Biomarkers Of Immune Function Research Articles

A Th2-type immune response and low-grade systemic inflammatory reaction as potential immunotoxic effects in intensive agriculture farmers exposed to pesticides

Pesticides are chemicals widely used in agriculture to keep crops healthy and prevent them from being destroyed by pests, thus contributing to a sustainable food and feed production. However, long-term exposure to these compounds may be harmful to human health as they can affect the function of various organs systems, including the immune system. There is growing evidence that pesticides may increase the risk of developing immune-based diseases and inflammation. This study assessed whether greenhouse farmers occupationally exposed to pesticides presented alterations in immunoregulatory proteins, used as surrogate biomarkers of immune function. The study population consisted of 175 greenhouse workers occupationally exposed to pesticides and 91 non-exposed controls. Serum levels of 27 cytokines, chemokines and growth factors were measured using a magnetic bead-based immunoassay in a subpopulation of 111 greenhouse workers and 79 non-exposed controls. Since analytical determinations were performed in two periods of the same crop season with different use of pesticides (period of high and low pesticide exposure), linear mixed models for repeated measures were used to optimize statistical inference. The increase in IL-13, IL-4 and IL-6 observed in greenhouse workers compared to controls, and in the period of high exposure to pesticides relative to that of low exposure, suggest an altered Th1/Th2 balance towards the Th2 response. This finding points to a type-2 inflammation commonly presented as allergic inflammation, which has often been reported in farm-workers and in which pesticide exposure is considered a risk factor. Furthermore, the increase in IL-1β and VEGF, mediators of inflammation and angiogenesis, may suggest a low-grade systemic inflammation that might underlie chronic pathological conditions linked to pesticide exposure.

WITHDRAWN: Psychoneuroimmunological characterization in schizophrenia requires health-related adjustments

Schizophrenia is severe and complex. It’s etiology, course, and severity are influe nced by biologica l (e.g., genetic) and psychosocial factors (e.g., urbanicity). Altera tions in cytokine s leve ls (im mune function bioma rkers) were reported in schizophrenia, which related to symptom severity, indicating a potentia l role of im mune activity in this dis order. Cytokine leve ls are influenced by life habits (e.g., smoking), personal characteristics (e.g., sex/ gender), and life conditions (e.g., care access).We used data from the Signature Biobank: 262 schizophrenic patients vis iting an emergency room in Montreal, Canada, and 145 healthy controls. We investigated pla sma concentrations of IL-6, TNF-α and CRP in relation to schizophrenia diagnosis and symptom severity and adjusted analyses with tobacco use, BMI, age and sex.Patients showed higher levels of IL-6 (t=2.67, p=0.008) than controls, along with females compared to ma le s (t=1.844, p=0.033), and smokers compared to non-smokers (t=2.304, p=0.029). Among non-smokers, IL-6 remained higher for patients (t=1.932, p(unila teral)=0.027), but not when controlling for age and BMI (F=2.849, p=0.093). Non-smoking female patients showed higher IL-6 levels, even when controlling for BMI and age (F=6.916, p=0.010). TNF-α correlated with depressive (r=0.162, p=0.010) and psychotic symptoms (r=0.213, p<0.001) among patients.Cytokine s in schizophrenia need contextua liza tion to refle ct life habits ’ influence. Each cytokine has a different role in im mune activity that relates differently with dia gnos is and symptom severity.Immunophenotyping among schizophre nic patients require s adjusting for individual characteristics. This characterizati

Dynamic expression analysis of peripheral blood derived small extracellular vesicle miRNAs in sepsis progression.

