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1.  Inflammatory Biomarkers and Emotional Approach Coping in Men with Prostate Cancer 
Brain, behavior, and immunity  2013;32:173-179.
Emotion-regulating coping is associated with improvements in psychological and physical health outcomes. Yet in the context of prostate cancer-related stressors, limited research has characterized associations of emotion-regulating coping processes (emotional expression, emotional processing) and inflammatory processes that are related to disease risk. This investigation examined the relation of Emotional Approach Coping (EAC) with markers of inflammation to test the hypothesis that higher EAC scores at study entry (T1) would be associated with lower proinflammatory markers four months later (T2), specifically sTNF-RII, CRP, and IL-6.
Forty-one men (M age=66.62 years; SD=9.62) who had undergone radical prostatectomy or radiation therapy for localized prostate cancer within two years completed questionnaires, including assessments of EAC, at T1, and provided blood samples for immune assessments at T2.
When controlling for relevant biobehavioral controls, emotional processing predicted lower IL-6 (B=−.66, p<.01), sTNF-RII (B=−.43, p<.05), and CRP (B=−.43, p<.10), whereas emotional expression was significantly associated with higher levels of sTNF-RII (B=.55, p<.05). Associations of emotional expression and IL-6 (B=.38, p<.10), and CRP (B=.44, p<.10) approached significance. Probing interactions of emotional processing and expression (though only approaching significance) suggested that expression of emotion is associated with higher inflammation (CRP and sTNF-RII) only in the context of low emotional processing.
Attempts at emotion regulation via emotional processing appear to modulate inflammatory processes. Understanding, making meaning of, and working through emotional experience may be a promising target of intervention to reduce inflammation with potential effects on psychological and cancer outcomes in men with prostate cancer.
PMCID: PMC3706095  PMID: 23624266
emotional approach coping; emotional processing; emotional expression; proinflammatory cytokines; inflammation; prostate cancer
2.  Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the Multicenter AIDS Cohort Study 
AIDS (London, England)  2010;24(7):1025-1033.
Cytokine stimulation of B-cell proliferation may be an important etiologic mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein-Barr virus may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N=160) or post-AIDS diagnosis (N=90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95 percent confidence intervals (95%CIs). Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR=0.3; 95%CI: 0.1, 0.7) but not systemically (CC vs. CT/TT: OR=1.0; 95%CI: 0.5, 1.9) (Pheterogeneity=0.03). Carriage of two copies of the “low IL10” haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend=0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important etiologic pathway for EBV-related lymphomagenesis.
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
3.  Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis 
We performed a pooled analysis of data on self-reported history of infections in relation to the risk of non-Hodgkin lymphoma (NHL) from 17 case-control studies that included 12,585 cases and 15,416 controls aged 16–96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two-stage random-effect or joint fixed-effect models, adjusting for age, sex and study centre. Data from the two years prior to diagnosis (or date of interview for controls) were excluded. A self-reported history of infectious mononucleosis (IM) was associated with an excess risk of NHL (OR=1.26, 95% CI=1.01–1.57 based on data from 16 studies); study-specific results indicate significant (I2=51%, p=0.01) heterogeneity. A self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self-reported medical history (particularly of childhood illness reported by older people) are well recognised.
PMCID: PMC3406230  PMID: 22266776
4.  Inflammation and Behavioral Symptoms After Breast Cancer Treatment: Do Fatigue, Depression, and Sleep Disturbance Share a Common Underlying Mechanism? 
Journal of Clinical Oncology  2011;29(26):3517-3522.
Fatigue, depression, and sleep disturbance are common adverse effects of cancer treatment and frequently co-occur. However, the possibility that inflammatory processes may underlie this constellation of symptoms has not been examined.
Patients and Methods
Women (N = 103) who had recently finished primary treatment (ie, surgery, radiation, chemotherapy) for early-stage breast cancer completed self-report scales and provided blood samples for determination of plasma levels of inflammatory markers: soluble tumor necrosis factor (TNF) receptor II (sTNF-RII), interleukin-1 receptor antagonist, and C-reactive protein.
Symptoms were elevated at the end of treatment; greater than 60% of participants reported clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms. Women treated with chemotherapy endorsed higher levels of all symptoms and also had higher plasma levels of sTNF-RII than women who did not receive chemotherapy (all P < .05). Fatigue was positively associated with sTNF-RII, particularly in the chemotherapy-treated group (P < .05). Depressive symptoms and sleep problems were correlated with fatigue but not with inflammatory markers.
This study confirms high rates of behavioral symptoms in breast cancer survivors, particularly those treated with chemotherapy, and indicates a role for TNF-α signaling as a contributor to postchemotherapy fatigue. Results also suggest that fatigue, sleep disturbance, and depression may stem from distinct biologic processes in post-treatment survivors, with inflammatory signaling contributing relatively specifically to fatigue.
