothermia of 32°C (HT 32°C ) as a post-HI therapy. Methods-An established neonatal rat HI model was used. Serial functional neurologic testing into adulthood 10 weeks after injury was performed, followed by global and regional brain histopathology evaluation. Results-In the combination Xe 50% HT 32°C group, complete restoration of long-term functional outcomes was seen.Hypothermia produced improvement on short-(PϽ0.001) and long-(PϽ0.001) term functional testing, whereas Xe 50% alone predominantly improved long-term function (PϽ0.05), suggesting that short-term testing does not always predict eventual outcome. Similarly, the Xe 50% HT 32°C combination produced the greatest (71%) improvement in global histopathology scores, a pattern mirrored in the regional scores, whereas Xe 50% and HT 32°C individually produced smaller improvements (PϽ0.05 and PϽ0.001, respectively). The interaction between the 2 treatments was additive. Conclusions-The xenon/hypothermia combination additively confers greater protection after HI than either treatment alone. The functional improvement is almost complete, is sustained long term, and is accompanied by greatly improved histopathology. The unique safety profile differentiates xenon as an attractive combination therapy with hypothermia to improve the otherwise bleak outcome from neonatal HI.

Together, these studies elucidate the role that TIMs play in mediating adaptive immune resistance in the GBM microenvironment and provide evidence that they can be manipulated pharmacologically with agents that are clinically available. Development of immune resistance in response to active vaccination in GBM can be reversed with dual administration of CSF-1Ri and PD-1 mAb.

While immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next generation sequencing (NGS) approach to determine whether quantitative assessments of tumor infiltrating lymphocyte (TIL) content and the degree of overlap of T cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma (GBM) patients treated with autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy. A significant correlation was found between a higher estimated TIL content and increased time to progression (TTP) and overall survival (OS). In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response.

Continuous monitoring of electrocortical brain activity with amplitude-integrated electroencephalography (aEEG) is important in neonatology. aEEG is affected by, for example, maturity, encephalopathy, and drugs. Neonatal research uses rat pups of different ages. Postnatal day (P) 7 rats are suggested to be equivalent neurodevelopmentally to near-term infants. We hypothesized that electroencephalography (EEG) and aEEG in P1-P21 rats follow the same developmental pattern with respect to background activity and the longest interburst interval (IBI) as that seen in infants from 23-wk gestational age (GA) to post-term. We examined aEEG and EEG on 49, unsedated rat pups with two clinical monitors. aEEG traces were analyzed for lower and upper margin amplitude, bandwidth and the five longest IBI in each trace were measured from the raw EEG. The median longest IBI decreased linearly with age by 5.24 s/d on average. The lower border of the aEEG trace was Ͻ5 V until P7 and rose exponentially reaching 10 V by P12. This correlated strongly with the decrease in IBI; both reflect increased continuity of brain activity with postnatal age. Based on aEEG trace analysis, the rat aEEG pattern at P1 corresponds to human aEEG at 23-wk gestation; P7 corresponds to 30 -32 wk and P10 to 40 -42 wk. (Pediatr Res 65: 62-66, 2009) A mplitude-integrated electroencephalography (aEEG) is increasingly used in neonatology for continuous monitoring of cerebral electrical activity (1) in relation to brain injury, seizures, and assessment of brain maturation. aEEG has gained widespread popularity as an adjunct to conventional EEG because of its simplicity of application and interpretation and feasibility for long-term recording alongside clinical care. Although multi-channel, raw electroencephalography (EEG) is still the "gold standard" in assessing the brain's functional state, its usefulness in the newborn is limited for several practical reasons (2,3). The assessment of background activity, presence of sleep wake cycling (SWC), and seizure identification, of particular importance in neonatology, require a longer recording period than the standard 30-min EEG. As global brain activity is the focus of interest in the newborn, one or two EEG channels are generally sufficient; thus reducing the number of electrodes attached to a small head.Translational research, the use of animals to model human disease, is essential in developing effective treatments for human disorders. The newborn rat has proven invaluable in increasing our understanding of mechanisms of brain injury and repair processes (4 -8). The Vanucci model, in which 7-d-old rats undergo unilateral ligation of the common carotid artery and exposure to 8% oxygen, is the most widely used animal model in the study of neonatal hypoxic-ischemic encephalopathy (HIE) (8); however, many models from postnatal day (P) 1 until P14 have been developed (5,8 -10). The usefulness of animal models is contingent on their validity. Previous research has correlated the maturation of the rat to the ...