Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biologic mechanisms contributing to this health ...disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves upregulation of proinflammatory genes and downregulation of genes involved in type I IFN response and antibody synthesis.
We compared pretransplant leukocyte CTRA gene expression between a group of 78 high versus low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes.
Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA upregulation compared with matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity, including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival.
Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT.
Abstract Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro-inflammatory cytokines play a role in ...cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue ( n = 11) and non-fatigued controls ( n = 10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-κB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-κB, and reduced expression of transcripts with response elements for glucocorticoids ( p < .05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-κB activity, specifically decreased expression of GR anti-inflammatory transcription factors.
Highlights • In pregnant women, socioeconomic disadvantage was associated with a placenta transcriptional profile indicative of higher immune activation and slower fetal maturation. • These patterns ...were particularly evident in pathways related to brain, heart, and immune development. • Cord blood cells of disadvantaged newborns also showed indications of immaturity, as reflected in down-regulation of pathways that coordinate myeloid cell development. • A small follow-up study found preliminary support for the hypothesis that group-based prenatal care, focusing on women’s psychosocial status, could ameliorate some of these socioeconomic differences.
Highlights • Examines sensitivity to social disconnection (SD) in context of endotoxin. • Greater sensitivity to SD was related to more inflammation in response to endotoxin. • This was found for ...both proinflammatory cytokines and multiple gene transcripts. • May have implications for links between social isolation and health.
Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However, little is known about relationships of biobehavioral factors with ...angiogenic cytokines and matrix metalloproteinases (MMP) produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro.
Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial ovarian cancer. Tumor samples were analyzed for macrophage (CD68(+)) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on MMP-9.
Depressed patients showed significant elevations of MMP-9 in CD68(+) cells, adjusting for stage (P<0.0001). Patients with higher levels of current stress (P=0.01), life stress over the last 6 months (P=0.004), and general negative affect (P=0.007) also showed significantly greater MMP-9 in CD68(+) cells. In contrast, higher social support was associated with lower levels of MMP-9 (P=0.023) and vascular endothelial growth factor (P=0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones norepinephrine and cortisol.
Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9 in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient outcomes in ovarian cancer.
Evidence of chronic, systemic, low levels of inflammation is present in several stress-related psychiatric conditions including schizophrenia, depression, and intermittent explosive disorder (IED). ...We analyzed leukocyte gene expression (mRNA) to quantify the activity of pro and anti-inflammatory signaling pathways. Work performed in non-aggressive populations has uncovered a Conserved Transcriptional Response to Adversity (CTRA) characterized by an upregulation of pro-inflammatory gene transcription in chronically stressed individuals. We used pathway-based bioinformatic analyses of genome-wide transcriptional profiles of peripheral blood leukocyte samples from IED study participants (N = 45) and controls healthy (n = 45) and psychiatric (n = 34), with analyses focusing on the pro-inflammatory transcription control pathway mediated by the NF-kB family of transcription factors (typically upregulated in CTRA) and the antiviral transcription control pathway mediated by anti-viral response (IRF) family transcription factors (typically downregulated in CTRA). Compared with both healthy and psychiatric controls, individuals with IED had upregulated transcriptional activity of the antiviral response (IRF), but no evidence of pro-inflammatory NF-kB activation. Analyses implicated CD4 + T cells, CD8 + T cells, and B lymphocytes in IED-related transcriptional alterations, but showed no significant indication of monocyte involvement. This suggests that the inflammatory profile of IED differs substantially from that observed previously in other stress-related disorders, and may involve a pathogen-driven adaptive immune etiology.
•Low levels of inflammation are present in several stress-related psychiatric conditions including those with recurrent impulsive aggression.•Leukocyte gene expression (mRNA) assessed activity of pro-/anti-inflammatory pathways in aggressive and non-aggressive individuals.•Compared with controls, aggressive individuals had upregulated activity for antiviral response but not for pro-inflammatory NF-kB activation.•The inflammatory profile of aggressive individuals differs from that in other disorders, possibly involving a pathogen-driven immune etiology.