PMCID: PMC3179252  PMID: 21825266
5.  Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation 
AIDS (London, England)  2011;25(3):303-314.
Chronic inflammation and B-cell hyperactivation are seen in HIV infection, contributing to an increased risk for the accrual of genetic errors that may result in B-cell lymphoma. The primary objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) on serum levels of molecules that are associated with immune activation and/or inflammation, including several that are associated with B-cell activation, specifically IL-6, sCD30, sCD27, IgG, IgA, CXCL13 (B lymphocyte chemoattractant, BLC), a B-lymphocyte chemokine involved in B-cell trafficking, as well as C-reactive protein, an acute-phase protein.
We used a retrospective cohort study design, measuring serum levels of these markers at each of four 1-year intervals, 2 years before and 2 years after HAART initiation, in a subgroup of 290 HIV-infected men enrolled in the Multicenter AIDS Cohort Study (MACS).
Serum levels of immune activation-associated molecules were measured by ELISA and multiplexed immunometric assays. Reference values were determined by the 5th to 95th percentiles from a sample of 109 HIV-uninfected MACS men.
HAART use was associated with a reduction, but not normalization, of most biomarkers tested. Serum levels of IL-6 and C-reactive protein appeared to be unaffected by HAART.
These results suggest a partial normalization of serum cytokine levels post HAART. However, a chronic state of B-cell hyperactivation continues 2–3 years after HAART initiation. These findings may explain, in part, the excess incidence of lymphoma still occurring in HIV-infected persons in the post-HAART era.
PMCID: PMC3322644  PMID: 21192231
activation; AIDS; antiretroviral therapy; B lymphocytes; highly active; HIV; non-Hodgkin’s lymphoma
6.  Birth Order and Risk of Non-Hodgkin Lymphoma—True Association or Bias? 
American Journal of Epidemiology  2010;172(6):621-630.
There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983–2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.
PMCID: PMC2950815  PMID: 20720098
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class
8.  Kaposi Sarcoma-Associated Herpesvirus Serum DNA and Antibodies Not Associated With Subsequent Non-Hodgkin Lymphoma Risk 
Kaposi sarcoma-associated herpes virus (KSHV) infects B-cells and is found in non-Hodgkin lymphoma (NHL) B-cell tumors and could therefore contribute to the occurrence of NHL. We performed a nested case–control study including 155 incident NHL cases and matched noncancer controls. Pre-NHL serum was tested for KSHV DNA and antibodies. Serum KSHV DNA was more common in cases than controls (14% versus 6%, P = 0.03), but after adjustment, the difference was not significant. Epstein-Barr virus serum DNA was similarly unassociated with NHL as were KSHV antibodies. KSHV is not a primary cause of NHL in HIV-infected men who have sex with men.
PMCID: PMC3073851  PMID: 21116187
Kaposi sarcoma-associated herpesvirusp; non-Hodgkin lymphoma; MACS; human herpesvirus 8; DNA; AIDS cancer
9.  The Major Histocompatibility Complex Conserved Extended Haplotype 8.1 in AIDS-related Non-Hodgkin’s Lymphoma 
Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA +252G, rs909253 A>G) and tumor necrosis factor (TNF −308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin’s lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with HLA-B* 08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in Caucasians most likely represents a true etiologic factor remains uncertain. We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL. SNPs in LTA and TNF and in six other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study. The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A) and rs6467 (C)) were associated with AIDS-NHL (OR=2.7, 95% CI: 1.5–4.8, p=0.0009 and OR=3.2, 95% CI: 1.6–6.6 p=0.0008; respectively). These two haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. The CEH 8.1-specific haplotype association of MHC class III variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both.
PMCID: PMC3015185  PMID: 19654554
Human Leukocyte Antigen; HIV; CD4; Multicenter AIDS Cohort NHL Study
11.  Expression and Function of the Chemokine, CXCL13, and Its Receptor, CXCR5, in Aids-Associated Non-Hodgkin's Lymphoma 
AIDS Research and Treatment  2010;2010:164586.
Background. The homeostatic chemokine, CXCL13 (BLC, BCA-1), helps direct the recirculation of mature, resting B cells, which express its receptor, CXCR5. CXCL13/CXCR5 are expressed, and may play a role, in some non-AIDS-associated B cell tumors. Objective. To determine if CXCL13/CXCR5 are associated with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL). Methods. Serum CXCL13 levels were measured by ELISA in 46 subjects who developed AIDS-NHL in the Multicenter AIDS Cohort Study and in controls. The expression or function of CXCL13 and CXCR5 was examined on primary AIDS-NHL specimens or AIDS-NHL cell lines. Results. Serum CXCL13 levels were significantly elevated in the AIDS-NHL group compared to controls. All primary AIDS-NHL specimens showed CXCR5 expression and most also showed CXCL13 expression. AIDS-NHL cell lines expressed CXCR5 and showed chemotaxis towards CXCL13. Conclusions. CXCL13/CXCR5 are expressed in AIDS-NHL and could potentially be involved in its biology. CXCL13 may have potential as a biomarker for AIDS-NHL.