Immune disorders caused by sepsis have recently drawn much attention. We sought to dynamically monitor the expression of small extracellular vesicle (sEV) miRNAs in peripheral blood during sepsis to explore these miRNAs as potential biomarkers for monitoring immune function in sepsis patients. This study included patients with sepsis. Blood samples were obtained from 10 patients on the first through 10th days, the 12th day and the 14th day since sepsis onset, resulting in 120 collected samples. Serum sEVs were extracted from peripheral venous blood, and levels of MIR497HG, miR-195, miR-497, and PD-L1 in serum sEVs were detected by qPCR, and clinical information was recorded. Our study revealed that the levels of MIR497HG, miR-195, miR-497 and PD-L1 in serum sEVs showed periodic changes; the time from peak to trough was approximately 4-5 days. The levels of sEV MIR497HG and miR-195 had a positive linear relationship with SOFA score (r values were -0.181 and -0.189; p values were 0.048 and 0.039, respectively). The recorded quantities of sEV MIR497HG, miR-195 and PD-L1 showed a substantial correlation with ARDS. ROC curve analysis revealed that sEV MIR497HG, miR-195 and miR-497 could predict the 28-day mortality of sepsis patients with an AUC of 0.66, 0.68 and 0.72, respectively. Levels of sEVs MIR497HG, miR-195, miR-497 and PD-L1 showed periodic changes with the immune status of sepsis, which provides a new exploration direction for immune function biomarkers and immunotherapy timing in sepsis patients.

Long-term assessment of relationships between changing environmental conditions and the physiology of southern Beaufort Sea polar bears (Ursus maritimus).

Climate change is influencing polar bear (Ursus maritimus) habitat, diet, and behavior but the effects of these changes on their physiology is not well understood. Blood-based biomarkers are used to assess the physiologic health of individuals but their usefulness for evaluating population health, especially as it relates to changing environmental conditions, has rarely been explored. We describe links between environmental conditions and physiologic functions of southern Beaufort Sea polar bears using data from blood samples collected from 1984 to 2018, a period marked by extensive environmental change. We evaluated associations between 13 physiologic biomarkers and circumpolar (Arctic oscillation index) and regional (wind patterns and ice-free days) environmental metrics and seasonal and demographic co-variates (age, sex, season, and year) known to affect polar bear ecology. We observed signs of dysregulation of water balance in polar bears following years with a lower annual Arctic oscillation index. In addition, liver enzyme values increased over time, which is suggestive of potential hepatocyte damage as the Arctic has warmed. Biomarkers of immune function increased with regional-scale wind patterns and the number of ice-free days over the Beaufort Sea continental shelf and were lower in years with a lower winter Arctic oscillation index, suggesting an increased allocation of energetic resources for immune processes under these conditions. We propose that the variation in polar bear immune and metabolic function is likely indicative of physiologic plasticity, a response that allows polar bears to remain in homeostasis even as they experience changes in nutrition and habitat in response to changing environments.

Nasal biomarkers of immune function differ based on smoking and respiratory disease status.

Respiratory biomarkers have the potential to identify airway injury by revealing inflammatory processes within the respiratory tract. Currently, there are no respiratory biomarkers suitable for clinical use to identify patients that warrant further diagnostic work-up, counseling, and treatment for toxic inhalant exposures or chronic airway disease. Using a novel, noninvasive method of sampling the nasal epithelial lining fluid, we aimed to investigate if nasal biomarker patterns could distinguish healthy nonsmoking adults from active smokers and those with chronic upper and lower airway disease in this exploratory study. We compared 28 immune mediators from healthy nonsmoking adults (n=32), former smokers with COPD (n=22), chronic rhinosinusitis (CRS) (n=22), and smoking adults without airway disease (n=13). Using ANOVA, multinomial logistic regressions, and weighted gene co-expression network analysis (WGCNA), we determined associations between immune mediators and each cohort. Six mediators (IL-7, IL-10, IL-13, IL-12p70, IL-15, and MCP-1) were lower among disease groups compared to healthy controls. Participants with lower levels of IL-10, IL-12p70, IL-13, and MCP-1 in the nasal fluid had a higher odds of being in the COPD or CRS group. The cluster analysis identified groups of mediators that correlated with disease status. Specifically, the cluster of IL-10, IL-12p70, and IL-13, was positively correlated with healthy and negatively correlated with COPD groups, and two clusters were correlated with active smoking. In this exploratory study, we preliminarily identified groups of nasal mucosal mediators that differed by airway disease and smoking status. Future prospective, age-matched studies that control for medication use are needed to validate these patterns and determine if nasosorption has diagnostic utility for upper and lower airway disease or injury.

