PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (32)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
Document Types
1.  The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation 
AIDS (London, England)  2015;29(4):463-471.
Objectives
To investigate the impact of HAART-induced HIV suppression on levels of 24 serological biomarkers of inflammation and immune activation.
Design
Prospective cohort study.
Methods
Biomarkers were measured with multiplex assays in centralized laboratories using stored serum samples contributed by 1,697 men during 8,903 person-visits in the Multicenter AIDS Cohort Study (MACS) from 1984–2009. Using generalized gamma models, we compared biomarker values across three groups, adjusting for possible confounders: HIV-uninfected (NEG); HIV+, HAART-naïve (NAI); and HAART-exposed with HIV RNA suppressed to <50 copies/mL plasma (SUP). We also estimated changes in biomarker levels associated with duration of HIV suppression, using splined generalized gamma regression with a knot at one year.
Results
Most biomarkers were relatively normalized in the SUP group relative to the NAI group; however, 12 biomarkers in the SUP group were distinct (p<0.002) from NEG values: CXCL10, CRP, sCD14, sTNFR2, TNF-α, sCD27, sGP130, IL-8, CCL13, BAFF, GM-CSF, and IL-12p70. Thirteen biomarkers exhibited significant changes in the first year after viral suppression, but none changed significantly after that time.
Conclusions
Biomarkers of inflammation and immune activation moved toward HIV-negative levels within the first year after HAART-induced HIV suppression. Although several markers of T cell activation returned to levels present in HIV-negative men, residual immune activation, particularly monocyte/macrophage activation, was present. This residual immune activation may represent a therapeutic target to improve the prognosis of HIV-infected individuals receiving HAART.
doi:10.1097/QAD.0000000000000545
PMCID: PMC4311407  PMID: 25630041
Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Biological Markers; Inflammation; Prospective Studies; Male
2.  Temporal stability of serum concentrations of cytokines and soluble receptors measured across two years in low-risk HIV seronegative men 
Background
Prospective cohort studies often quantify serum immune biomarkers at a single time point to determine risk of cancer and other chronic diseases that develop years later. Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements, and may have important implications for the design of prospective studies of chronic disease risk.
Methods
Using archived sera collected from 200 HIV-seronegative men at three visits spaced over approximately two years, concentrations of 14 biomarkers (ApoA1, sCD14, sgp130, sIL-6R, sIL-2Rα, sTNFR2, BAFF/BLyS, CXCL13, IFN-γ, IL-1β, IL-6, IL-8, IL-10, TNF-α) were measured in a single laboratory. Age-and ethnicity-adjusted intraclass correlation coefficients (ICC) were calculated for each biomarker, and mixed linear regression models were utilized to examine the influence of age, ethnicity, season, and study site on biomarker concentrations.
Results
Across all three study visits, most biomarkers had ICC values indicating fair to excellent within-person stability. ApoA1 (ICC=0.88)and TNF-α (ICC=0.87) showed the greatest stability; the ICC for IL-8 (ICC=0.33) was remarkably less stable. The ICCs were similar when calculated between pairs of consecutive visits. The covariables did not influence biomarker levels or their temporal stability. All biomarkers showed moderate to strong pairwise correlations across visits.
Conclusions
Serum concentrations of most evaluated immune biomarkers displayed acceptable to excellent within-person temporal reliability over a 2-year period. Further investigation may be required to clarify the stability of IL-8.
Impact
These findings lend support to using these serologic immune biomarkers in prospective studies investigating associations with chronic diseases.
doi:10.1158/1055-9965.EPI-13-0379
PMCID: PMC3829469  PMID: 23983237
Temporal stability; biomarkers; cytokines; soluble receptors; intraclass correlation coefficient
3.  Serum biomarkers of immune activation and subsequent risk of non-Hodgkin B cell lymphoma among HIV-infected women 
Background
There is increasing evidence that chronic immune activation predisposes to non-Hodgkin’s lymphoma (NHL). Whether this association exists among women representative of the current HIV epidemic in the U.S. who are at high risk of HIV-associated NHL (AIDS-NHL), remains to be determined.
