Enhancing cancer immunotherapy through nanotechnology-mediated tumor infiltration and activation of immune cells.

Cancer immunotherapy has become arguably the most promising advancement in cancer research and therapy in recent years. The efficacy of cancer immunotherapy is critically dependent on specific physiological and physical processes - collectively referred to as transport barriers - including the activation of T cells by antigen presenting cells, T cells migration to and penetration into the tumor microenvironment, and movement of nutrients and other immune cells through the tumor microenvironment. Nanotechnology-based approaches have great potential to help overcome these transport barriers. In this review, we discuss the ways that nanotechnology is being leveraged to improve the efficacy and potency of various cancer immunotherapies.

Rigor and reproducibility in analysis of rodent behavior utilizing the forelimb reaching task following a cervical spinal cord injury.

Spinal cord injury (SCI) research with animals aims to understand the neurophysiological responses resultant of injury and to identify effective interventions that can translate into clinical treatments in the future. Consistent and reliable assessments to properly measure outcomes are essential to achieve this aim and avoid issues with reproducibility. The objective of this study was to establish a baseline for implementing the forelimb reaching task (FRT) assessment and analysis that increased reproducibility of our studies. For this study, we implemented a weekly FRT training program for six weeks. During this time the language of the scoring rubric for movement elements that comprise a reaching task was simplified and expanded. We calculated intra- and inter-rater variability among participants of the study both before and after training to determine the effect changes made had on rigor and reproducibility of this behavioral assessment in a cervical SCI rodent model. All animals (n = 19) utilized for FRT behavioral assessments received moderate contusion injuries using the Ohio State University device and were tested for a period of 5 weeks post-SCI. Videos used for scoring were edited and shared with all participants of this study to test FRT score variability and the effect simplification of the scoring rubric had on overall inter-rater reliability. From our results we determined training for a minimum of three weeks in FRT analysis is necessary for rigor and reproducibility of our behavioral studies, as well as the need for two raters to be assigned per animal to ensure accuracy of results.

Housing in environmental complexity following wheel running augments survival of newly generated hippocampal neurons in a rat model of binge alcohol exposure during the third trimester equivalent.

BACKGROUND: Binge-like alcohol exposure in neonatal rats during the brain growth spurt causes deficits in adult neurogenesis in the hippocampal dentate gyrus (DG). Previous data from our laboratory demonstrated that 12 days of voluntary wheel running (WR) beginning on postnatal day (PD) 30 significantly increased the number of newly generated cells evident in the DG on PD42 in both alcohol-exposed (AE) and control rats, but 30 days later a sustained beneficial effect of WR was evident only in control rats. This study tested the hypothesis that housing rats in environmental complexity (EC) following WR would promote the survival of the newly generated cells stimulated by WR, particularly in AE rats. METHODS: On PD4 to 9, pups were intubated with alcohol in a binge-like manner (5.25 g/kg/d), sham-intubated (SI), or reared normally. In Experiment 1, animals were either assigned to WR during PD30 to 42 or socially housed (SH). On PD42, animals were injected with bromodeoxyuridine (BrdU; 200 mg/kg) and perfused 2 hours later to confirm the WR-induced stimulation of proliferation. In Experiment 2, all animals received WR on PD30 to 42 and were injected with BrdU on the last full day of WR. On PD42, animals were randomly assigned either to EC (WR/EC) or to SH (WR/SH) for 30 days and subsequently perfused and brains were processed for immunohistochemical staining to identify BrdU+-, Ki67+-, and BrdU+/NeuN+-labeled cells in DG. RESULTS: In Experiment 1, WR exposure significantly increased the number of proliferating cells in all 3 postnatal conditions. In Experiment 2, the AE rats given WR/SH had significantly fewer BrdU+ cells compared with control rats given WR/SH. However, WR/EC experience significantly increased the number of surviving BrdU+ cells in both the AE and SI groups compared with WR/SH rats of the same neonatal treatment. Approximately 80% of the surviving BrdU+ cells in the DG across the conditions were colabeled with NeuN. CONCLUSIONS: WR followed by EC could provide a behavioral model for developing interventions in humans to ameliorate hippocampal-dependent impairments associated with fetal alcohol spectrum disorders.

Postnatal binge-like alcohol exposure decreases dendritic complexity while increasing the density of mature spines in mPFC Layer II/III pyramidal neurons.

