Molecular mechanisms of the interaction between pain and reward associated with pain relief processes in the human brain are still incompletely understood. This is partially due to the invasive nature of the available techniques to visualize and measure metabolic activity. Positron Emission Tomography (PET) radioligand studies using radioactive substances are still the only available modality to date that allows for the investigation of the molecular mechanisms in the human brain. For pain and reward studies, the most commonly studied PET radiotracers are [11C]-carfentanil (CFN) and [11C]- or [18F]-diprenorphine (DPN), which bind to opioid receptors, and [11C]-raclopride (RAC) and [18F]-fallypride (FAL) tracers, which bind to dopamine receptors. The current meta-analysis looks at 15 pain-related studies using opioid radioligands and 8 studies using dopamine radioligands in an effort to consolidate the available data into the most likely activated regions. Our primary goal was to identify regions of shared opioid/dopamine neurotransmission during pain-related experiences. SDM analysis of previously published voxel coordinate data showed that opioidergic activations were strongest in the bilateral caudate, thalamus, right putamen, cingulate gyrus, midbrain, inferior frontal gyrus, and left superior temporal gyrus. The dopaminergic studies showed that the bilateral caudate, thalamus, right putamen, cingulate gyrus, and left putamen had the highest activations. We were able to see a clear overlap between opioid and dopamine activations in a majority of the regions during pain-related processing, though there were some unique areas of dopaminergic activation such as the left putamen. Regions unique to opioidergic activation include the midbrain, inferior frontal gyrus, and left superior temporal gyrus. By investigating the regions of dopaminergic and opioidergic activation, we can potentially provide more targeted treatment to these sets of receptors in patients with pain conditions. These findings could eventually assist in the development of more targeted medication in order to help treat pain conditions and simultaneously prevent physical dependency.
Background There are ~3 million transposable elements in the human genome constituting about 42% of all basepairs. Retroelements (REs) are ~90% of the transposable elements present in the human genome. Active REs are considered highly mutagenic and have been implicated in multiple steps of cancer development and progression, as well as in neurologic diseases. RE activity has functional effects on the genome, including the maintenance of centromere and telomere integrity, and deleterious gene expression. Previous studies have shown that certain families of RE (HERVK, L1, Alu) are expressed in gliomas, however, their specific role as arbitrators of oncogenesis or promoters of the innate anti-tumor immune response remains uncertain. Moreover, it has been shown that a soluble form of PD-L1 (sPD-L1) that blocks its inhibitory activity is produced by exaptation of an intronic endogenous retroelement (LINE-2A) in the gene encoding PD-L1, highlighting the importance of REs as potential therapeutic targets. In this analysis we aim to identify the unique patterns of RE expression across major subtypes of glioma. Material and Methods We conducted a differential expression analysis of 49 RE families using RNA-seq data measured in glioma tumors from The Cancer Genome Atlas (TCGA). RE counts were produced using the software REDiscoverTE. Pairwise comparisons between glioma subtypes (defined by WHO2021) were done using in 625 tumor samples adjusting for age, sex and race. Results 10 of the 49 considered RE families exhibited significantly different (false discovery rate, FDR, <0.05) expression in at least one glioma subtype. Alu(Fold change, FC=1.5), RNA(FC=11.3), PiggyBac(FC=1.6), rRNA(FC=5.23) and Dong-R4(FC=1.8) were overexpressed in IDH-wildtype glioblastoma while Gypsy(FC=0.4) and CRP1(FC=0.26) were decreased in expression. scRNA (FC=2.7) were overexpressed in IDH-mutant oligodendroglioma compared to glioblastoma while Dong-R4 (FC = 0.53) showed decreased expression. LTR (FC=2.02) and tRNA-Deu (FC=1.46), showed increased expression in IDH-wildtype diffuse astrocytomas compared to IDH-mutant, 1p/19q-codeleted oligodendrogliomas while Gypsy (FC =0.41) showed decreased expression. Conclusion We have shown that expression of certain RE families within gliomas have subtype-specific patterns. While it is well established that RE expression is dysregulated in cancer, our analysis is the first at exploring a wide range of retroelements in the context of glioma by subtype. Given the important role of REs in transcriptional control, genomic instability, chromosomal rearrangements, and oncogenic activation, the identification of individual families and specific REs in glioma holds an intrinsic value to potential biomarkers and immunotherapy targets.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.