Methods
We conducted a nested case-control study within the Women’s Interagency HIV Study with longitudinally collected risk factor data and sera. Cases were HIV-infected women with stored sera collected at three time-windows 3–5 years, 1–3 years, and 0–1 year prior to AIDS-NHL diagnosis (n=22). Three to six HIV-infected controls, without AIDS-NHL, were matched to each case on age, race, CD4+ T cell count, and study follow-up time (n=78). Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between one unit increase in log-transformed biomarker levels and AIDS-NHL were computed using random effect multivariate logistic regression models.
Results
Elevated levels of sCD27 (OR=7.21, 95% CI=2.62–19.88), sCD30 (OR=2.64, 95% CI=1.24–5.64), and CXCL13 (OR=2.56, 95% CI=1.32–4.96) were associated with subsequent diagnosis of AIDS-NHL overall. Elevated sCD23 was associated with a 2-to 4-fold increased risk of AIDS-NHL in certain subgroups, while elevated IL6 was associated with a 2-fold increased risk in the 0–1 year time-window, only.
Conclusion
These findings support the hypothesis that chronic B cell activation contributes to the development of AIDS-NHL in women.
Impact
sCD23, sCD27, sCD30, and CXCL13 may serve as biomarkers for AIDS-NHL.
doi:10.1158/1055-9965.EPI-13-0614
PMCID: PMC3833437  PMID: 24045923
lymphoma; B cell; cytokines; AIDS; immune activation
4.  Inflammatory Biomarkers and Emotional Approach Coping in Men with Prostate Cancer 
Brain, behavior, and immunity  2013;32:173-179.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.bbi.2013.04.008
PMCID: PMC3706095  PMID: 23624266
emotional approach coping; emotional processing; emotional expression; proinflammatory cytokines; inflammation; prostate cancer
5.  Do Older Americans Undergo Stoma Reversal Following Low Anterior Resection for Rectal Cancer? 
The Journal of surgical research  2012;183(1):238-245.
Objective
For low-lying rectal cancers, proximal diversion can reduce anastomotic leak after sphincter preserving surgery; however, evidence suggests that such temporary diversions are often not reversed. We aimed to evaluate non-reversal and delayed stoma reversal in elderly patients undergoing low anterior resection (LAR).
Design
SEER-Medicare linked analysis from 1991-2007.
Settings and Participants
1,179 primary stage I-III rectal cancer patients over age 66 who underwent LAR with synchronous diverting stoma.
Main Outcome Measures
1) Stoma creation and reversal rates. 2) Time to reversal. 3) Characteristics associated with reversal and shorter time to reversal.
Results
Within 18 months of LAR, 51% (603/1179) of patients underwent stoma reversal. Stoma reversal was associated with age < 80 years (p<0.0001), male gender (p=0.018), less comorbidities (p=0.017), higher income [quartile 4 vs. 1, (p=0.002)], early tumor stage [1 vs. 3; (p<0.001)], neoadjuvant radiation (p<0.0001), rectal tumor location [vs. rectosigmoid, (p=0.001)], more recent diagnosis (p=0.021), and shorter length of stay on LAR admission (p=0.021). Median time to reversal was 126 days (IQR: 79-249). Longer time to reversal was associated with older age (p=0.031), presence of comorbidities (p=0.014), more advanced tumor stage (p=0.007), positive lymph nodes (p=0.009), receipt of adjuvant radiation therapy (p=0.008), more recent diagnosis (p=0.004) and longer LOS on LAR admission (p <0.0001).
Conclusions
Half of elderly rectal cancer patients who undergo LAR with temporary stoma have not undergone stoma reversal by 18 months. Identifiable risk factors predict both non-reversal and longer time to reversal. These results help inform pre-operative discussions and promote realistic expectations for elderly rectal cancer patients.
doi:10.1016/j.jss.2012.11.057
PMCID: PMC3686838  PMID: 23298948
6.  Circulating Mediators of Inflammation and Immune Activation in AIDS-Related Non-Hodgkin Lymphoma 
PLoS ONE  2014;9(6):e99144.
Background
Non-Hodgkin lymphoma (NHL) is the most common AIDS-related malignancy in developed countries. An elevated risk of developing NHL persists among HIV-infected individuals in comparison to the general population despite the advent of effective antiretroviral therapy. The mechanisms underlying the development of AIDS-related NHL (A-NHL) are not fully understood, but likely involve persistent B-cell activation and inflammation.