Prenatal exposure to alcohol in humans can result in a wide range of deficits collectively referred to as fetal alcohol spectrum disorders. Of these deficits, cognitive impairments are among the most debilitating and long-lasting. Specifically, cognitive impairments in executive functioning suggest damage to the prefrontal cortex (PFC). Several external stimuli, such as morphine, chronic stress, and maternal stress have been found to alter the dendritic structure of cells within the PFC. In this study, three groups of rat pups were used: intubated with alcohol (5.25 g/kg/day; AE), sham intubated (SI), or suckle controls (SC) on PD 4-9. On PD 26-30 rats were anesthetized, perfused with saline and brains were processed for Golgi-Cox staining. Basilar dendritic complexity, spine density, and spine phenotypes were evaluated for Layer II/III neurons in the medial PFC. Results indicate that AE rats have an altered basilar dendritic complexity due to a significant decrease in both length and number of intersections in proximity to the neuronal soma. Furthermore, spine density patterns of basilar dendrites remain unchanged while the density of mature vs. immature spines significantly changes. These effects were not seen in the apical dendrites, indicating alcohol's influence on different neuronal parts in a single cell. In addition, these results suggest that the innervations of the soma and basilar dendrites by thalamic projections may play a role. Thus, our data demonstrates that postnatal exposure to alcohol produces changes in the neuronal organization of rat adolescent PFC that may affect the performance on prefrontal-dependant behavioral tasks.

Neural Stimulation and Molecular Mechanisms of Plasticity and Regeneration: A Review.

Neural stimulation modulates the depolarization of neurons, thereby triggering activity-associated mechanisms of neuronal plasticity. Activity-associated mechanisms in turn play a major role in post-mitotic structure and function of adult neurons. Our understanding of the interactions between neuronal behavior, patterns of neural activity, and the surrounding environment is evolving at a rapid pace. Brain derived neurotrophic factor is a critical mediator of activity-associated plasticity, while multiple immediate early genes mediate plasticity of neurons following bouts of neural activity. New research has uncovered genetic mechanisms that govern the expression of DNA following changes in neural activity patterns, including RNAPII pause-release and activity-associated double stranded breaks. Discovery of novel mechanisms governing activity-associated plasticity of neurons hints at a layered and complex molecular control of neuronal response to depolarization. Importantly, patterns of depolarization in neurons are shown to be important mediators of genetic expression patterns and molecular responses. More research is needed to fully uncover the molecular response of different types of neurons-to-activity patterns; however, known responses might be leveraged to facilitate recovery after neural damage. Physical rehabilitation through passive or active exercise modulates neurotrophic factor expression in the brain and spinal cord and can initiate cortical plasticity commensurate with functional recovery. Rehabilitation likely relies on activity-associated mechanisms; however, it may be limited in its application. Electrical and magnetic stimulation direct specific activity patterns not accessible through passive or active exercise and work synergistically to improve standing, walking, and forelimb use after injury. Here, we review emerging concepts in the molecular mechanisms of activity-derived plasticity in order to highlight opportunities that could add value to therapeutic protocols for promoting recovery of function after trauma, disease, or age-related functional decline.

Activity and social behavior in a complex environment in rats neonatally exposed to alcohol.

Environmental complexity (EC) is a powerful, stimulating paradigm that engages animals through a variety of sensory and motor pathways. Exposure to EC (30 days) following 12 days of wheel running preserves hippocampal neuroplasticity in male rats neonatally exposed to alcohol during the third-trimester equivalent (binge-like exposure on postnatal days [PD] 4-9). The current experiment investigates the importance of various components of EC (physical activity, exploration, social interaction, novelty) and examines whether neonatal alcohol exposure affects how male rats interact with their environment and other male rats. Male pups were assigned to 1 of 3 neonatal conditions from PD 4-9: suckle control (SC), sham-intubated (SI), or alcohol-exposed (AE, 5.25 g/kg/day). From PD 30-42 animals were housed with 24-h access to a voluntary running wheel. The animals were then placed in EC from PD 42-72 (9 animals/cage, counterbalanced by neonatal condition). During EC, the animals were filmed for five 30-min sessions (PD 42, 48, 56, 64, 68). For the first experiment, the videos were coded for distance traveled in the cage, overall locomotor activity, time spent near other animals, and interaction with toys. For the second experiment, the videos were analyzed for wrestling, mounting, boxing, grooming, sniffing, and crawling over/under. AE animals were found to be less active and exploratory and engaged in fewer mounting behaviors compared to control animals. Results suggest that after exposure to wheel running, AE animals still have deficits in activity and social behaviors while housed in EC compared to control animals with the same experience.

Long-term consequences of developmental alcohol exposure on brain structure and function: therapeutic benefits of physical activity.

Developmental alcohol exposure both early in life and during adolescence can have a devastating impact on normal brain structure and functioning, leading to behavioral and cognitive impairments that persist throughout the lifespan. This review discusses human work as well as animal models used to investigate the effect of alcohol exposure at various time points during development, as well as specific behavioral and neuroanatomical deficits caused by alcohol exposure. Further, cellular and molecular mediators contributing to these alcohol-induced changes are examined, such as neurotrophic factors and apoptotic markers. Next, this review seeks to support the use of aerobic exercise as a potential therapeutic intervention for alcohol-related impairments. To date, few interventions, behavioral or pharmacological, have been proven effective in mitigating some alcohol-related deficits. Exercise is a simple therapy that can be used across species and also across socioeconomic status. It has a profoundly positive influence on many measures of learning and neuroplasticity; in particular, those measures damaged by alcohol exposure. This review discusses current evidence that exercise may mitigate damage caused by developmental alcohol exposure and is a promising therapeutic target for future research and intervention strategies.