Similar to Those Who Are Breastfed, Infants Fed a Formula Containing 2′-Fucosyllactose Have Lower Inflammatory Cytokines in a Randomized Controlled Trial

Background: Evidence suggests that human milk oligosaccharides (HMOs) provide multiple benefits to infants, including prebiotic effects, gut maturation, antimicrobial activities, and immune modulation. Clinical intervention studies with HMOs are required to confirm these benefits in infants.Objective: Our objective was to investigate the effects of feeding formulas supplemented with the HMO 2′-fucosyllactose (2′-FL) on biomarkers of immune function in healthy term infants.Methods: We performed a substudy nested within a randomized, double-blind, controlled growth and tolerance study in healthy singleton infants (birth weight ≥2490 g) who were enrolled by 5 d of life and exclusively formula-fed (n = 317) or breastfed (n = 107) from enrollment to 4 mo of age. Formula-fed infants were randomly assigned to receive 1 of 3 formulas, all containing 2.4 g total oligosaccharides/L [control: galacto-oligosaccharides (GOS) only; experimental formulas: GOS + 0.2 or 1.0 g 2′-FL/L], and compared with a breastfed reference group. For this substudy, blood samples were drawn from infants at 6 wk of age (n = 31–42/group). Peripheral blood mononuclear cells (PBMCs) were isolated for cellular phenotyping and stimulated ex vivo with phytohemagglutinin for proliferation and cell cycle progression or respiratory syncytial virus (RSV). Cytokine concentrations were measured in plasma and in ex vivo–stimulated culture supernatants.Results: Breastfed infants and infants fed either of the experimental formulas with 2′-FL were not different but had 29–83% lower concentrations of plasma inflammatory cytokines than did infants fed the control formula [interleukin (IL) receptor antagonist (IL-1ra), IL-1α, IL-1β, IL-6, and tumor necrosis factor α (TNF-α)] (P ≤ 0.05). In ex vivo RSV–stimulated PBMC cultures, breastfed infants were not different than either of the groups fed formula with 2′-FL, but they had lower concentrations of TNF-α (31%) and interferon γ (IFN-γ 54%) (P ≤ 0.05) and tended to have lower IL-1ra (25%) and IL-6 (38%) (unadjusted P ≤ 0.05) and IL-1β (30%) (unadjusted P = 0.06) than did infants fed the control formula.Conclusions: Our data indicate that infants fed formula supplemented with 2′-FL exhibit lower plasma and ex vivo inflammatory cytokine profiles, similar to those of a breastfed reference group. This trial was registered at clinicaltrials.gov as NCT01808105.

Online, low-volume meditation does not alter immune-related biomarkers

ObjectivesPrior studies of mindfulness meditation have demonstrated anti-inflammatory and immunoregulatory effects but whether meditation courses delivered online can exert similar effects is poorly understood. Barriers to large scale implementation of traditional mindfulness meditation programs has created an increased interest in the effect of less time- and resource-intensive online meditation courses. The purpose of this study was to determine whether a 6-week online mindfulness program with low time demands on nurses would lead to changes in gene expression, cytokine profiles, telomerase activity, and cortisol profiles. MethodsThis was a randomized, parallel pilot study comparing an online mindfulness-based stress management program to an active control group from December 2018 to May 2019. Healthy nurses with above average levels of perceived stress were randomized to receive a 6-week online mindfulness-based stress management program including ≥5 min daily meditation practice or listen to relaxing music for ≥5 min daily as the control arm. Blood samples were collected at baseline and after 6 weeks, and various self-reported measures of stress, physical and emotional health were collected at baseline, after 6 weeks, and after 12 weeks. Whole transcriptome mRNA sequencing of whole blood at baseline and after 6 weeks was performed along with measurement of plasma IL-6, IL-8, IL-10, TNF-α, and IFN-γ. Peripheral blood mononuclear cells were isolated, and telomerase activity was measured. Diurnal salivary cortisol profiles were assessed at baseline and after 6 weeks. The primary outcome was change over time in a pre-determined set of 53 genes representative of the immune-related changes seen with stress, which was analyzed using a mixed linear model. Secondary outcomes included all other self-reported measures and biomarkers mentioned above. ResultsA total of 61 nurses were randomized, with 52 having sufficient data to include in the final analysis. After 6 weeks, nurses in the control group reported significant reductions in stress as measured by the Perceived Stress Scale while those in the mindfulness group did not. However, after 12 weeks, the mindfulness group also showed a significant reduction in stress. When compared to the control group, no significant changes in RNA gene expression or any other biomarkers were observed in the nurses who participated in the mindfulness program. ConclusionsOur study found that this brief online mindfulness-based intervention was effective in reducing stress in nurses, albeit with a delayed effect compared to listening to relaxing music. Regarding immunoregulatory effects, there were no significant differences between treatment and control groups in transcriptomic or other tested biomarkers of immune function. This study provides evidence for a floor effect of mindfulness on transcriptional and circulating biomarkers of immune function.

