Severe PTSD is marked by reduced oxytocin and elevated vasopressin.

Neuroendocrine analyses of posttraumatic stress disorder (PTSD) have generally focused on hypothalamic-pituitary-adrenal (HPA) axis alterations. In the present analyses, we examine two additional neuroendocrine factors that have been previously implicated in biological stress responses: oxytocin (OT) and arginine vasopressin (AVP). Here we examined basal neuropeptide status in military veterans clinically diagnosed with PTSD (n = 29) and in two non-traumatized comparison groups with previous stress exposure (n = 11 SWAT trainees and n = 21 ultramarathon runners). PTSD patients showed low levels of plasma OT and high levels of AVP. The ratio of AVP/OT robustly related to PTSD status, and emerged as a statistically plausible mediator of relationships between the number of personal traumatic experiences and subsequent PTSD symptom burden. Over the course of behavioral therapy for PTSD, measures of OT showed a significant but modest normalization. Plasma cortisol levels were not statistically different among the three groups. This study suggests that AVP/OT ratios may represent a neuroendocrine predictor of severe PTSD, as well as a potential treatment response biomarker.

Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells.

Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in "kick and kill" strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach.

A tale of two marital stressors: Comparing proinflammatory responses to partner distress and marital conflict.

Marital quality shares ties to inflammatory conditions like cardiovascular disease and diabetes. For decades, research has focused on marital conflict as a primary mechanism given its potential to trigger inflammatory responses. However, longitudinal evidence suggests that marital conflict declines over time, and little attention has been paid to the inflammatory aftermath of other types of marital exchanges. A spouse's emotional distress is an important but overlooked marital context, as partners are exposed to each other's upsetting emotions throughout adulthood. To directly compare reactivity in proinflammatory gene expression to these two marital stressors and to examine differences by age and marital satisfaction, 203 community adults ages 25-90 (N = 102 couples) provided blood samples and rated their negative mood before and after they 1) watched their partner relive an upsetting personal memory and, in a separate visit 1-2 weeks later, 2) discussed a conflictual topic in their relationship. Controlling for age, sex, race/ethnicity, BMI, alcohol use, smoking, and comorbidities, increases in proinflammatory gene expression were significantly larger after the partner's upsetting disclosure than after marital conflict (B = 0.073, SE = 0.031, p = .018). This pattern paralleled emotional reactivity to the tasks, wherein negative mood rose more in response to the partner's disclosure than to marital conflict (B = 4.305, SE = 1.468, p = .004). In sum, proinflammatory and mood reactivity to spousal distress exceeded reactivity to marital conflict, a well-established marital stressor. Findings reveal spousal distress as a novel mechanism that may link marriage to inflammation-related diseases, and even pose risks for both happy and unhappy couples across adulthood.

Avanzando Caminos (Leading Pathways): Design and Procedures of The Hispanic/Latino Cancer Survivorship Study.

PURPOSE: Avanzando Caminos (Leading Pathways): The Hispanic/Latino Cancer Survivorship Cohort Study aims to examine the influence of sociocultural, medical, stress, psychosocial, lifestyle, behavioral, and biological factors on symptom burden, health-related quality of life, and clinical outcomes among Hispanics/Latinos who have been previously treated for cancer. METHODS: Avanzando Caminos is a prospective, cohort-based study of 3,000 Hispanics/Latinos who completed primary cancer treatment within the past five years that is representative of the general Hispanic/Latino population in the U.S. Participants will complete self-report measures at baseline (T1), 6 months (T2), 1 year (T3), 2 years (T4), 3 years (T5), 4 years (T6), and 5 years (T7). Blood draws to assess leukocyte gene expression, cardiometabolic markers, and genetic admixture will be collected at baseline (T1), 1 year (T3), 3 years (T5), and 5 years (T7). Medical and cancer characteristics and clinical outcomes will be extracted from the electronic medical record and/or state cancer registry at each time point. Data analysis will include general latent variable modeling and latent growth modeling. CONCLUSIONS: Avanzando Caminos will fill critical gaps in knowledge to guide future secondary and tertiary prevention efforts to mitigate cancer disparities and optimize health-related quality of life among Hispanic/Latino cancer survivors.

