The co-occurrence of multiple psychoneurological symptoms, including pain, sleep disturbance, fatigue, depression, anxiety, and cognitive disturbance among adult cancer survivors led us to question which common biological mechanisms are shared among these conditions. Variances in tryptophan (Trp) levels and downstream metabolites of the kynurenine (Kyn) metabolic pathway are known to affect immune response and psychoneurological symptoms. The objective of this systematic review was to help us (a) better understand the role of the Kyn pathway in psychoneurological symptoms among adult cancer survivors and (b) identify common significant biomarkers across psychoneurological symptoms as a guide for future research. Some evidence has shown that decreased Trp levels and increased Kyn, Trp/Kyn ratio, and kynurenic acid/Trp ratio in parallel with immune activation are correlated with some psychoneurological symptoms among people undergoing cancer treatment, although discrepancies exist between studies. Kyn pathway activation could also be associated with psychoneurological symptoms among adult cancer survivors, but further research is needed to confirm its exact etiological role with respect to psychoneurological symptoms.

Incorporating biologically based data into symptom science research can contribute substantially to understanding commonly experienced symptoms across chronic conditions. The purpose of this literature review was to identify functional polymorphisms associated with common symptoms (i.e., pain, sleep disturbance, fatigue, affective and cognitive symptoms) with the goal of identifying a parsimonious list of functional genetic polymorphisms with evidence to advocate for their inclusion in symptom science research. PubMed was searched to identify genes and functional polymorphisms associated with symptoms across chronic conditions, revealing eight functional genetic polymorphisms in seven different genes that showed evidence of association with at least three or more symptoms and/or symptom clusters: BDNF rs6265, COMT rs4680, FKBP5 rs3800373, IL-6 rs1800795, NFKB2 rs1056890, SLC6A4 5-HTTLPR+rs25531, and TNFA rs1799964 and rs1800629. Of these genes, three represent protein biomarkers previously identified as common data elements for symptom science research (BDNF, IL-6, and TNFA), and the polymorphisms in these genes identified through the search are known to impact secretion or level of transcription of these protein biomarkers. Inclusion of genotype data for polymorphisms offers great potential to further advance scientific knowledge of the biological basis of individual symptoms and symptom clusters across studies. Additionally, these polymorphisms have the potential to be used as targets to optimize precision health through the identification of individuals at risk for poor symptom experiences as well as the development of symptom management interventions.

Background: Following aneurysmal subarachnoid hemorrhage (aSAH), the brain is susceptible to ferroptosis, a type of iron-dependent cell death. Therapeutic intervention targeting the iron homeostasis pathway shows promise for mitigating ferroptosis and improving recovery in animal models, but little work has been conducted in humans. DNA methylation (DNAm) plays a key role in gene expression and brain function, plasticity, and injury recovery, making it a potentially useful biomarker of outcomes or therapeutic target for intervention. Therefore, in this longitudinal, observational study, we examined the relationships between trajectories of DNAm in candidate genes related to iron homeostasis and acute (cerebral vasospasm and delayed cerebral ischemia) and long-term (Glasgow Outcome Scale [GOS, unfavorable = 1–3] and death) patient outcomes after aSAH.Results: Longitudinal, genome-wide DNAm data were generated from DNA extracted from post-aSAH cerebrospinal fluid (n= 260 participants). DNAm trajectories of 637 CpG sites in 36 candidate genes related to iron homeostasis were characterized over 13 days post-aSAH using group-based trajectory analysis, an unsupervised clustering method. Significant associations were identified between inferred DNAm trajectory groups at several CpG sites and acute and long-term outcomes. Among our results, cg25713625 in the STEAP3 metalloreductase gene (STEAP3) stood out. Specifically, in comparing the highest cg25713625 DNAm trajectory group with the lowest, we observed significant associations (i.e., based onp-values less than an empirical significance threshold) with unfavorable GOS at 3 and 12 months (OR= 11.7,p= 0.0006 andOR= 15.6,p= 0.0018, respectively) and death at 3 and 12 months (OR= 19.1,p= 0.0093 andOR= 12.8,p= 0.0041, respectively). These results were replicated in an independent sample (n= 100 participants) observing significant associations with GOS at 3 and 12 months (OR= 8.2,p= 0.001 andOR= 6.3,p= 0.0.0047, respectively) and death at 3 months (OR= 2.3,p= 0.008) and a suggestive association (i.e.,p-value < 0.05 not meeting an empirical significance threshold) with death at 12 months (OR= 2.0,p= 0.0272). In both samples, an additive effect of the DNAm trajectory group was observed as the percentage of participants with unfavorable long-term outcomes increased substantially with higher DNAm trajectory groups.Conclusion: Our results support a role for DNAm of cg25713625/STEAP3in recovery following aSAH. Additional research is needed to further explore the role of DNAm of cg25713625/STEAP3as a biomarker of unfavorable outcomes, or therapeutic target to improve outcomes, to translate these findings clinically.