Cytokine-Effects on Glucocorticoid Receptor Function: Relevance to Glucocorticoid Resistance and the Pathophysiology and Treatment of Major Depression

Abstract Glucocorticoids play an essential role in the response to environmental stressors, serving initially to mobilize bodily responses to challenge and ultimately serving to restrain neuroendocrine and immune reactions. A number of diseases including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids (glucocorticoid resistance), which is believed to be related in part to impaired functioning of the glucocorticoid receptor (GR). Glucocorticoid resistance, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways, which are known to contribute to a variety of diseases as well as behavioral alterations. Recent data indicate that glucocorticoid resistance may be a result of impaired GR function secondary to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress. Indeed, inflammatory cytokines and their signaling pathways including mitogen-activated protein kinases, nuclear factor-kB, signal transducers and activators of transcription, and cyclooxygenase have been found to inhibit GR function. Mechanisms include disruption of GR translocation and/or GR-DNA binding through protein-protein interactions of inflammatory mediators with the GR itself or relevant steroid receptor cofactors as well as alterations in GR phosphorylation status. Interestingly, cAMP signal transduction pathways can enhance GR function and inhibit cytokine signaling. Certain antidepressants have similar effects. Thus, further understanding the effects of cytokines on GR signaling and the mechanisms involved may reveal novel therapeutic targets for reversal of glucocorticoid resistance and restoration of glucocorticoid-mediated inhibition of relevant bodily/immune responses during stress and immune challenge

Cognitively-Based Compassion Training versus cancer health education to improve health-related quality of life in survivors of solid tumor cancers and their informal caregivers: study protocol for a randomized controlled pilot trial

Background: Cancer survivors and their informal caregivers (family members, close friends) often experience significant impairments in health-related quality of life (HRQOL), including disruptions in psychological, physical, social, and spiritual well-being both during and after primary cancer treatment. The purpose of this in-progress pilot trial is to determine acceptability and preliminary efficacy (as reflected by effect sizes) of CBCT (R) (Cognitively-Based Compassion Training) compared with a cancer health education (CHE) attention control to improve the primary outcome of depressive symptoms and secondary outcomes of other HRQOL domains (e.g., anxiety, fatigue), biomarkers of inflammation and diurnal cortisol rhythm, and healthcare utilization-related outcomes in both cancer survivors and informal caregivers. Methods: Forty dyads consisting of solid tumor survivors who have completed primary treatments (chemotherapy, radiation, surgery) and their informal caregivers, with at least one dyad member with mild depressive symptoms or anxiety, will be recruited from Tucson, Arizona, USA. Survivor-caregiver dyads will be randomized together to complete either CBCT or CHE. CBCT is a manualized, 8-week, group meditation-based intervention that starts with attention and mindfulness and builds to contemplative practices aimed at cultivating compassion to the self and others. The goal of CBCT is to challenge unexamined assumptions about feelings and behaviors, with a focus on generating spontaneous self-compassion and increased empathic responsiveness and compassion for others. CHE is an 8-week, manualized group intervention that provides cancer-specific education on various topics (e.g., cancer advocacy, survivorship wellness). Patient-reported HRQOL outcomes will be assessed before, immediately after (week 9), and 1month after CBCT or CHE (week 13). At the same time points, stress-related biomarkers of inflammation (e.g., plasma interleukin-6) and saliva cortisol relevant for survivor and informal caregiver wellness and healthcare utilization will be measured. Discussion: If CBCT shows acceptability, a larger trial will be warranted and appropriately powered to formally test the efficacy of this dyadic intervention. Interventions such as CBCT directed toward both survivors and caregivers may eventually fill a gap in supportive oncology care programs to improve HRQOL and healthcare utilization in both dyad members. Trial registration Clinicaltrials.gov, NCT03459781. Prospectively registered on 9 March 2018.The Jack Challem Trust [001]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

The AURORA Study: A Longitudinal, Multimodal Library of Brain Biology and Function after Traumatic Stress Exposure

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Relationship Between Health-Related Quality of Life and Saliva C-Reactive Protein and Diurnal Cortisol Rhythm in Latina Breast Cancer Survivors and Their Informal Caregivers: A Pilot Study