Rationale and study design of Randomized Controlled Trial of Dietary Supplementation with prune (dried plums) on bone density, geometry, and estimated bone strength in postmenopausal women: The Prune study

The use of non-pharmacological alternatives to pharmacological interventions, e.g., nutritional therapy, to improve or maintain bone mineral density (BMD) in postmenopausal women has gained traction over the past decade, but limited data exist regarding its efficacy. This paper describes the design of the Prune Study, a randomized controlled trial (RCT) that explored the effectiveness of a 12-month intervention of daily prune consumption on bone density, bone structure and strength estimates, bone turnover, various biomarkers of immune function, inflammation, and cardiovascular health, as well as phenolic and gut microbiota analyses. Postmenopausal women between the ages of 55–75 years were randomized into either control group (no prune consumption; n = 78), 50g prune (50g prune/day; n = 79), or 100g prune (100g prune/day; n = 78). All participants received 1200 mg calcium +800 IU vitamin D3 daily as standard of care. The Prune Study is the largest and most comprehensive investigation of a dose response of prune consumption on bone health, biomarkers of immune function, inflammation, and cardiovascular health, as well as detailed phenolic and gut microbiota analyses in postmenopausal women. 235 women were randomized and 183 women completed the entire study. The findings of this study will help expand our current understanding of clinical implications and mechanisms underlying the resultant health effects of prune as a functional food therapy.

Lower lymphocyte count is associated with increased risk of Parkinson’s disease

ObjectivesPatients with established Parkinson’s disease (PD) display differences in blood biomarkers of immune function, including leukocyte differentials, compared to controls. These may be useful biomarkers to predict PD and inform pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with risk of subsequent PD.MethodsWe examined the relationship between incident PD and baseline leukocyte differential count in UK Biobank, a longitudinal cohort with &gt;500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations.ResultsAfter excluding individuals with comorbidities which could influence inflammation biomarkers, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of PD diagnosis (per 1-SD decrease in count OR 1.18, 95% CI 1.07–1.32, padjusted=0.01). The association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; ORMR 1.09, 95% CI 1.01–1.18, p=0.02).ConclusionsWe provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD.m.jensen@cantab.net

Quantification of torque teno virus (TTV) DNA in saliva and plasma samples in patients at short time before and after kidney transplantation

ABSTRACT Background Several reports have proposed that the viral load of torque teno virus (TTV) in plasma is a biomarker of immune function in solid organ transplantation (SOT) and in allogeneic hematopoietic stem cell transplantation. Additionally, for the latter one, TTV-DNA quantification in saliva has also been suggested. Aim to investigate the correlation between the TTV viral load and immune function in paired saliva and plasma samples in patients on kidney transplantation. Materials and Methods TTV-DNA viral load was quantified in paired samples of saliva and plasma from 71 patients before and a short-time after renal-transplantation by real-time PCR. Results The data obtained from 213 paired samples showed a slight consistency in the comparison between saliva and plasma, with prevalence of TTV-DNA being 58%, 52% and 60% in saliva samples and 60%, 73% and 90% in plasma samples before and at 15–20 and 45–60 days after transplantation, respectively. Additionally, a high TTV viral load was observed in plasma at 15–20 and 45–60 days after transplantation compared to that observed in saliva at the same time. Conclusions Overall, monitoring TTV-DNA in saliva samples could be an additional fast non-invasive option to assess the immune functionality in SOT populations.

Evaluation of Quantiferon®-Monitor as a biomarker of immunosuppression and predictor of infection in lung transplant recipients.