A dyadic longitudinal analysis of parent-adolescent inflammation trends and the role of shared socioeconomic characteristics on family inflammation.

The objective of the present study was to evaluate the interdependency of parent-adolescent inflammation trends across time and to examine whether shared family socioeconomic characteristics explained between-family differences in parents' and adolescents' risk for inflammation. A total of N = 348 families, consisting of one parent and one adolescent child, were followed every two years in a three-wave longitudinal study. Sociodemographic questionnaires were used to determine parental educational attainment and family income-to-needs ratio (INR). At each time point, parents and adolescents collected dried blood spot (DBS) samples that were assayed for circulating CRP and log-transformed prior to analysis by longitudinal dyadic models. Models revealed significant differences in parents' and adolescents' inflammation trends over time (bint = - 0.13, p < 0.001). While parental CRP levels remained relatively stable across the study period, adolescent CRP increased by approximately 38% between study waves. Parents' average CRP levels were positively correlated with adolescents' average CRP (r = 0.32, p < 0.001), but parental change in CRP over time was not significantly related to change in adolescents' CRP over time. Family dyads with higher parental educational attainment had lower average CRP (b = -0.08, p = 0.01), but parental education did not predict change in dyads' inflammation over time. Study findings suggest that shared family socioeconomic characteristics contribute to baseline similarities in parents' and adolescents' inflammation and potentially point to adolescence as a period of inflammatory change where youth may diverge from parental inflammation trends.

Loneliness, epigenetic age acceleration, and chronic health conditions.

Having associations with a range of adverse physical health outcomes including mortality, loneliness is increasingly recognized as a pressing public health concern, but the mechanisms studied to date do not yet explain all loneliness-related health risk. We sought to evaluate whether epigenetic influences on DNA methylation could help explain the relationship between loneliness and health. To do so, we first estimated associations between loneliness and epigenetic age acceleration (EAA) in a subsample of participants in the study of midlife in the United States (n = 1,310), before testing whether EAA mediated and/or moderated the association between loneliness and the onset of chronic health conditions in older adulthood (n = 445 completing longitudinal follow-ups). Greater loneliness was weakly associated with greater EAA in the Horvath, DunedinPACE, and GrimAge measures after accounting for demographic (0.08 ≤ ß ≤ 0.11) and behavioral (0.06 ≤ ß ≤ 0.08) covariates. Loneliness also predicted increases in chronic condition counts and these effects were more pronounced for individuals with higher DunedinPACE EAA values (interaction term ß = 0.09, p = .009), suggesting possible synergistic impacts. EAA measures appear to be promising in helping to understand individual variations in the health impacts of loneliness, but the specific mechanisms involved require further research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Psychoneuroimmunology in multiple myeloma and autologous hematopoietic stem cell transplant: Opportunities for research among patients and caregivers.

