Sleep disturbance and activation of cellular and transcriptional mechanisms of inflammation in older adults.

BACKGROUND: Sleep disturbance, including poor subjective sleep quality and insomnia disorder, is common in older adults and associated with increases in age-related morbidity risk. Accumulating evidence implicates inflammation as an underlying mechanism. In two complementary studies, we examined whether sleep disturbance is associated with activation of cellular and transcriptional mechanisms of inflammation in older adults. METHODS: Study 1 examined whether healthy older adults with poor subjective sleep quality (n = 62), compared to those with good subjective sleep quality (n = 101), differed in monocytic production of interleukin (IL)-6 and/or tumor necrosis factor (TNF)-α following stimulation with lipopolysaccharide. Study 2 examined whether older adults with insomnia disorder (n = 17), compared to those without insomnia disorder (n = 25), differed in the regulation of transcription factors (TFs) related to immune activation (i.e., nuclear factor-κB/Rel family), sympathetic nervous system (SNS) activity (i.e., cAMP-response element-binding protein), hypothalamic-pituitary-adrenal (HPA) axis activity (i.e., glucocorticoid receptor) and anti-viral responses (i.e., interferon-regulatory factor/interferon-stimulated response element) assessed in peripheral blood mononuclear cells. RESULTS: In Study 1, older adults with poor subjective sleep quality, compared to those with good subjective sleep quality, showed higher percentages of stimulated monocytes producing IL-6 only (25.4 ± 16.8 % vs 20.4 ± 13.9 %; p < 0.05, ηp2 = 0.03), producing TNF-α only (37.6 ± 13.1 % vs 31.2 ± 14.3 %; p < 0.01, ηp2 = 0.05), and co-producing IL-6/TNF-α simultaneously (17.8 ± 11.7 % vs 13.9 ± 9.6 %; p < 0.05, ηp2 = 0.03). In Study 2, older adults with insomnia disorder, compared to those without insomnia disorder, showed higher TF activity related to immune activation (p's < 0.05) and SNS function (p's < 0.001), along with lower TF activity related to HPA axis function (p's < 0.05). CONCLUSION: In older adults, poor subjective sleep quality and insomnia diagnosis are associated with increases in monocytic cytokine production and changes in TF activity related to immune activation, SNS function, and HPA axis function. Activation of markers of cellular and transcriptional inflammation might contribute to the link between sleep disturbance and age-related morbidity risk.

Low-dose exposure to PBDE disrupts genomic integrity and innate immunity in mammary tissue.

The low-dose mixture hypothesis of carcinogenesis proposes that exposure to an environmental chemical that is not individually oncogenic may nonetheless be capable of enabling carcinogenesis when it acts in concert with other factors. A class of ubiquitous environmental chemicals that are hypothesized to potentially function in this low-dose capacity are synthesized polybrominated diphenyl ethers (PBDEs). PBDEs can affect correlates of carcinogenesis that include genomic instability and inflammation. However, the effect of low-dose PBDE exposure on such correlates in mammary tissue has not been examined. In the present study, low-dose long-term (16 weeks) administration of PBDE to mice modulated transcriptomic indicators of genomic integrity and innate immunity in normal mammary tissue. PBDE increased transcriptome signatures for the Nuclear Factor Erythroid 2 Like 2 (NFE2L2) response to oxidative stress and decreased signatures for non-homologous end joining DNA repair (NHEJ). PBDE also decreased transcriptome signatures for the cyclic GMP-AMP Synthase - Stimulator of Interferon Genes (cGAS-STING) response, decreased indication of Interferon Stimulated Gene Factor 3 (ISGF3) and Nuclear Factor Kappa B (NF-κB) transcription factor activity, and increased digital cytometry estimates of immature dendritic cells (DCs) in mammary tissue. Replication of the PBDE exposure protocol in mice susceptible to mammary carcinogenesis resulted in greater tumor development. The results support the notion that ongoing exposure to low levels of PBDE can disrupt facets of genomic integrity and innate immunity in mammary tissue. Such effects affirm that synthesized PBDEs are a class of environmental chemicals that reasonably fit the low-dose mixture hypothesis.

Chronic stress increases transcriptomic indicators of biological aging in mouse bone marrow leukocytes.