Introduction: To date, no study has explored associations between objective stress-related biomarkers (i.e., inflammatory markers, diurnal rhythm of cortisol) and health-related quality of life (HRQOL) in Latina breast cancer survivors and their informal caregivers (i.e., family, friends). Method: This cross-sectional feasibility study assessed saliva C-reactive protein, saliva diurnal cortisol rhythm (cortisol slope), and self-reported HRQOL (psychological, physical, and social domains) in 22 Latina survivor-caregiver dyads. Feasibility was defined as >= 85% samples collected over 2 days (on waking, in afternoon, and in evening). Associations between biomarkers and HRQOL were examined with correlational analyses. Results: Collection of saliva was feasible. Strongest associations were observed between survivor evening cortisol (as well as cortisol slope) and fatigue, a component of physical HRQOL. Discussion: Associations presented may help promote investigations of mechanisms linking stress-related biomarkers and HRQOL in Latina breast cancer survivor-caregiver dyads, which will facilitate development of culturally congruent interventions for this underserved group

The Relationship Between Health-Related Quality of Life and Saliva C-Reactive Protein and Diurnal Cortisol Rhythm in Latina Breast Cancer Survivors and Their Informal Caregivers: A Pilot Study

Introduction: To date, no study has explored associations between objective stress-related biomarkers (i.e., inflammatory markers, diurnal rhythm of cortisol) and health-related quality of life (HRQOL) in Latina breast cancer survivors and their informal caregivers (i.e., family, friends). Method: This cross-sectional feasibility study assessed saliva C-reactive protein, saliva diurnal cortisol rhythm (cortisol slope), and self-reported HRQOL (psychological, physical, and social domains) in 22 Latina survivor-caregiver dyads. Feasibility was defined as >= 85% samples collected over 2 days (on waking, in afternoon, and in evening). Associations between biomarkers and HRQOL were examined with correlational analyses. Results: Collection of saliva was feasible. Strongest associations were observed between survivor evening cortisol (as well as cortisol slope) and fatigue, a component of physical HRQOL. Discussion: Associations presented may help promote investigations of mechanisms linking stress-related biomarkers and HRQOL in Latina breast cancer survivor-caregiver dyads, which will facilitate development of culturally congruent interventions for this underserved group.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Use of a Guided Imagery Mobile App (See Me Serene) to Reduce COVID-19–Related Stress: Pilot Feasibility Study

BackgroundThe SARS-CoV-2 pandemic has led to concerns about mental health resulting from regional and national lockdowns, social isolation, job loss, and concern about disease exposure. ObjectiveWe describe results of the pilot feasibility study of the See Me Serene mHealth app. The app provides users with immersive, vivid, nature experiences to reduce stress and anxiety related to COVID-19 and other isolation. The goals of the study were to develop the See Me Serene app and test the feasibility and acceptability of study procedures, and explore the potential impact of the app on stress and anxiety. MethodsWe developed and tested the See Me Serene app and our study procedures for feasibility, and gathered preliminary data with a goal of 100 participants. The research was conducted in 2 phases: (1) development and internal testing of the app; and (2) feasibility and pilot testing with participants recruited online through earned media (eg, news stories), presentations at a university campus, and social media (eg, online sharing of earned media and presentations). The feasibility study employed a mixed methods, within-subjects, pre-/posttest design. At baseline and 30-day follow-up, we assessed stress-related variables via validated self-report measures and saliva samples for determination of cortisol concentrations. ResultsWe met or surpassed all our feasibility benchmarks for recruitment (101 participants recruited), retention (91% [90/99] of 30-day assessment completed), and data collection (99 participants completed all baseline data; 85% [84/99] of salivary cortisol samples returned). Participants adhered to the intervention. On average, participants listened to 48.2 audio files over 30 days or approximately 1.6 audio files per day. Participants were satisfied with the app, with 87% (78/90) rating the app as helpful in dealing with stress and anxiety. The app showed the potential to reduce stress, anxiety, loneliness, and worry. We did not find significant differences (P=.41) in cortisol levels over time. Our findings suggest that future research is warranted to test the efficacy of the See Me Serene app with a representative, diverse sample. ConclusionsThere is a need for evidence-based and easily disseminable stress-reduction interventions. See Me Serene is a feasible intervention and has the potential to reduce stress related to COVID-19 and other forms of social isolation. More research on See Me Serene is warranted