Cotebigum9932

In this issue, the study by Dagnino and colleagues represents an important addition to the maturing field of blood-based biomarkers for lung cancer screening. Their comprehensive approach to analyzing circulating inflammatory proteins identified CDCP1 as a potential biomarker for distinguishing patients with or without lung cancer, a finding that was confirmed in a validation cohort. CDCP1 blood levels, when combined with smoking history, gave an AUC receiver operator characteristic of 0.75. Analysis of transcripts in peripheral blood cells suggested a Wnt/β-catenin signaling-based mechanism for CDCP1 in tumorigenesis providing biologic plausibility. CDCP1 now joins the ranks of other potential blood-based lung cancer screening biomarkers (including epithelial tumor marker proteins, tumor-associated miRNA, antitumor antibodies, and tumor-specific DNA methylation) that need validation in future clinical trials. Further exploration of how CDCP1 levels might be integrated into current lung cancer screening programs, including both detection of lung cancer, and evaluation of the need for invasive biopsies, as well as how CDCP1 performs in different racial populations, is warranted.See related article by Dagnino et al., p. 3738.Systemic treatment with resiniferatoxin (RTX) induces small-fiber sensory neuropathy by damaging TRPV1-expressing primary sensory neurons and causes distinct thermal sensory impairment and tactile allodynia, which resemble the unique clinical features of postherpetic neuralgia. However, the synaptic plasticity associated with RTX-induced tactile allodynia remains unknown. In this study, we found that RTX-induced neuropathy is associated with α2δ-1 upregulation in the dorsal root ganglion (DRG) and increased physical interaction between α2δ-1 and GluN1 in the spinal cord synaptosomes. Y-27632 in vivo RNAscope in situ hybridization showed that RTX treatment significantly increased α2δ-1 expression in DRG neurons labeled with calcitonin gene-related peptide, isolectin B4, NF200, and tyrosine hydroxylase. Electrophysiological recordings revealed that RTX treatment augmented the frequency of miniature excitatory postsynaptic currents (mEPSCs) and the amplitude of evoked EPSCs in spinal dorsal horn neurons, and these effects were atients. The synaptic plasticity underlying touch-induced pain hypersensitivity in PHN remains unclear. Using a nonviral animal model of PHN, we found that glutamatergic input from primary sensory nerves to the spinal cord is increased via tonic activation of glutamate NMDA receptors. Also, we showed that α2δ-1 (encoded by Cacna2d1), originally considered a calcium channel subunit, serves as an auxiliary protein that promotes activation of presynaptic NMDA receptors and pain hypersensitivity. This new information advances our understanding of the molecular mechanism underlying PHN and suggests new strategies for treating this painful condition.Understanding the bioenergetics of axon extension and maintenance has wide ranging implications for neurodevelopment and disease states. Glycolysis is a pathway consisting of 10 enzymes and separated into preparatory and payoff phases, the latter producing ATP. Using embryonic chicken sensory neurons, we report that glycolytic enzymes are found through the axon and the growth cone. Pharmacological inhibition of glycolysis in the presence of NGF impairs axon extension and growth cone dynamics within minutes without affecting axon maintenance. Experiments using microfluidic chambers show that the effect of inhibiting glycolysis on axon extension is local along distal axons and can be reversed by promoting mitochondrial respiration. Knockdown of GAPDH simplifies growth cone morphology and is rescued by shRNA-resistant GAPDH expression. Rescue of GAPDH using KillerRed fused to GAPDH followed by localized chromophore-assisted light inactivation of KillerRed-GAPDH in distal axons halts growth cone dynamics. Considederstood. The data reveal that the glycolytic pathway is required for normal sensory axon extension in the presence of NGF, while in the absence of NGF the glycolytic pathway is required for axon maintenance. The results have implications for the understanding of the bioenergetics of axon morphogenesis and plasticity and indicate that NGF has protective effects on sensory axon maintenance in hypoglycemic states.N-methyl-d-aspartate receptors (NMDARs) are important for synaptic plasticity associated with many physiological functions and neurologic disorders. Protein kinase C (PKC) activation increases the phosphorylation and activity of NMDARs, and α2δ-1 is a critical NMDAR-interacting protein and controls synaptic trafficking of NMDARs. In this study, we determined the relative roles of PKC and α2δ-1 in the control of NMDAR activity. We found that α2δ-1 coexpression significantly increased NMDAR activity in HEK293 cells transfected with GluN1/GluN2A or GluN1/GluN2B. PKC activation with phorbol 12-myristate 13-acetate (PMA) increased receptor activity only in cells coexpressing GluN1/GluN2A and α2δ-1. Remarkably, PKC inhibition with Gӧ6983 abolished α2δ-1-coexpression-induced potentiation of NMDAR activity in cells transfected with GluN1/GluN2A or GluN1/GluN2B. Treatment with PMA increased the α2δ-1-GluN1 interaction and promoted α2δ-1 and GluN1 cell surface trafficking. PMA also significantly increased NMDAR activitpathways are coordinated in response to neuronal activity to shape synaptic plasticity. PKC phosphorylates transporters, ion channels, and G-protein-coupled receptors in signal transduction. In this study, we showed that α2δ-1 is indispensable for PKC-activation-induced surface and synaptic trafficking of NMDARs, whereas the α2δ-1-NMDAR interaction is controlled by PKC-induced phosphorylation. Our findings reveal that α2δ-1 mainly functions as a phospho-binding protein in the control of NMDAR trafficking and activity. This information provides new mechanistic insight into the reciprocal roles of PKC-mediated phosphorylation and α2δ-1 in regulating NMDARs and in the therapeutic actions of gabapentinoids.

Perioperative anxiety is a major burden to patients undergoing surgeries with general anesthesia.

The present study investigated whether a virtual operating room tour (VORT) before surgery can be used to ameliorate perioperative anxiety.

We employed a randomized parallel group design with two study arms to compare VORT to the standard operation preparation procedure (STOPP). 84 patients were included in the study. A validated inventory (STOA-State) was used to asses perioperative state anxiety before surgery (T1) and after (T2). Trait operation anxiety was evaluated with an additional validated inventory (STOA-Trait). Moreover, user ratings on the usefulness of VORT were assessed with an evaluation questionnaire. Study arms were compared with respect to perioperative state anxiety with independent samples t-tests. To investigate possible associations of perioperative anxiety with perceived usefulness, subjective ratings were correlated with STOA-Trait values.

No significant differences in state anxiety were determined between VORT and STOPP before and after the surgery.