Research with animals and humans has demonstrated that chronic stress exposure can impact key biological aging pathways such as inflammation and DNA damage, suggesting a mechanism through which stress may increase risk for age-related disease. However, it is less clear whether these effects extend to other hallmarks of the aging process, such as cellular senescence. Male SCID mice were exposed to 14 days of restraint stress, with (n â€‹= â€‹6) or without (n â€‹= â€‹10) propranolol administration, or a non-stress control condition (n â€‹= â€‹10). Normal femoral bone marrow leukocytes were isolated from engrafted leukemia cells that had been injected prior to the stressor, as the mice were also under a cancer challenge. We performed whole genome transcriptional profiling to assess indicators of biological aging: cell stress, DNA damage repair, cellular senescence markers p16INK4a and p21, and the pro-inflammatory senescence-associated secretory phenotype (SASP). ANCOVAs that adjusted for tumor load and Fisher's pairwise comparisons revealed that stressed mice had enhanced p16INK4a (p â€‹= â€‹.02) and p21 (p â€‹= â€‹.004), lower DNA damage repair (p â€‹< â€‹.001), and higher SASP (p â€‹= â€‹.03) gene expression than control mice. Stressed mice also showed up-regulated beta-adrenergic (CREB) and inflammatory (NF-кB, AP-1) and down-regulated cell stress (Nrf2) transcription factor activity relative to control mice (ps â€‹< â€‹.01). Propranolol reversed CREB and Nrf2 activity (ps â€‹< â€‹.03). Findings suggest that chronic stress exposure can impact several key biological aging pathways within bone marrow leukocytes and these effects may be partially mediated by sympathetic beta-adrenergic receptor activation.

Physical activity modulates mononuclear phagocytes in mammary tissue and inhibits tumor growth in mice.

The risk for breast cancer is significantly reduced in persons who engage in greater amounts of physical activity, and greater physical activity before or after diagnosis associates with reduced disease-specific mortality. Previous mechanistic studies indicate that components of innate immunity can mediate an inhibitory effect of physical activity on several types of tumor. However, in breast cancer specifically, the myeloid compartment of innate immunity is thought to exhibit high propensity for an immunosuppressive role that obstructs anti-tumor immunity. Thus, we tested the notion that greater physical activity alters mononuclear phagocytes in mammary tissue when inhibiting nascent tumor in a murine model of breast cancer. To model greater physical activity, we placed an angled running wheel in each mouse's home cage for two weeks before tumor engraftment with EO771 mammary cancer cells that express luciferase for bioluminescent detection. Fully immunocompetent mice and mice with compromised adaptive immunity showed significantly less mammary tumor signal when given access to running wheels, although the effect size was smaller in this latter group. To investigate the role of the myeloid compartment, mononuclear phagocytes were ablated by systemic injection of clodronate liposomes at 24 h before tumor engraftment and again at the time of tumor engraftment, and this treatment reversed the inhibition in wheel running mice. However, clodronate also inhibited mammary tumor signal in sedentary mice, in conjunction with an expected decrease in gene and protein expression of the myeloid antigen, F4/80 (Adgre1), in mammary tissue. Whole transcriptome digital cytometry with CIBERSORTx was used to analyze myeloid cell populations in mammary tissue following voluntary wheel running and clodronate treatment, and this approach found significant changes in macrophage and monocyte populations. In exploratory analyses, whole transcriptome composite scores for monocytic myeloid-derived suppressor cell (M-MDSC), macrophage lactate timer, and inflammation resolution gene expression programs were significantly altered. Altogether, the results support the hypothesis that physical activity inhibits nascent mammary tumor growth by enhancing the anti-tumor potential of mononuclear phagocytes in mammary tissue.

Translating Preclinical Research for Exercise Oncology: Take It to the VO2max.