PMCID: PMC3065842  PMID: 21490903
12.  Atopic disease and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis 
Cancer research  2009;69(16):6482-6489.
We performed a pooled analysis of data on atopic disease and risk of non-Hodgkin lymphoma (NHL) from 13 case-control studies, including13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed two or more years before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals were computed in two-stage random-effects or joint fixed-effects models, adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, a specific allergy (excluding hay fever, asthma and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with history of allergy (OR 0.80, 95% CI 0.68–0.94), and reduced B-cell NHL risk was associated with history of hay fever (OR 0.85, 95% CI 0.77–0.95) and allergy (OR 0.84, 95% CI 0.76–0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic - those with hay fever, allergy or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study demonstrates evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy.
PMCID: PMC2758272  PMID: 19654312
non-Hodgkin lymphoma; atopy; case-control; pooled analysis; risk
13.  Population differences in immune marker profiles associated with human T-lymphotropic virus type I infection in Japan and Jamaica 
The natural history of human T-lymphotropic virus type I (HTLV-I) has been shown to differ markedly by geographic area. The differences include contrasting patterns of risk of adult T-cell lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which may be due in part to differences in host immune response to infection. To characterize variations in host immunity across populations, we compared serologic immune marker patterns in HTLV-I-endemic populations in Japan and Jamaica. We matched 204 participants with archived blood from the Miyazaki Cohort Study (Japan) and the Food Handlers Study (Jamaica)-i.e., 51 HTLV-I-positive (“carriers”) and 51 HTLV-I-negative individuals (“non-carriers”) from each population-by age, sex, and blood collection year. We compared plasma concentrations of markers of T-cell-mediated (antigen-specific) and non-specific immunity using regression models and correlation coefficients. Compared to Jamaican HTLV-I non-carriers, Japanese non-carriers had higher covariate-adjusted mean levels of T-cell activation markers, including antibody to Epstein-Barr virus nuclear antigen-1 (reciprocal titer 27 v. 71, respectively, p=0.005), soluble interleukin-2 receptor-α (477 v. 623 pg/mL, p=0.0008) and soluble CD30 (34 v. 46 U/mL, p=0.0001), and lower levels of C-reactive protein (1.1 v. 0.43 μg/mL, p=0.0004). HTLV-I infection was associated with activated T-cell immunity in Jamaicans but with diminished T-cell immunity in Japanese persons. The observed population differences in background and HTLV-I-related host immunity correspond closely to the divergent natural histories of infection observed among HTLV-I carriers in Japan and Jamaica and corroborate a role for host immune status in the contrasting patterns of ATL and HAM/TSP risk.
PMCID: PMC2701897  PMID: 18989900
HTLV-I; epidemiology; natural history; host immunity; viral markers
14.  Cytokine Gene Expression in Normal Human Lymphocytes in Response to Stimulation 
Sequential gene expression of two type 1 cytokines (interleukin 2 [IL-2] and gamma interferon), one type 2 cytokine (IL-10), two monokines (IL-6 and tumor necrosis factor alpha), and one cytokine receptor (IL-2 receptor [IL-2R]) in normal human peripheral blood mononuclear cells (PBMC) following in vitro stimulation was investigated by reverse transcription-PCR methods. Two stimuli were utilized: phytohemagglutinin (PHA), which acts on the CD2 molecule and T-cell receptors, and anti-CD3 monoclonal antibody, which acts on the CD3 molecule and on T-cell receptors. Increased expression of all studied genes occurred between 1 and 4 hours after stimulation, except for that of the gene encoding IL-10, which was delayed. Expression of all but one of the genes was transient, with a maximal mRNA accumulation at about 8 h on average. IL-2R mRNA expression was an exception, showing a prolonged increase (72 h). The general profiles of expression of the five cytokine genes were similar but not identical, suggesting some shared regulatory mechanisms. When responses to four additional stimuli (pokeweed mitogen, Candida albicans, and IL-2 at high and low doses) were compared, similar profiles of cytokine gene expression were found. Thus, the various stimuli caused induction of all cytokines with quantitative, not qualitative, differences. Altogether, the present data are useful for defining the kinetics of gene expression for key cytokines in response to standard immune-cell stimuli.
PMCID: PMC104521  PMID: 9605988

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