Surface-Engineered Extracellular Vesicles in Cancer Immunotherapy.

Extracellular vesicles (EVs) are lipid bilayer-enclosed bodies secreted by all cell types. EVs carry bioactive materials, such as proteins, lipids, metabolites, and nucleic acids, to communicate and elicit functional alterations and phenotypic changes in the counterpart stromal cells. In cancer, cells secrete EVs to shape a tumor-promoting niche. Tumor-secreted EVs mediate communications with immune cells that determine the fate of anti-tumor therapeutic effectiveness. Surface engineering of EVs has emerged as a promising tool for the modulation of tumor microenvironments for cancer immunotherapy. Modification of EVs' surface with various molecules, such as antibodies, peptides, and proteins, can enhance their targeting specificity, immunogenicity, biodistribution, and pharmacokinetics. The diverse approaches sought for engineering EV surfaces can be categorized as physical, chemical, and genetic engineering strategies. The choice of method depends on the specific application and desired outcome. Each has its advantages and disadvantages. This review lends a bird's-eye view of the recent progress in these approaches with respect to their rational implications in the immunomodulation of tumor microenvironments (TME) from pro-tumorigenic to anti-tumorigenic ones. The strategies for modulating TME using targeted EVs, their advantages, current limitations, and future directions are discussed.

Musical Training Facilitates Exogenous Temporal Attention via Delta Phase Entrainment within a Sensorimotor Network.

Temporal orienting of attention plays an important role in our day-to-day lives and can use timing information from exogenous or endogenous sources. Yet, it is unclear what neural mechanisms give rise to temporal attention, and it is debated whether both exogenous and endogenous forms of temporal attention share a common neural source. Here, older adult nonmusicians (N = 47, 24 female) were randomized to undergo 8 weeks of either rhythm training, which places demands on exogenous temporal attention, or word search training as a control. The goal was to assess (1) the neural basis of exogenous temporal attention and (2) whether training-induced improvements in exogenous temporal attention can transfer to enhanced endogenous temporal attention abilities, thereby providing support for a common neural mechanism of temporal attention. Before and after training, exogenous temporal attention was assessed using a rhythmic synchronization paradigm, whereas endogenous temporal attention was evaluated via a temporally cued visual discrimination task. Results showed that rhythm training improved performance on the exogenous temporal attention task, which was associated with increased intertrial coherence within the δ (1-4 Hz) band as assessed by EEG recordings. Source localization revealed increased δ-band intertrial coherence arose from a sensorimotor network, including premotor cortex, anterior cingulate cortex, postcentral gyrus, and the inferior parietal lobule. Despite these improvements in exogenous temporal attention, such benefits were not transferred to endogenous attentional ability. These results support the notion that exogenous and endogenous temporal attention uses independent neural sources, with exogenous temporal attention relying on the precise timing of δ band oscillations within a sensorimotor network.SIGNIFICANCE STATEMENT Allocating attention to specific points in time is known as temporal attention, and may arise from external (exogenous) or internal (endogenous) sources. Despite its importance to our daily lives, it is unclear how the brain gives rise to temporal attention and whether exogenous- or endogenous-based sources for temporal attention rely on shared brain regions. Here, we demonstrate that musical rhythm training improves exogenous temporal attention, which was associated with more consistent timing of neural activity in sensory and motor processing brain regions. However, these benefits did not extend to endogenous temporal attention, indicating that temporal attention relies on different brain regions depending on the source of timing information.

How musical rhythm training improves short-term memory for faces.

Playing a musical instrument engages numerous cognitive abilities, including sensory perception, selective attention, and short-term memory. Mounting evidence indicates that engaging these cognitive functions during musical training will improve performance of these same functions. Yet, it remains unclear the extent these benefits may extend to nonmusical tasks, and what neural mechanisms may enable such transfer. Here, we conducted a preregistered randomized clinical trial where nonmusicians underwent 8 wk of either digital musical rhythm training or word search as control. Only musical rhythm training placed demands on short-term memory, as well as demands on visual perception and selective attention, which are known to facilitate short-term memory. As hypothesized, only the rhythm training group exhibited improved short-term memory on a face recognition task, thereby providing important evidence that musical rhythm training can benefit performance on a nonmusical task. Analysis of electroencephalography data showed that neural activity associated with sensory processing and selective attention were unchanged by training. Rather, rhythm training facilitated neural activity associated with short-term memory encoding, as indexed by an increased P3 of the event-related potential to face stimuli. Moreover, short-term memory maintenance was enhanced, as evidenced by increased two-class (face/scene) decoding accuracy. Activity from both the encoding and maintenance periods each highlight the right superior parietal lobule (SPL) as a source for training-related changes. Together, these results suggest musical rhythm training may improve memory for faces by facilitating activity within the SPL to promote how memories are encoded and maintained, which can be used in a domain-general manner to enhance performance on a nonmusical task.

Embedded adaptive deep brain stimulation for cervical dystonia controlled by motor cortex theta oscillations.

Dystonia is a disabling movement disorder characterized by excessive muscle contraction for which the underlying pathophysiology is incompletely understood and treatment interventions limited in efficacy. Here we utilize a novel, sensing-enabled, deep brain stimulator device, implanted in a patient with cervical dystonia, to record local field potentials from chronically implanted electrodes in the sensorimotor cortex and subthalamic nuclei bilaterally. This rechargeable device was able to record large volumes of neural data at home, in the naturalistic environment, during unconstrained activity. We confirmed the presence of theta (3-7 Hz) oscillatory activity, which was coherent throughout the cortico-subthalamic circuit and specifically suppressed by high-frequency stimulation. Stimulation also reduced the duration, rate and height of theta bursts. These findings motivated a proof-of-principle trial of a new form of adaptive deep brain stimulation - triggered by theta-burst activity recorded from the motor cortex. This facilitated increased peak stimulation amplitudes without induction of dyskinesias and demonstrated improved blinded clinical ratings compared to continuous DBS, despite reduced total electrical energy delivered. These results further strengthen the pathophysiological role of low frequency (theta) oscillations in dystonia and demonstrate the potential for novel adaptive stimulation strategies linked to cortico-basal theta bursts.

Multimodal sensory integration: Diminishing returns in rhythmic synchronization.

Synchronizing movements with events in the surrounding environment is a ubiquitous aspect of behavior. Experiments studying multimodal integration and rhythmic synchronization tend to focus on how bimodal (e.g., audio-visual) stimuli enhances synchronization performance (i.e., reduced variability) compared with synchronization with its unimodal constituents. As such, it is unclear whether trimodal (i.e., audio-visual-tactile) stimuli may yield additional performance benefits. To address this, we developed a multimodal sensorimotor synchronization assessment that incorporates audio, visual, and vibrotactile stimuli. Results replicate performance improvements with bimodal compared with unimodal stimuli. However, trimodal stimuli yields less, or in some cases no advantage compared with bimodal stimuli. These results demonstrate that in this case, increasing the amount of sensory information beyond bimodal stimuli yields little or no additional performance benefits. (PsycInfo Database Record (c) 2020 APA, all rights reserved).