Several observational studies have found that the risk for breast cancer is significantly reduced in persons who engage in greater amounts of physical activity. Additional observational studies of breast cancer survivors indicate that greater physical activity before or after diagnosis associates with reduced disease-specific mortality. However, no large randomized controlled trials have examined the effect of structured exercise training on disease outcomes in breast cancer. Among the many hurdles in designing such trials lies the challenge of determining how a given regimen of exercise from efficacious preclinical studies can be extrapolated to an equivalent "dose" in humans to guide decisions around treatment regimen in early-phase studies. We argue that preclinical researchers in exercise oncology could better facilitate this endeavor by routinely measuring changes in exercise capacity in the subjects of their breast cancer models. VO2max, the maximal rate of whole-organism oxygen consumption during a progressive exercise test, is emphasized here because it has become a standard measure of cardiorespiratory fitness, is well-integrated in clinical settings, and scales allometrically among nonhuman animals in preclinical research and breast cancer patients/survivors in the clinic. We also conduct secondary analyses of existing whole-transcriptome datasets to highlight how greater uptake and delivery of oxygen during exercise may reverse the typically hypoxic microenvironment of breast tumors, which often associates with more aggressive disease and worse prognosis.

Sleep disturbances and inflammatory gene expression among pregnant women: Differential responses by race.

Excessive inflammation in pregnancy predicts adverse birth outcomes, including shortened gestational length and lower birthweight, with African American women at greater risk. As substantial racial disparities in sleep quality, and evidence that African Americans have increased vulnerability for sleep-induced inflammatory dysregulation, sleep may be a critical, modifiable health behavior that contributes to racial disparities in birth outcomes. The present study examined sleep disturbance as a predictor of genome-wide transcriptome profiles of peripheral blood samples from 103 pregnant women (33 African American, 70 white) assessed at 18.7 ± 7.2 weeks gestation. We hypothesized that pregnant women with significant sleep disturbances would have gene expression profiles indicating over-expression of inflammatory pathways, with greater effects among African American compared to white women. Promoter-based bioinformatics analyses of differentially expressed genes indicated greater activation of NF-кB, AP1, and CREB transcription factors among African American women with sleep disturbances (all p < 0.05), and enhanced activation of AP1, but not NF-кB and reduced CREB activity among white women with sleep disturbances (p < 0.05). Differences in glucocorticoid receptor (GR) activity were also observed, in which African American women with sleep disturbances had reduced GR activity (p < 0.05), but white women with sleep disturbances showed a trend for enhanced GR activity (p = 0.11). Similarly, Interferon Response Factor (IRF) activity was reduced in African American women while increased in white women with sleep disturbances (p < 0.05). The current study provides novel evidence for gene expression related to inflammation, glucocorticoids, and anti-viral immunity among pregnant women with sleep disturbances, with differential effects by race. African Americans showed greater breadth and magnitude in these proinflammatory and anti-viral pathways than whites, with divergence in anti-inflammatory glucocorticoid, proinflammatory adrenergic-mediated cAMP, and anti-viral interferon responses. These data elucidate the role of sleep disturbances in intracellular inflammatory and anti-viral immunity in pregnancy and provide a potential target for intervention.

C/EBPß regulates the M2 transcriptome in ß-adrenergic-stimulated macrophages.

At the M2 terminal of the macrophage activation spectrum, expression of genes is regulated by transcription factors that include STAT6, CREB, and C/EBPß. Signaling through ß-adrenergic receptors drives M2 activation of macrophages, but little is known about the transcription factors involved. In the present study, we found that C/EBPß regulates the signaling pathway between ß-adrenergic stimulation and expression of Arg1 and several other specific genes in the greater M2 transcriptome. ß-adrenergic signaling induced Cebpb gene expression relatively early with a peak at 1 h post-stimulation, followed by peak Arg1 gene expression at 8 h. C/EBPß transcription factor activity was elevated at the enhancer region for Arg 1 at both 4 and 8 h after stimulation but not near the more proximal promoter region. Knockdown of Cebpb suppressed the ß-adrenergic-induced peak in Cebpb gene expression as well as subsequent accumulation of C/EBPß protein in the nucleus, which resulted in suppression of ß-adrenergic-induced Arg1 gene expression. Analysis of genome-wide transcriptional profiles identified 20 additional M2 genes that followed the same pattern of regulation by ß-adrenergic- and C/EBPß-signaling. Promoter-based bioinformatic analysis confirmed enrichment of binding motifs for C/EBPß transcription factor across these M2 genes. These findings pinpoint a mechanism that may be targeted to redirect the deleterious influence of ß-adrenergic signaling on macrophage involvement in M2-related diseases such as cancer.

Transcriptomic predictors of inflammation-induced depressed mood.

