Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming.

A population of Natural Killer (NK) cells expressing the activating receptor NKG2C and the maturation marker CD57 expands in response to human cytomegalovirus (HCMV) infection. CD3-CD56dimCD57+NKG2C+ NK cells are similar to CD8+ memory T cells with rapid and robust effector function upon re-stimulation, persistence, and epigenetic remodeling of the IFNG locus. Chronic antigen stimulation drives CD8+ memory T cell proliferation while also inducing genome-wide epigenetic reprograming and dysfunction. We hypothesized that chronic stimulation could similarly induce epigenetic reprograming and dysfunction in NK cells. Here we show that chronic stimulation of adaptive NK cells through NKG2C using plate-bound agonistic antibodies in combination with IL-15 drove robust proliferation and activation of CD3-CD56dimCD57+NKG2C+ NK cells while simultaneously inducing high expression of the checkpoint inhibitory receptors LAG-3 and PD-1. Marked induction of checkpoint inhibitory receptors was also observed on the surface of adaptive NK cells co-cultured with HCMV-infected endothelial cells. Chronically stimulated adaptive NK cells were dysfunctional when challenged with tumor targets. These cells exhibited a pattern of epigenetic reprograming, with genome-wide alterations in DNA methylation. Our study has important implications for cancer immunotherapy and suggest that exhausted NK cells could be targeted with inhibitory checkpoint receptor blockade.

Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells.

Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C-expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response.

The Development of a Validated Checklist for Ultrasound-Guided Thyroid Nodule Fine-Needle Aspiration Biopsies: Preliminary Results.

Ultrasound-guided fine-needle aspiration (USgFNA) is the procedure of choice for biopsy of thyroid nodules (TNs) that are suspicious for malignancy. Poor technique in performing this procedure can result in nondiagnostic specimens, increased patient anxiety, repeated aspirations, and unnecessary surgery. Validated checklists are a central component of teaching and assessing procedural skills. The results of the first step of the validation of a TN USgFNA checklist are described. A comprehensive review of articles published on TN fine-needle aspiration did not yield a validated checklist. A modified Delphi technique, involving a panel of 8 interdisciplinary experts, was used to develop a TN USgFNA checklist. The internal consistency coefficient using Cronbach α was 0.74. Development of the 23-item TN USgFNA checklist for teaching and assessing TN USgFNA is the first step in the validation process. Further validation can be achieved via implementation and study of the checklist in clinical settings.

Retrieval of contextual memories increases activity-regulated cytoskeleton-associated protein in the amygdala and hippocampus.

Activity-regulated cytoskeleton-associated protein (Arc) integrates information from multiple intracellular signaling cascades and, in turn, regulates cytoskeletal proteins involved in structural synaptic modifications. The purposes of the present study were: (1) to determine if the retrieval of contextual memories would induce Arc in hippocampal and amygdalar neurons; (2) use unbiased stereology at the ultrastructural level to quantify synapses contacting Arc-labeled (Arc+) and unlabeled (Arc-) postsynaptic structures in brain regions in which the amount of Arc integrated density (ID) correlated strongly with the degree of amphetamine conditioned place preference (AMPH CPP). The retrieval of contextual memories increased the Arc ID in the dentate gyrus, cornu ammonis (CA)1, and CA3 fields of the hippocampus and the basolateral, lateral, and central nuclei of the amygdala but not the primary auditory cortex, a control region. Stereological quantification of Arc+ and Arc- synapses in the basolateral nucleus of the amygdala (BLA) was undertaken because the strongest relationship between the amount of Arc ID and AMPH CPP was observed in the BLA. The retrieval of contextual memories increased the number and density of asymmetric (presumed excitatory) synapses contacting Arc+ spines and dendrites of BLA neurons, symmetric (presumed inhibitory or modulatory) synapses contacting Arc+ dendrites of BLA neurons, and multisynaptic boutons contacting Arc+ postsynaptic structures. Thus, the retrieval of contextual memories increases Arc in the amygdala and hippocampus, an effect that could be important for approach behavior to a drug-associated context.

Utility of early high dose statins in acute coronary syndrome.

In accordance with the recommendations of the American College of Cardiology/American Heart Association Joint Task Force, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are prescribed before hospital discharge after an episode of acute coronary syndrome. Yet, optimal timing and dosage have not been agreed upon. Recent evidence suggests a pleiotropic mechanism of action including vasoprotective, anti-inflammatory, and antiarrhythmic properties that imply an immediate role for statin medications. Our review suggests that early (<24 hours) high dose (80 mg of atorvastatin) statins may significantly reduce adverse cardiovascular outcomes and may improve long-term mortality.