Multiple myeloma (MM) is an incurable cancer and is the leading indication for autologous hematopoietic stem cell transplantation (HSCT). To be eligible for HSCT, a patient must have a caregiver, as caregivers play a central role in HSCT preparation and recovery. MM patients remain on treatment indefinitely, and thus patients and their caregivers face long-term challenges including the intensity of HSCT and perpetual therapy after transplant. Importantly, both patients and their caregivers show heightened depressive and anxiety symptoms, with dyadic correspondence evidenced and caregivers' distress often exceeding that of patients. An extensive psychoneuroimmunology (PNI) literature links distress with health via immune and neuroendocrine dysregulation as well as biological aging. However, data on PNI in the context of multiple myeloma - in patients or caregivers - are remarkably limited. Distress in MM patients has been associated with poorer outcomes including higher inflammation, greater one year post-HSCT hospital readmissions, and worse overall survival. Further, anxiety and depression are linked to biological aging and may contribute to the poor long-term health of both patients and caregivers. Because MM generally affects older adults, individual differences in biological aging may represent an important modifier of MM biology and HSCT treatment outcomes. There are a number of clinical scenarios in which biologically younger people could be prescribed more intensive therapies, with potential for greater benefit, by using a personalized cancer therapy approach based on the quantification of physiologic reserve. Further, despite considerable psychological demands, the effects of distress on health among MM caregivers is largely unexamined. Within this context, the current critical review highlights gaps in knowledge at the intersection of HSCT, inflammation, and biological aging in the context of MM. Research in this area hold promise for opportunities for novel and impactful psychoneuroimmunology (PNI) research to enhance health outcomes, quality of life, and longevity among both MM patients and their caregivers.

Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo.

While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for its attachment and entry into splenic B cells. Single-cell RNA sequencing analysis of the transduced cells demonstrated that different pseudotypes transduce distinct B cell subpopulations characterized by specific B cell receptor (BCR) genotypes. Functional analysis of the BCRs of the transduced cells demonstrated that BCRs specific to the pseudotyping envelope proteins mediate viral entry, enabling the vectors to selectively transduce the B cell populations that are capable of producing antibodies specific to their envelope proteins. Lentiviral vector entry via the BCR activated the transduced B cells and induced proliferation and differentiation into mature effectors, such as memory B and plasma cells. BCR-mediated viral entry into clonally specific B cell subpopulations raises new concepts for understanding the biodistribution of transgene expression after systemic administration of lentiviral vectors and offers new opportunities for BCR-targeted gene delivery by pseudotyped lentiviral vectors.

ZIP Code to Genomic Code: Neighborhood Disadvantage, Aggressive Breast Cancer Biology, and Breast Cancer Outcomes.

OBJECTIVE: To determine the association between objective (geospatial) and subjective (perceived) measures of neighborhood disadvantage (ND) and aggressive breast cancer (BCa) tumor biology, defined using validated social adversity-associated transcription factor (TF) activity and clinical outcomes. SUMMARY BACKGROUND DATA: ND is associated with shorter BCa recurrence-free survival (RFS), independent of individual, tumor, and treatment characteristics, suggesting potential unaccounted biological mechanisms by which ND influences RFS. METHODS: We quantified TF-binding motif prevalence within promoters of differentially expressed genes for 147 tissue samples prospectively collected on protocol. Covariate-adjusted multivariable regression analyzed objective and subjective ND scores with 5 validated TFs of social adversity and aggressive biology-pro-inflammatory activity (NF-kB, AP-1), sympathetic nervous system (SNS) activity (CREB), and protective cellular responses (IRF, STAT). To clinically validate these TFs as prognostic biomarkers of aggressive biology, logistic regression and multivariable Cox proportional-hazards models analyzed their association with Oncotype DX scores and RFS, respectively. RESULTS: Increasing objective ND was associated with aggressive tumor biology (up-regulated NF-kB, AP-1, down-regulated IRF, STAT) and SNS activation (up-regulated CREB). Increasing subjective ND (e.g., threat to safety), was associated with up-regulated NF-kB and CREB and down-regulated IRF. These TF patterns were associated with high-risk Oncotype DX scores and shorter RFS. CONCLUSIONS: In the largest human social genomics study, objective and subjective ND were significantly associated with TFs of aggressive biology and SNS activation. These TFs also correlated with worse clinical outcomes, implicating SNS activation as one potential mechanism behind ND survival disparities. These findings remain to be validated in a national cohort.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

BACKGROUND: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment. METHODS: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes. RESULTS: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant. CONCLUSIONS: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.

Peri-operative individually tailored psychological intervention in breast cancer patients improves psychological indices and molecular biomarkers of metastasis in excised tumors.