Inflammation plays a significant role in the pathophysiology of depression. However, not all individuals exposed to inflammatory challenge develop depression, and identifying those at risk is necessary to develop targeted monitoring, prevention, and treatment strategies. Within a randomized double-blind placebo-controlled study (n = 115), we examined whether leukocyte transcriptome profiles predicted inflammation-induced depressed mood in volunteers who received low-dose intravenous endotoxin (n = 58; aged 18-50). At baseline, transcription factor (TF) activities were assessed using genome-wide transcriptional profiling of peripheral blood mononuclear cells and promoter-based bioinformatic analyses. Then, participants were administered endotoxin. Self-reported depressed mood was assessed using the Profile of Mood States. Based on extant studies linking transcriptional profiles to depressive disorder, we examined whether post-endotoxin depressed mood is predicted by baseline activity of TFs related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR). Twenty-one participants (36%) experienced an increase in depressed mood from baseline to 2 h post endotoxin, when depressive response peaks. Bioinformatics analyses controlling for age, sex, ethnicity, body mass index, and physical sickness response revealed that post-endotoxin depressed mood was predicted by increased baseline activity of TFs related to inflammation (NF-kB) and beta-adrenergic signaling (CREB) and by decreased activity of GR-related TFs (P's < 0.001). Inflammation-induced depressed mood is predicted by peripheral transcriptome profiles related to immune activation, sympathetic activation, and glucocorticoid insensitivity. With further replication, these stress-related molecular profiles could be used for a novel genomic approach for identifying individuals at high-risk for the inflammatory subtype of depression.

Prometastatic Molecular Profiles in Breast Tumors From Socially Isolated Women.

BACKGROUND: Social isolation is associated with accelerated breast cancer progression and increased disease recurrence and mortality, but the underlying biological mechanisms remain poorly understood. In preclinical models, beta-adrenergic signaling from fight-or-flight stress responses can stimulate prometastatic processes in the tumor microenvironment including upregulation of M2 macrophages, epithelial-mesenchymal transition (EMT), and lymphovascular invasion. This study examines whether the same pathways are upregulated in breast tumors from socially isolated cancer patients. METHODS: EMT and M1/M2 macrophage gene expression programs were analyzed by genome-wide transcriptional profiling, and lymphatic and vascular density were assessed by immunohistochemistry in primary tumors from 56 early-stage breast cancer patients who were part of the UCLA RISE study. Social isolation was quantified by the Social Provisions Scale, and disease characteristics were assessed by medical record review. General linear models were used to quantify differential gene expression across risk factor groups. Linear regression models were used to examine associations between social isolation and lymphovascular invasion. RESULTS: Tumors from socially isolated patients showed upregulated expression of genes involved in EMT (average score difference = +0.080 log2 mRNA abundance ± 0.034 standard error) and M2 macrophage polarization (+0.033 ± 0.014) as well as increased density of lymphatic vessels (ß= -.29) but no difference in blood vessel density. TELiS promoter-based bioinformatics analyses indicated activation of CREB family transcription factors that mediate the gene-regulatory effects of ß-adrenergic signaling (log2 fold-difference in promoter binding site prevalence: mean ± standard error = +0.49 ± 0.19). CONCLUSIONS: Primary breast tumors from socially isolated patients show multiple prometastatic molecular alterations, providing a plausible biological pathway through which poor social support may accelerate breast cancer progression and defining new targets for intervention.

ß-Adrenergic-stimulated macrophages: Comprehensive localization in the M1-M2 spectrum.

ß-Adrenergic signaling can regulate macrophage involvement in several diseases and often produces anti-inflammatory properties in macrophages, which are similar to M2 properties in a dichotomous M1 vs. M2 macrophage taxonomy. However, it is not clear that ß-adrenergic-stimulated macrophages may be classified strictly as M2. In this in vitro study, we utilized recently published criteria and transcriptome-wide bioinformatics methods to map the relative polarity of murine ß-adrenergic-stimulated macrophages within a wider M1-M2 spectrum. Results show that ß-adrenergic-stimulated macrophages did not fit entirely into any one pre-defined category of the M1-M2 spectrum but did express genes that are representative of some M2 side categories. Moreover, transcript origin analysis of genome-wide transcriptional profiles located ß-adrenergic-stimulated macrophages firmly on the M2 side of the M1-M2 spectrum and found active suppression of M1 side gene transcripts. The signal transduction pathways involved were mapped through blocking experiments and bioinformatics analysis of transcription factor binding motifs. M2-promoting effects were mediated specifically through ß2-adrenergic receptors and were associated with CREB, C/EBPß, and ATF transcription factor pathways but not with established M1-M2 STAT pathways. Thus, ß-adrenergic-signaling induces a macrophage transcriptome that locates on the M2 side of the M1-M2 spectrum but likely accomplishes this effect through a signaling pathway that is atypical for M2-spectrum macrophages.

