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Background: The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer., Methods: Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques., Results: Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220)., Conclusions: Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes., (© 2021 American Cancer Society.)

Background: Many cancer survivors experience fatigue as a nagging symptom lasting years after treatment. To learn of the relevant biological pathways involved in fatigue among cancer survivors, the authors tested for an association between fatigue levels and leukocyte gene expression profiles and determined the specific mediating immune cell types., Methods: A sample of 89 Hispanic/Latino adults aged 60.5 years, 62% of whom were male, who were diagnosed with colorectal cancer and were 2.9 years since diagnosis provided blood for transcriptome profiling and completed a validated measure of fatigue (Multidimensional Fatigue Symptom Inventory-Short Form). The authors applied genome-wide transcriptional profiling of leukocyte RNA to identify gene expression activity associated with fatigue, tested for the activity of specific transcription factors involved in previously established markers of inflammation and immunologic activation, and identified the specific cell types mediating these transcriptional alterations., Results: In analyses adjusting for demographic and behavioral health risk factors, results linked fatigue with increased activation of B lymphocytes and CD8-positive T cells, as well as several transcription factors involved in immune activation (nuclear factor κB [NF-κB], signal transducer and activator of transcription [STAT], and cAMP responsive element-binding protein [CREB]). Results also replicated several specific genomic effects previously observed in fatigued cancer survivors, including upregulated expression of α-synuclein (SNCA) and hemoglobin subunits (HBA and HBB)., Conclusions: Cancer survivors' heightened fatigue levels may be partially explained by activation of specific immune cell subsets, thereby providing a potential molecular biomarker for clinical interventions targeting the remediation of fatigue. Cancer 2018;124:2637-44. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Background: Natural mutations in the human glucocorticoid receptor (hGR, NR3C1) gene cause Chrousos syndrome, a rare condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids., Objective: To present a new case of Chrousos syndrome caused by a novel mutation in the hGR gene, and to elucidate the molecular mechanisms through which the natural mutant receptor affects glucocorticoid signal transduction., Design and Results: The index case presented with hirsutism, acne, alopecia, anxiety, fatigue and irregular menstrual cycles, but no clinical manifestations suggestive of Cushing's syndrome. Endocrinologic evaluation revealed elevated 08:00 h plasma adrenocorticotropic hormone, serum cortisol and androstenedione concentrations and increased urinary free cortisol excretion. The patient harbored a novel A > G transition at nucleotide position 2177, which resulted in histidine (H) to arginine (R) substitution at amino acid position 726 of the receptor (c.2177A > G, p.H726R). Compared with the wild-type receptor, the mutant receptor hGRαH726R demonstrated decreased ability to transactivate glucocorticoid-responsive genes and to transrepress the nuclear factor-κB signalling pathway, displayed 55% lower affinity for the ligand and a four-fold delay in nuclear translocation, and interacted with the glucocorticoid receptor-interacting protein 1 coactivator mostly through its activation function-1 domain. Finally, a 3-dimensional molecular modelling study of the H726R mutation revealed a significant structural shift in the rigidity of helix 10 of the receptor, which resulted in reduced flexibility and decreased affinity of the mutant receptor for binding to the ligand., Conclusions: The natural mutant receptor hGRαH726R impairs multiple steps of glucocorticoid signal transduction, thereby decreasing tissue sensitivity to glucocorticoids., (© 2015 Stichting European Society for Clinical Investigation Journal Foundation.)

A 10-month-old boy presented with a history of a generalized cutaneous bullous eruption since 3 months of age. Emesis, flush, pruritus, and fatigue had accompanied relapsing episodes of sometimes extensive blistering. Histopathology showed dense dermal infiltrates of mast cells on hematoxylin and eosin and corroborating immunohistochemical staining. Laboratory examination revealed a markedly high level of serum tryptase. Based on these results and after consecutive staging, the patient was diagnosed with diffuse cutaneous bullous mastocytosis (BM). Mutation analysis detected a deletion mutation (del419) in C-Kit by direct exon sequencing. This rare entity must be considered in the differential diagnosis whenever a child presents with bullae and erosions. A crucial diagnostic hint is that rubbing of affected skin areas results in whealing (Darier's sign). A comprehensive diagnostic approach, advanced therapeutic strategies, regular follow-ups, and instruction of patients and relatives on prevention and prophylaxis are highly indicated., (© 2011 Wiley Periodicals, Inc.)