Methods
This was a nested case-control study within the ongoing prospective Multicenter AIDS Cohort Study (MACS). Cases included 47 HIV-positive male subjects diagnosed with high-grade B-cell NHL. Controls were matched to each case from among participating HIV-positive males who did not develop any malignancy. Matching criteria included time HIV+ or since AIDS diagnosis, age, race and CD4+ cell count. Sera were tested for 161 serum biomarkers using multiplexed bead-based immunoassays.
Results
A subset of 17 biomarkers, including cytokines, chemokines, acute phase proteins, tissue remodeling agents and bone metabolic mediators was identified to be significantly altered in A-NHL cases in comparison to controls. Many of the biomarkers included in this subset were positively correlated with HIV viral load. A pathway analysis of our results revealed an extensive network of interactions between current and previously identified biomarkers.
Conclusions
These findings support the current hypothesis that A-NHL develops in the context of persistent immune stimulation and inflammation. Further analysis of the biomarkers identified in this report should enhance our ability to diagnose, monitor and treat this disease.
doi:10.1371/journal.pone.0099144
PMCID: PMC4055650  PMID: 24922518
7.  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.
doi:10.1097/QAD.0b013e328332d5b1
PMCID: PMC3950937  PMID: 20299965
cytokine; SNPs; AIDS-related lymphoma
8.  Yogic meditation reverses NF-κB and IRF-related transcriptome dynamics in leukocytes of family dementia caregivers in a randomized controlled trial 
Psychoneuroendocrinology  2012;38(3):348-355.
Background
Although yoga and meditation have been used for stress reduction with reported improvement in inflammation, little is known about the biological mechanisms mediating such effects. The present study examined if a yogic meditation might alter the activity of inflammatory and antiviral transcription control pathways that shape immune cell gene expression.
Methods
Forty-five family dementia caregivers were randomized to either Kirtan Kriya Meditation (KKM) or Relaxing Music (RM) listening for 12 minutes daily for 8 weeks and 39 caregivers completed the study. Genome-wide transcriptional profiles were collected from peripheral blood leukocytes sampled at baseline and 8-week follow-up. Promoter-based bioinformatics analyses tested the hypothesis that observed transcriptional alterations were structured by reduced activity of the pro-inflammatory nuclear factor (NF)-κB family of transcription factors and increased activity of Interferon Response Factors (IRF; i.e., reversal of patterns previously linked to stress).
Results
In response to KKM treatment, 68 genes were found to be differentially expressed (19 up-regulated, 49 down-regulated) after adjusting for potentially confounded differences in sex, illness burden, and BMI. Up-regulated genes included immunoglobulin-related transcripts. Down-regulated transcripts included pro-inflammatory cytokines and activation-related immediate-early genes. Transcript origin analyses identified plasmacytoid dendritic cells and B lymphocytes as the primary cellular context of these transcriptional alterations (both p < .001). Promoter-based bioinformatic analysis implicated reduced NF-κB signaling and increased activity of IRF1 in structuring those effects (both p < .05).
Conclusion
A brief daily yogic meditation intervention may reverse the pattern of increased NF-κB-related transcription of pro-inflammatory cytokines and decreased IRF1-related transcription of innate antiviral response genes previously observed in healthy individuals confronting a significant life stressor.
doi:10.1016/j.psyneuen.2012.06.011
PMCID: PMC3494746  PMID: 22795617
Dementia caregiver; stress; Kirtan Kriya; yoga; meditation; relaxation; NF-κB; genomics; gene expression profiling; microarray
9.  Acute Painful Stress and Inflammatory Mediator Production 
Neuroimmunomodulation  2013;20(3):127-133.
Pro-inflammatory pathways may be activated under conditions of painful stress, which is hypothesized to worsen the pain experience and place medically-vulnerable populations at risk for increased morbidity.
Objectives
To evaluate the effects of pain and subjective pain-related stress on pro-inflammatory activity.
Methods
A total of 19 healthy control subjects underwent a single standard cold-pressor pain test (CPT) and a no-pain control condition. Indicators of pain and stress were measured and related to inflammatory immune responses (CD811a, IL-1RA, and IL-6) immediately following the painful stimulus, and compared to responses under non-pain conditions. Heart rate and mean arterial pressure were measured as indicators of sympathetic stimulation.