α2-Adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression.

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of ß-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase ß-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective ß-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of ß-adrenergic signaling on tumor progression-relevant biology.

Individually ventilated cages impose cold stress on laboratory mice: a source of systemic experimental variability.

Individual ventilated cages (IVC) are increasing in popularity. Although mice avoid IVC in preference testing, they show no aversion when provided additional nesting material or the cage is not ventilated. Given the high ventilation rate in IVC, we developed 3 hypotheses: that mice housed in IVC experience more cold stress than do mice housed in static cages; that IVC-induced cold stress affects the results of experiments using mice; and that, when provided shelters, mice behaviorally thermoregulate and thereby rescue the cold-stress effects of IVC. To test these hypotheses, we housed mice in IVC, IVC with shelters, and static cages maintained at 20 to 21 °C. We quantified the cold stress of each housing system on mice by assessing nonshivering thermogenesis and brown adipose vacuolation. To test housing effects in a common, murine model of human disease, we implanted mice with subcutaneous epidermoid carcinoma cells and quantified tumor growth, tumor metabolism, and adrenal weight. Mice housed in IVC had histologic signs of cold stress and significantly higher nonshivering thermogenesis, smaller subcutaneous tumors, lower tumor metabolism, and larger adrenal weights than did mice in static cages. Shelters rescued IVC-induced nonshivering thermogenesis, adrenal enlargement, and phenotype-dependent cold-mediated histologic changes in brown adipose tissue and tumor size. IVC impose chronic cold stress on mice, alter experimental results, and are a source of systemic confounders throughout rodent-dependent research. Allowing mice to exhibit behavioral thermoregulation through seeking shelter markedly rescues the experiment-altering effects of housing-imposed cold stress, improves physiologic uniformity, and increases experimental reproducibility across housing systems.

Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications.

Fatigue is one of the most common and distressing side effects of cancer and its treatment, and may persist for years after treatment completion in otherwise healthy survivors. Guided by basic research on neuro-immune interactions, a growing body of research has examined the hypothesis that cancer-related fatigue is driven by activation of the pro-inflammatory cytokine network. In this review, we examine the current state of the evidence linking inflammation and cancer-related fatigue, drawing from recent human research and from experimental animal models probing effects of cancer and cancer treatment on inflammation and fatigue. In addition, we consider two key questions that are currently driving research in this area: what are the neural mechanisms of fatigue, and what are the biological and psychological factors that influence the onset and/or persistence of inflammation and fatigue in cancer patients and survivors? Identification of the mechanisms driving cancer-related fatigue and associated risk factors will facilitate the development of targeted interventions for vulnerable patients.

Paraneoplastic thrombocytosis in ovarian cancer.

BACKGROUND: The mechanisms of paraneoplastic thrombocytosis in ovarian cancer and the role that platelets play in abetting cancer growth are unclear. METHODS: We analyzed clinical data on 619 patients with epithelial ovarian cancer to test associations between platelet counts and disease outcome. Human samples and mouse models of epithelial ovarian cancer were used to explore the underlying mechanisms of paraneoplastic thrombocytosis. The effects of platelets on tumor growth and angiogenesis were ascertained. RESULTS: Thrombocytosis was significantly associated with advanced disease and shortened survival. Plasma levels of thrombopoietin and interleukin-6 were significantly elevated in patients who had thrombocytosis as compared with those who did not. In mouse models, increased hepatic thrombopoietin synthesis in response to tumor-derived interleukin-6 was an underlying mechanism of paraneoplastic thrombocytosis. Tumor-derived interleukin-6 and hepatic thrombopoietin were also linked to thrombocytosis in patients. Silencing thrombopoietin and interleukin-6 abrogated thrombocytosis in tumor-bearing mice. Anti-interleukin-6 antibody treatment significantly reduced platelet counts in tumor-bearing mice and in patients with epithelial ovarian cancer. In addition, neutralizing interleukin-6 significantly enhanced the therapeutic efficacy of paclitaxel in mouse models of epithelial ovarian cancer. The use of an antiplatelet antibody to halve platelet counts in tumor-bearing mice significantly reduced tumor growth and angiogenesis. CONCLUSIONS: These findings support the existence of a paracrine circuit wherein increased production of thrombopoietic cytokines in tumor and host tissue leads to paraneoplastic thrombocytosis, which fuels tumor growth. We speculate that countering paraneoplastic thrombocytosis either directly or indirectly by targeting these cytokines may have therapeutic potential. (Funded by the National Cancer Institute and others.).