Perioperative stress and inflammatory signaling can invigorate pro-metastatic molecular processes in patients' tumors, potentially worsening long-term survival. Yet, it is unknown whether pre-operative psychotherapeutic interventions can attenuate such effects. Herein, three weeks before surgery, forty women diagnosed with stage I-III invasive ductal/lobular breast carcinoma were randomized to a 6-week one-on-one psychological intervention (6 meetings with a medical psychologist and bi-weekly phone calls) versus standard nursing-staff-attention. The intervention protocol was individually tailored based on evaluation of patients' emotional, cognitive, physiological, and behavioral stress response-patterns, and also included psychoeducation regarding medical treatments and recruitment of social support. Resected primary tumors were subjected to whole-genome RNA sequencing and bioinformatic analyses, assessing a priori hypothesized cancer-relevant molecular signatures. Self-report questionnaires (BSI-18, Hope-18, MSPSS, and a stress-scale) were collected three (T1) and one (T2) week before surgery, a day before (T3) and after (T4) surgery, and three weeks (T5) and 3-months (T6) following surgery. The intervention reduced distress (GSI), depression, and somatization scores (BSI-18: p < 0.01, p < 0.05, p < 0.05; T5 vs. T1). Additionally, tumors from treated patients (vs. controls) showed: (i) decreased activity of transcription control pathways involved in adrenergic and glucocorticoid signaling (CREB, GR) (p < 0.001), pro-inflammatory signaling (NFkB) (p < 0.01), and pro-malignant signaling (ETS1, STAT and GATA families) (p < 0.001, p < 0.01, p < 0.005); (ii) increased M1 macrophage polarization (p < 0.05), and CD4+ T cell activity (p < 0.01); and an unexpected increase in epithelial-to-mesenchymal-transition (EMT) signature (p < 0.005). This is the first randomized controlled trial to show beneficial effects of a psychological perioperative intervention on tumor pro-metastatic molecular biomarkers.

Psychosocial predictors of the innate immune response to influenza vaccination.

Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research.

Childhood Maltreatment and Immune Cell Gene Regulation during Adolescence: Transcriptomics Highlight Non-Classical Monocytes.

Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.

Protocol for teen inflammation glutamate emotion research (TIGER): Toward predictors of treatment response and clinical course in depressed adolescents.

Adolescent-onset depression is a prevalent and debilitating condition commonly associated with treatment refractory depression and non-response to first-line antidepressants. There are, however, no objective tests to determine who may or may not respond to antidepressants. As depressed adolescents are especially vulnerable to the lifelong consequences of ineffectively-treated depression, it is critical to identify neurobiological predictors of treatment non-response in this population. Here, we describe the scientific rationale and protocol for the Teen Inflammation Glutamate Emotion Research (TIGER) study, a prospective 18-month investigation of 160 depressed adolescents who will be assessed before and after treatment with selective serotonin reuptake inhibitors. TIGER will be using ultra-high field imaging to test the effects of acute stress and antidepressant treatment on inflammatory and glutamatergic processes hypothesized to underlie depression maintenance. Results from this work will motivate future studies testing alternative therapeutics for depressed adolescents at risk for treatment resistant depression. ClinicalTrials.gov Identifier: NCT05329441.

Impact of Neighborhood Disadvantage on Tumor Biology and Breast Cancer Survival.