Results
CPT was clearly painful and generated an activation of the sympathetic nervous system. CD811a increased in both conditions, but with no statistically significant greater increase following CPT (p < .06). IL-1RA demonstrated a non-statistically significant increase following CPT (p < .07). The change in IL-6 following CPT differed significantly from the response seen in the control condition (p < .02).
Conclusions
These findings suggest that CP acute pain may affect proinflammatory pathways, possibly through mechanisms related to adrenergic activation.
doi:10.1159/000346199
PMCID: PMC3932154  PMID: 23407214
pain; stress; cytokines; cellular adhesion molecules; neuro-hormonal response; neuro-immune
10.  Serum levels of the chemokine CXCL13, genetic variation in CXCL13 and its receptor CXCR5, and HIV-associated non-Hodgkin B cell lymphoma risk 
Background
CXCL13 and CXCR5 are a chemokine and receptor pair whose interaction is critical for naïve B cell trafficking and activation within germinal centers. We sought to determine whether CXCL13 levels are elevated prior to HIV-associated non-Hodgkin B-cell lymphoma (AIDS-NHL), and whether polymorphisms in CXCL13 or CXCR5 are associated with AIDS-NHL risk and CXCL13 levels in a large cohort of HIV-infected men.
Methods
CXCL13 levels were measured in sera from 179 AIDS-NHL cases and 179 controls at three time-points. TagSNPs in CXCL13 (n=16) and CXCR5 (n=11) were genotyped in 183 AIDS-NHL cases and 533 controls. Odds ratios (OR) and 95% confidence intervals (CIs) for the associations between one unit increase in log CXCL13 levels and AIDS-NHL, as well as tagSNP genotypes and AIDS-NHL, were computed using logistic regression. Mixed linear regression was used to estimate mean ratios (MR) for the association between tagSNPs and CXCL13 levels.
Results
CXCL13 levels were elevated >3 years (OR=3.24, 95% CI=1.90–5.54), 1–3 years (OR=3.39, 95% CI=1.94–5.94) and 0–1 year (OR=3.94, 95% CI=1.98–7.81) prior to an AIDS-NHL diagnosis. The minor allele of CXCL13 rs355689 was associated with reduced AIDS-NHL risk (ORTCvsTT=0.65; 95% CI=0.45–0.96) and reduced CXCL13 levels (MRCCvsTT=0.82, 95% CI=0.68–0.99). The minor allele of CXCR5 rs630923 was associated with increased CXCL13 levels (MRAAvsTT=2.40, 95% CI=1.43–4.50).
Conclusions
CXCL13 levels were elevated preceding an AIDS-NHL diagnosis, genetic variation in CXCL13 may contribute to AIDS-NHL risk, and CXCL13 levels may be associated with genetic variation in CXCL13 and CXCR5.
Impact
CXCL13 may serve as a biomarker for early AIDS-NHL detection.
doi:10.1158/1055-9965.EPI-12-1122
PMCID: PMC3703445  PMID: 23250934
Non-Hodgkin Lymphoma; HIV; CXCL13; CXCR5; chemokine
11.  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.
doi:10.1002/ijc.27438
PMCID: PMC3406230  PMID: 22266776
12.  When grief makes you sick: Bereavement induced systemic inflammation is a question of genotype 
Brain, behavior, and immunity  2012;26(7):1066-1071.
Although bereavement is associated with increased morbidity and mortality in the surviving spouse, some widow(er)s remain healthy. Genetic variability in expression of inflammatory markers in response to stress may be the key to this observation. The present study compares bereaved vs. married/partnered older adults, investigating the impact of bereavement status, pro-inflammatory cytokine single nucleotide polymorphisms (SNPs) on circulating markers of inflammation and hypothesizing a gene by environment (GxE) effect. The study sample included 64 older adults, of which 36 were widow(er)s. Circulating levels of inflammatory markers IL-6, IL-1RA and sTNFRII were measured. Participants were genotyped for SNPs in the IL-6 gene (IL-6 – 174 and –572), the IL-1β gene (IL-1β –511), and TNF-α gene (TNF-α –308). Grief severity was assessed with the Inventory of Complicated Grief. Bereaved participants had higher circulating levels of IL-1RA and IL-6. This increase could not be explained by pro-inflammatory genotype frequency differences, or Complicated Grief diagnosis. However, a GxE effect with the IL-6 –174 SNP moderated individual vulnerability to higher circulating levels of inflammation resulting from bereavement exposure. These results suggest a possible mechanism for the increase in morbidity and mortality in the surviving spouse. Genetic variability interacts with an environmental stressor, leading to increased inflammatory markers in genetically susceptible subjects only. For these patients, clinical interventions for bereavement-related stressor reduction might be crucial for overall health.