Chronic stress enhances progression of acute lymphoblastic leukemia via ß-adrenergic signaling.

Clinical studies suggest that stress-related biobehavioral factors can accelerate the progression of hematopoietic cancers such as acute lymphoblastic leukemia (ALL), but it is unclear whether such effects are causal or what biological pathways mediate such effects. Given the network of sympathetic nervous system (SNS) fibers that innervates the bone marrow to regulate normal (non-leukemic) hematopoietic progenitor cells, we tested the possibility that stress-induced SNS signaling might also affect ALL progression. In an orthotopic mouse model, Nalm-6 human pre-B ALL cells were transduced with the luciferase gene for longitudinal bioluminescent imaging and injected i.v. into male SCID mice for bone marrow engraftment. Two weeks of daily restraint stress significantly enhanced ALL tumor burden and dissemination in comparison to controls, and this effect was blocked by the ß-adrenergic antagonist, propranolol. Although Nalm-6 ALL cells expressed mRNA for ß1- and ß3-adrenergic receptors, they showed no evidence of cAMP signaling in response to norepinephrine, and norepinephrine failed to enhance Nalm-6 proliferation in vitro. These results show that chronic stress can accelerate the progression of human pre-B ALL tumor load via a ß-adrenergic signaling pathway that likely involves indirect regulation of ALL biology via alterations in the function of other host cell types such as immune cells or the bone marrow microenvironment.

Cancer induces inflammation and depressive-like behavior in the mouse: modulation by social housing.

Considerable data demonstrate a high prevalence of depressive symptoms in cancer patients. This study introduces an experimental model to examine the effect of tumor on depressive-like behavior. Female C57BL/6 mice were injected i.p. with syngeneic ID8 ovarian carcinoma. Experiment 1 measured sucrose intake before and after tumor incubation to assess the effect of tumor on anhedonic depressive-like behavior. Experiment 2 examined effects of tumor and social housing on anhedonia and a second depressive-like behavior, tail suspension test (TST) immobility. Systemic proinflammatory and antiinflammatory cytokines were measured following each experiment. Additional behaviors assessed the specificity of tumor's effect on depressive-like behavior. Tumor caused a reduction in sucrose intake relative to baseline and control levels (P<.05). Moreover, individually-housed tumor-bearing mice exhibited a lower sucrose preference than group-housed tumor-bearing or control mice in either housing condition (P<.05). Although tumor-bearing mice exhibited less locomotion than controls (P<.001), there was no significant effect of tumor on TST immobility. Tumor caused higher levels of systemic proinflammatory and antiinflammatory cytokines and smaller body weight (P<.05), but appetite and motor capacity were not significantly affected. Statistical mediation analysis showed that circulating interleukin-6 partially mediated the effect between tumor and home cage locomotion (P<.01) but not between tumor and sucrose intake. It is concluded that tumor elicits anhedonic depressive-like behavior in a murine model of ovarian cancer. This may have important implications for etiology of depression in the clinical cancer setting.

Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.