OBJECTIVE: The aim of this study was to evaluate the association between neighborhood disadvantage and Oncotype DX score, a surrogate for tumor biology, among a national cohort. BACKGROUND: Women living in disadvantaged neighborhoods have shorter breast cancer (BC) survival, even after accounting for individual-level, tumor, and treatment characteristics. This suggests unaccounted social and biological mechanisms by which neighborhood disadvantage may impact BC survival. METHODS: This cross-sectional study included stage I and II, ER + /HER2 - BC patients with Oncotype DX score data from the National Cancer Database (NCDB) from 2004 to 2019. Multivariate regression models tested the association of neighborhood-level income on Oncotype DX score controlling for age, race/ethnicity, insurance, clinical stage, and education. Cox regression assessed overall survival. RESULTS: Of the 294,283 total BC patients selected, the majority were non-Hispanic White (n=237,197, 80.6%) with 7.6% non-Hispanic Black (n=22,495) and 4.5% other (n=13,383). 27.1% (n=797,254) of the population lived in the disadvantaged neighborhoods with an annual neighborhood-level income of <$48,000, while 59.62% (n=175,305) lived in advantaged neighborhoods with a neighborhood-level income of >$48,000. On multivariable analysis controlling for age, race/ethnicity, insurance status, neighborhood-level education, and pathologic stage, patients in disadvantaged neighborhoods had greater odds of high-risk versus low-risk Oncotype DX scores compared with those in advantaged neighborhoods [odds ratio=1.04 (1.01-1.07), P =0.0067]. CONCLUSION AND RELEVANCE: This study takes a translational epidemiologic approach to identify that women living in the most disadvantaged neighborhoods have more aggressive tumor biology, as determined by the Oncotype DX score.

Unfavorable transcriptome profiles and social disadvantage in hematopoietic cell transplantation: a CIBMTR analysis.

Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population.

Social relationships and epigenetic aging in older adulthood: Results from the Health and Retirement Study.

Growing evidence suggests that social relationship quality can influence age-related health outcomes, although how the quality of one's relationships directly relates to the underlying aging process is less clear. We hypothesized that the absence of close relationships as well as lower support and higher strain within existing relationships would be associated with an accelerated epigenetic aging profile among older adults in the Health and Retirement Study. Adults (N = 3,647) aged 50-100 years completed ratings of support and strain in relationships with their spouse, children, other family members, and friends. They also provided a blood sample that was used for DNA methylation profiling to calculate a priori-specified epigenetic aging measures: Horvath, Hannum, PhenoAge, GrimAge, and Dunedin Pace of Aging methylation (DunedinPoAm38). Generalized linear models that adjusted for chronological age, sex, and race/ethnicity and applied a false discovery rate correction revealed that the absence of marital and friend relationships related to an older GrimAge and faster DunedinPoAm38. Among those with existing relationships, lower support from a spouse, child, other family, and friends and higher strain with friends related to an older PhenoAge and GrimAge and faster DunedinPoAm38. In secondary analyses that further adjusted for socioeconomic and lifestyle factors, lower support from other family members and friends was associated with greater epigenetic aging. Findings suggest that the absence of close relationships and lower support within existing relationships-particularly with family members and friends-relate to accelerated epigenetic aging in older adulthood, offering one mechanism through which social relationships might influence risk for age-related declines and disease.

Short sleep and insomnia are associated with accelerated epigenetic age.

OBJECTIVE: Short sleep and insomnia are each associated with greater risk for age-related disease, which suggests that insufficient sleep may accelerate biological aging. We examine whether short sleep and insomnia alone or together relate to epigenetic age among older adults. METHODS: A total of 3,795 men (46.3%) and women aged 56-100 years from the Health and Retirement Study were included. Insomnia was defined as reporting at least one insomnia symptom (difficulty falling asleep, waking up at night, or waking up too early in the morning) and feeling unrested when waking up most of the time. Those reporting <6 hours of bedtime were categorized as short sleepers. Three second- or third-generation epigenetic age acceleration clocks were derived from the 2016 HRS Venous Blood Study. The linear regression analysis was adjusted for age, sex, race/ethnicity, education, and obesity status. RESULTS: Insomnia and short sleep were associated with an 0.49 (95%CI:0.03-0.94; P:0.04) and 1.29 (95%CI:0.52-2.07; P:0.002) years acceleration of GrimAge, respectively, as well as a faster pace of aging (DunedinPACE; 0.018 (95%CI:0.004-0.033; P:0.02); 0.022(95%CI:-0.004-0.048; P:0.11)). Compared to healthy sleepers, individuals with the combination of short sleep and insomnia had an accelerated GrimAge (0.97 years; 95%CI:0.07-1.87; P:0.04) and a greater DunedinPACE (0.032; 95%CI:0.003-0.060; P:0.04). CONCLUSION: Our findings indicate short sleep, insomnia, and the combination of the two, are linked to epigenetic age acceleration, suggesting that these individuals have an older biological age that may contribute to risk for comorbidity and mortality.