AbstractObjectiveTo determine the feasibility of pharmacologic beta-adrenergic blockade in women with newly diagnosed stage II-IV epithelial ovarian cancer (EOC) throughout primary treatment. ...MethodsPatients initiated propranolol prior to beginning chemotherapy or surgery. Feasibility was assessed as proportion able to complete 6 chemotherapy cycles while on adrenergic suppression. Descriptive statistics summarized surveys, and paired changes were analyzed using signed rank tests. Random-intercept Tobit models examined immune response. ResultsMedian age was 59.9; 88.5% were stage IIIC/IV; and 38.5% underwent primary debulking. Thirty-two patients were enrolled; 3 excluded because they never took propranolol; an additional 3 didn't meet inclusion criteria, leaving 26 evaluable. Eighteen of 26 (69%), 90% credible interval (CI) of 53–81%, completed 6 chemotherapy cycles plus propranolol (an 82% posterior probability that the true proportion of success is ≥60%). Among the 23 patients with baseline and six month follow up data, overall QOL, anxiety, and depression improved (P < 0.05) and leukocyte expression of pro-inflammatory genes declined (P = 0.03) after completion of therapy. Decrease from baseline of serum IL-6 and IL-8 preceded response to chemotherapy (P < 0.0014). Change from baseline IL-10 preceded complete response. ConclusionUse of propranolol during primary treatment of EOC is feasible and treatment resulted in decrease in markers of adrenergic stress response. In combination with chemotherapy, propranolol potentially results in improved QOL over baseline.
Adverse social conditions in early life have been linked to increased expression of proinflammatory genes and reduced expression of antiviral genes in circulating immune cells—the conserved ...transcriptional response to adversity (CTRA). However, it remains unclear whether such effects are specific to the Western, educated, industrialized, rich, and democratic (WEIRD) cultural environments in which previous research has been conducted. To assess the roles of early adversity and individual psychological resilience in immune system gene regulation within a non-WEIRD population, we evaluated CTRA gene-expression profiles in 254 former child soldiers and matched noncombatant civilians 5 y after the People’s War in Nepal. CTRA gene expression was up-regulated in former child soldiers. These effects were linked to the degree of experienced trauma and associated distress—that is, posttraumatic stress disorder (PTSD) severity—more than to child soldier status per se. Self-perceived psychological resilience was associated with marked buffering of CTRA activation such that PTSD-affected former child soldiers with high levels of personal resilience showed molecular profiles comparable to those of PTSD-free civilians. These results suggest that CTRA responses to early life adversity are not restricted to WEIRD cultural contexts and they underscore the key role of resilience in determining the molecular impact of adverse environments.
Background
Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. In patients with ovarian cancer, social isolation has been ...found to be related to decreased survival and multiple biomarkers supporting tumor progression. However, to the authors' knowledge, little is known regarding the relationship between social isolation and the molecular characteristics of ovarian tumors. Herein, the authors have used genome‐wide transcriptional profiling to quantify associations between social isolation and epithelial‐mesenchymal transition (EMT) polarization in ovarian tumors and transcriptome‐driven, promoter‐based bioinformatics analyses to identify gene regulatory pathways that may potentially underlie these changes.
Methods
Tumor was sampled during primary surgical resection and immediately frozen in liquid nitrogen. After RNA extraction, microarray analysis of the transcriptome was performed and samples were analyzed to assess associations between EMT‐related gene transcripts and social isolation (as indicated by a Social Provisions Scale Attachment subscale score <15). Convergent validation was provided by a promoter‐based bioinformatic analysis of transcription factor activity.
Results
Primary analyses of 99 women demonstrated a lower average expression of gene transcripts previously associated with epithelial differentiation in women with high social isolation (−0.143 ± 0.048 log2 mRNA abundance; P = .004), but no difference in mesenchymal differentiation as a function of social isolation (+0.007 ± 0.0064 log2 mRNA abundance; P = .900). Upregulated activity was shown for 3 of the 4 targeted EMT‐related transcription factors, including GATA4 (P = .014); SMAD2, SMAD3, and/or SMAD4 (P < .001); and TWIST1 (P < .001). Analyses of SNAIL2/SLUG activity indicated a directional trend toward increased activity that did not reach statistical significance (P = .123).
Conclusions
The findings of the current study demonstrated differential EMT polarization and EMT‐related transcription factor activity according to social isolation, a known socioenvironmental risk factor.
Lay Summary
Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. Herein, the authors examined the relationship between social isolation and the molecular characteristics of ovarian tumors.
The authors investigated the epithelial‐mesenchymal transition (EMT), a process whereby tumor cells lose epithelial characteristics and become more embryonic (mesenchymal), thereby enhancing invasiveness.
Primary analyses demonstrated lower expression of genes previously associated with epithelial differentiation and increased activity of specific EMT‐related transcription factors in individuals with high social isolation, indicating increased EMT polarization in these patients. These findings extend the understanding of how socioenvironmental factors may modulate tumor growth.
Transcriptome profiling of tumor is used to investigate relationships between social isolation and the molecular characteristics of ovarian tumors. Primary analyses demonstrate lower expression of gene transcripts previously associated with epithelial differentiation and increased activity of targeted epithelial‐mesenchymal transition (EMT)–related transcription factors in individuals with high social isolation, indicating increased EMT polarization in these patients.
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