OBJECTIVE: To assess the magnitude and direction of associations of depression with C-reactive protein (CRP), interleukin (IL)-1, and IL-6 in community and clinical samples. METHODS: Systematic review of articles published between January 1967 and January 2008 in the PubMed and PsycINFO electronic databases was performed. Effect sizes were calculated as stat d and meta-analyzed, using random-effects models. RESULTS: Each inflammatory marker was positively associated with depression; CRP, d = 0.15 (95% CI = 0.10, 0.21), p < .001; IL-6, d = 0.25 (95% CI = 0.18, 0.31), p < .001; IL-1, d = 0.35 (95% CI = 0.03, 0.67), p = .03; IL-1ra, d = 0.25 (95% CI = 0.04, 0.46), p = .02. Associations were strongest in clinically depressed patient samples--but were also significant in community-based samples--and when clinical interviews were used. Studies adjusting for body mass index (BMI) had smaller associations, albeit significant. Relationships were inconsistent with respect to age, medication, and sex. Depression was related to CRP and IL-6 among patients with cardiac disease or cancer. CONCLUSIONS: Depression and CRP, IL-1, and IL-6 are positively associated in clinical and community samples and BMI is implicated as a mediating/moderating factor. Continuity in clinic- and community-based samples suggests there is a dose-response relationship between depression and these inflammatory markers, lending strength to the contention that the cardiac (or cancer) risk conferred by depression is not exclusive to patient populations. Available evidence is consistent with three causal pathways: depression to inflammation, inflammation to depression, and bidirectional relationships.

Glucose as a prognostic factor in ovarian carcinoma.

BACKGROUND: Research suggests that glucose levels in cancer patients may be an important prognostic indicator. In ovarian tumors, increased expression of glucose transporter 1 (GLUT1), a transmembrane protein responsible for glucose uptake, is related to shorter survival time in ovarian cancer patients. This study tested the hypothesis that higher presurgical glucose levels predict shorter disease-specific survival time and time to recurrence in ovarian cancer patients. METHODS: Nonfasting plasma glucose levels were determined for 74 patients with ovarian cancer at the time of their presurgical consultation and for 125 ovarian cancer patients in an independent validation set. Survival time and time to recurrence (disease-free interval [DFI]) were ascertained from medical records. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) for survival time and DFI in relation to glucose level, adjusting for body mass index (BMI), stage, grade, and cytoreduction as appropriate. RESULTS: Higher glucose levels were associated with shorter survival times in univariate analyses (HR, 1.88; P = .05). Multivariate analysis adjusting for stage showed that higher glucose levels were associated with shorter survival times (HR, 2.01; P = .04) and DFI (HR, 2.32; P = .05). In the validation set, higher glucose levels were associated with shorter survival times (HR, 2.01; P = .02) and DFI (HR, 2.48; P = .001) in univariate analysis, although glucose was not independent of the effect of cytoreduction when predicting survival time in this latter set. CONCLUSIONS: These findings contribute to mounting evidence that glucose levels have prognostic value in ovarian carcinoma.

Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma.

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Depressed and anxious mood and T-cell cytokine expressing populations in ovarian cancer patients.

The adaptive immune response of ovarian cancer patients has been linked to survival, and is known to be impaired in the tumor microenvironment. Little is known about relationships between biobehavioral factors such as depressed mood and anxiety and the adaptive immune response in ovarian cancer. Thirty-seven patients with epithelial ovarian cancer and 14 patients with benign ovarian neoplasms completed psychosocial questionnaires pre-surgery. Lymphocytes from peripheral blood, tumor, and ascites (fluid around the tumor), were obtained on the day of surgery. Expression of the Type-1 cytokine interferon-gamma (IFN gamma), and the Type-2 cytokine interleukin-4 (IL-4) by T-helper (CD4(+)) and T-cytotoxic (CD8(+)) cells was measured under autologous tumor-stimulated, polyclonally-stimulated, or unstimulated conditions. Links with mood were examined. Among cancer patients, marked elevations in unstimulated and tumor-stimulated Type-2 responses were seen, particularly in ascites and tumor-infiltrating lymphocytes (P values<0.01). With polyclonal stimulation, lymphocytes from all compartments expressed elevated Type-1 cytokines (P values<0.014). Depressed and anxious mood were both associated with significantly lower ratios of polyclonally-stimulated CD4(+) cells producing IFN gamma (TH(1) cells) vs. IL-4 (TH(2) cells) in all compartments (depressed mood: P=0.012; anxiety: P=0.038) and depressed mood was also related to lower ratios of polyclonally-stimulated CD8(+) cells producing IFN gamma (TC(1)) vs. IL-4 (TC(2)) (P=0.035). Although effects of polyclonal stimulation should be generalized with caution to the in vivo immune response, findings suggest that depressed and anxious mood are associated with greater impairment of adaptive immunity in peripheral blood and in the tumor microenvironment among ovarian cancer patients.