Purpose: To examine phenotypic considerations in the study of fatigue and to explore significant issues affecting the extension of biobehavioral research of fatigue by the inclusion of genetic and genomic markers. THEORETICAL ORGANIZATION: Fatigue is a condition that has an adverse effect on quality of life that has been a focus of nursing inquiry. Yet, the study of fatigue has been stymied by the lack of phenotypic clarity. To expand the biobehavioral inquiry of fatigue, phenotypic clarity is needed. In addition, examining genomic factors associated with fatigue may help to elucidate the pathophysiology of fatigue and, in the future, lead to targeted interventions that address the molecular basis of fatigue., Conclusions: Given that nursing has been at the forefront of the study of fatigue, nurse scientists should consider enhancing phenotypic clarity by the development of a case-definition and use of a core measure of fatigue, one that can be augmented by condition- or population-specific measures as needed. Following the establishment of phenotypic clarity, the integration of genomics into biobehavioral research offers an opportunity for further clarity of phenotypes and for theoretical specification of the pathophysiology of conditions such as fatigue., Clinical Relevance: The development of targeted interventions for fatigue depend on a more precise definition of fatigue and a better understanding of the biologic processes that contribute to its development and persistence., (© 2011 Sigma Theta Tau International.)

Background: Previous research has demonstrated that many lung cancer survivors report difficulties with symptom control and experience a poor quality of life (QOL). Although recent studies have suggested a relationship of single nucleotide polymorphisms (SNPs) in several cytokine genes with cancer susceptibility and prognosis, associations with symptom burden and QOL have not been examined. The current study was conducted to identify SNPs related to symptom burden and QOL outcomes in lung cancer survivors., Methods: All participants were enrolled in the Mayo Clinic Lung Cancer Cohort following diagnosis of lung cancer. A total of 1149 Caucasian lung cancer survivors completed questionnaires and had genetic samples available. The main outcome measures were symptom burden as measured by the Lung Cancer Symptom Scale and health-related QOL as measured by the Short-Form General Health Survey., Results: Twenty-one SNPs in cytokine genes were associated with symptom burden and QOL outcomes. Our results suggested both specificity and consistency of cytokine gene SNPs in predicting outcomes., Conclusions: These results provide support for genetic predisposition to QOL and symptom burden and may aid in identification of lung cancer survivors at high risk for symptom management and QOL difficulties., (Cancer 2010. (c) 2010 American Cancer Society.)

Fatigue is a common symptom and includes both physical and mental components. It can be associated with a variety of different syndromes and diseases, but in many cases is not associated with other comorbid conditions. Most humans have experienced acute fatigue in relation to different stressors. Acute fatigue typically decreases as the effect of the triggering factor is reduced and a normal homeostatic balance is restored. Fatigue that persists for 6 months or more is termed chronic fatigue. Chronic fatigue (CF) in combination with a minimum of 4 of 8 symptoms and the absence of diseases that could explain these symptoms, constitute the case definition for chronic fatigue syndrome. In spite of its prevalence, the biology of fatigue is relatively poorly understood and biological markers have not yet been identified. This literature search was performed in PubMed to identify research on the genetics and epigenetics of fatigue. Publications were included if fatigue was a major topic and the topic was combined with genetic and/or epigenetic measurements in adult humans. A total of 40 publications were identified. Although altered functioning in the hypothalamic-pituitary-adrenal axis, the serotonergic system, and associations with infectious agents have been identified, the search for genetic or epigenetic markers of fatigue, either in the context of CF or chronic fatigue syndrome (CFS) has been relatively unproductive or, in the case of epigenetics, nonexistent. Although several studies, both hypothesis-testing and hypothesis-generating, have been performed to search for biomarkers, they have mostly been underpowered, restricted by the heterogeneity of the phenotype, or limited by an unsystematic study design. To be able to confirm the hypothesis that risk for, or levels of, fatigue are influenced by the genetic or epigenetic background of an individual, studies need to be based on larger sample sizes with a more clearly defined phenotype. Studies need to focus not only on the influence of a single aspect such as single nucleotide polymorphisms (SNPs) or differential gene expression on disease risk or state, but also on the systems biology behind the disease in combination with information on environmental influences and validation of findings in functional studies., (Copyright (c) 2010 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)