doi:10.1016/j.bbi.2012.06.009
PMCID: PMC3601554  PMID: 22735772
Aging; Bereavement; Cytokines; Gene; Gene by environment; Grief; IL-1; IL-6, TNF-a; Inflammation
13.  Mindfulness-Based Stress Reduction Training Reduces Loneliness and Pro-Inflammatory Gene Expression in Older Adults: A Small Randomized Controlled Trial 
Brain, behavior, and immunity  2012;26(7):1095-1101.
Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N=40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35)=7.86, p=.008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33)=3.39, p=.075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults.
doi:10.1016/j.bbi.2012.07.006
PMCID: PMC3635809  PMID: 22820409
meditation; mindfulness; older adults; aging; loneliness; genetics; gene expression; stress
14.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1200/JCO.2011.36.1154
PMCID: PMC3179252  PMID: 21825266
15.  B cell-stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B cell lymphoma 
Background
The risk of developing non-Hodgkin lymphoma (NHL) is greatly increased in HIV infection. The aim of this study was to determine if elevated serum levels of molecules associated with B cell activation precede the diagnosis of AIDS-associated NHL.
Methods
Serum levels of B cell activation-associated molecules, interleukin-6 (IL6), interleukin-10 (IL10), soluble CD23 (sCD23), soluble CD27 (sCD27), soluble CD30 (sCD30), C-reactive protein (CRP), and IgE were determined in 179 NHL cases and HIV+ controls in the Multicenter AIDS Cohort Study, collected at up to three time points per subject, 0–5 years prior to AIDS-NHL diagnosis.
Results
Serum IL6, IL10, CRP, sCD23, sCD27, and sCD30 levels were all significantly elevated in the AIDS-NHL group, when compared to HIV+ controls or to AIDS controls, after adjusting for CD4 T cell number. Elevated serum levels of B cell activation-associated molecules were seen to be associated with the development of systemic (non-CNS) NHL, but not with the development of primary CNS lymphoma.
Conclusions
Levels of certain B cell stimulatory cytokines and molecules associated with immune activation are elevated for several years preceding the diagnosis of systemic AIDS-NHL. This observation is consistent with the hypothesis that chronic B cell activation contributes to the development of these hematologic malignancies.
Impact
Marked differences in serum levels of several molecules are seen for several years pre-diagnosis in those who eventually develop AIDS-NHL. Some of these molecules may serve as candidate biomarkers and provide valuable information to better define the etiology of NHL.
doi:10.1158/1055-9965.EPI-11-0037
PMCID: PMC3132317  PMID: 21527584
lymphoma; B cell; cytokines; AIDS; immune activation
16.  Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation 
AIDS (London, England)  2011;25(3):303-314.
Objective
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.
Design
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).
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/QAD.0b013e32834273ad
PMCID: PMC3322644  PMID: 21192231
activation; AIDS; antiretroviral therapy; B lymphocytes; highly active; HIV; non-Hodgkin’s lymphoma
17.  Multisite Comparison of High-Sensitivity Multiplex Cytokine Assays▿† 
The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1β was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.
doi:10.1128/CVI.05032-11
PMCID: PMC3147360  PMID: 21697338
18.  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.
doi:10.1093/aje/kwq167
PMCID: PMC2950815  PMID: 20720098
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class
20.  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.
doi:10.1097/QAI.0b013e3181ff976b
PMCID: PMC3073851  PMID: 21116187
Kaposi sarcoma-associated herpesvirusp; non-Hodgkin lymphoma; MACS; human herpesvirus 8; DNA; AIDS cancer
21.  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.
doi:10.1097/QAI.0b013e3181b017d5
PMCID: PMC3015185  PMID: 19654554
Human Leukocyte Antigen; HIV; CD4; Multicenter AIDS Cohort NHL Study

Results 1-25 (32)