Effects of neighborhood disadvantage on cortisol and interviewer-rated anxiety symptoms in breast cancer patients initiating treatment.

PURPOSE: Shorter breast cancer (BC) survival outcomes persist by neighborhood disadvantage independent of patient, tumor, and treatment characteristics. This suggests unaccounted mechanisms by which neighborhood disadvantage "gets under the skin" to impact BC survival outcomes. Here, we evaluate the relationship between neighborhood disadvantage and clinical and neuroendocrine markers of stress in BC patients. METHODS: Women with stage 0-III BC were enrolled 2-10 weeks post-surgery and before initiating adjuvant treatment in a study examining stress and stress management processes. Women provided an afternoon-evening (PM) serum cortisol sample and were administered the Hamilton Anxiety Rating Scale (HAM-A). Home addresses were used to determine the Area Deprivation Index (ADI), a validated measure of neighborhood disadvantage. Multiple regression assessed the relationship between ADI and PM serum cortisol and the presence of elevated HAM-A symptoms. RESULTS: Our sample (n = 225) was predominately middle-aged (M = 50.4 years; range 23-70 years), non-Hispanic White (64.3%), with stage I (38.1%), or II (38.6%) disease. The majority (n = 175) lived in advantaged neighborhoods (ADI 1-3). After controlling for age, stage, and surgery type, women from high ADI (4-10) (vs low ADI) neighborhoods had higher PM cortisol levels (ß = 0.19, 95% CI [0.24, 5.00], p = 0.031) and were nearly two times as likely to report the presence of elevated anxiety symptoms (OR = 1.96, 95% CI [1.00, 3.86], p = 0.050). CONCLUSION: Neighborhood disadvantage is significantly associated with higher levels of PM cortisol and elevated anxiety symptoms suggesting stress pathways could potentially contribute to relationships between neighborhood disadvantage and BC survival.

Daily heart rate variability biofeedback training decreases locus coeruleus MRI contrast in younger adults in a randomized clinical trial.

As an arousal hub region in the brain, the locus coeruleus (LC) has bidirectional connections with the autonomic nervous system. Magnetic resonance imaging (MRI)-based measures of LC structural integrity have been linked to cognition and arousal, but less is known about factors that influence LC structure and function across time. Here, we tested the effects of heart rate variability (HRV) biofeedback, an intervention targeting the autonomic nervous system, on LC MRI contrast and sympathetic activity. Younger and older participants completed daily HRV biofeedback training for five weeks. Those assigned to an experimental condition performed biofeedback involving slow, paced breathing designed to increase heart rate oscillations, whereas those assigned to a control condition performed biofeedback to decrease heart rate oscillations. At the pre- and post-training timepoints, LC contrast was assessed using turbo spin echo MRI scans, and RNA sequencing was used to assess cAMP-responsive element binding protein (CREB)-regulated gene expression in circulating blood cells, an index of sympathetic nervous system signaling. We found that left LC contrast decreased in younger participants in the experimental group, and across younger participants, decreases in left LC contrast were related to the extent to which participants increased their heart rate oscillations during training. Furthermore, decreases in left LC contrast were associated with decreased expression of CREB-associated gene transcripts. On the contrary, there were no effects of biofeedback on LC contrast among older participants in the experimental group. These findings provide novel evidence that in younger adults, HRV biofeedback involving slow, paced breathing can decrease both LC contrast and sympathetic nervous system signaling.