Optimizing immunosuppression in lung transplant recipients (LTR) is crucially important in minimizing the risk of infection and rejection. Quantiferon®-Monitor (QFM) is a candidate immune function biomarker which has not yet been rigorously evaluated in the lung transplant setting. The aim of this prospective cohort study was to explore relationships between QFM results, immunosuppression, and infection/rejection in LTR. QFM, which measures interferon-γ after stimulation with innate and adaptive immune antigens, was tested before and at 2, 6, 12, 24 and 52weeks post-transplant. Immunosuppression relationships were assessed with linear mixed effects models. Clinical outcomes were analyzed based on the preceding QFM result. Eighty LTR were included. Median pre-transplant QFM levels were 171IU/mL (IQR 45-461), decreasing to 3IU/mL (IQR 1-8) at 2weeks post-transplant then progressively recovering toward baseline with time from transplant. Prednisolone was strongly inversely associated with QFM level (0.1mg/kg dose increase correlating with 88IU/mL QFM decrease, 95% CI 61-114, P<.001). Patients with QFM values <10 and <60IU/mL were more likely to develop a serious opportunistic infection between 3 and 6months (HR 6.38, 95% CI 1.37-29.66, P=.02) and 6-12months (HR 3.25, 95% CI 1.11-9.49, P=.03) post-transplant, respectively. QFM values declined significantly post-transplant, with patients recovering at different rates. Prednisolone dose significantly impacted QFM results. Low levels were associated with infection beyond 3months post-transplant, suggesting that QFM may be able to identify overly immunosuppressed patients who could be targeted for dose reduction. Larger prospective studies are needed to further evaluate this promising assay.

Plasma biomarkers of inflammation reflect disease state in autosomal dominant forms of familial frontotemporal dementia

AbstractBackgroundImmune dysregulation may influence disease pathogenesis in familial frontotemporal dementia (fFTD), but the utility of peripheral biomarkers of inflammation remains unclear in this cohort. We sought to investigate candidate plasma biomarkers of immune function within a large cohort of fFTD kindreds from the ARTFL and LEFFTDS Consortia.MethodsWe examined plasma samples from 148 non‐carrier healthy controls and 256 asymptomatic and symptomatic individuals carrying autosomal dominant fFTD‐associated mutations (n=73 MAPT, n=120 C9ORF72, and n=63 GRN). ELISA was used to measure three plasma biomarkers of inflammation (YKL‐40, TNF‐α,IL‐6). We used Mann–Whitney U tests to compare concentrations amongst controls and subgroups of fFTD differing in disease severity, defined by the Clinical Dementia Rating Scale plus National Alzheimer’s Disease Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR® plus NACC FTLD) global score (asymptomatic=0, early symptomatic=0.5, late symptomatic ≥1). We also used linear mixed models to assess the utility of baseline inflammatory biomarkers in predicting the subsequent annual rate of decline in functional clinical severity (CDR® plus NACC FTLD sum of boxes) and psychomotor speed (Trails A).ResultsPlasma YKL‐40 concentrations were elevated in late symptomatic fFTD (59.3ng/ml [50.1]) relative to controls (32.9ng/ml [24.0]) (p=0.0003) and asymptomatic mutation carriers (30.9ng/ml [25.4], p=0.0001). Plasma TNF‐α concentrations were relatively low in asymptomatic mutation carriers (1.96pg/ml [0.56]) compared to early symptomatic fFTD (2.35pg/ml [0.83], p= 0.009). Amongst mutation carriers (including 140 with follow up clinical data), higher baseline plasma IL‐6 and YKL‐40 concentrations were associated with greater increase in functional clinical severity and declines in psychomotor speed, respectively.ConclusionPlasma biomarkers of inflammation increase with disease severity in fFTD and predict worse clinical trajectories. While the role of inflammation remains unclear in familial FTD, plasma markers of inflammation appear to reflect the processes influencing disease trajectory in patients carrying mutations associated with familial frontotemporal dementia.

Age-associated changes in the circulating human antibody repertoire are upregulated in autoimmunity

BackgroundThe immune system undergoes a myriad of changes with age. While it is known that antibody-secreting plasma and long-lived memory B cells change with age, it remains unclear how the binding profile of the circulating antibody repertoire is impacted.ResultsTo understand humoral immunity changes with respect to age, we characterized serum antibody binding to high density peptide microarrays in a diverse cohort of 1675 donors. We discovered thousands of peptides that bind antibodies in age-dependent fashion, many of which contain di-serine motifs. Peptide binding profiles were aggregated into an “immune age” by a machine learning regression model that was highly correlated with chronological age. Applying this regression model to previously-unobserved donors, we found that a donor’s predicted immune age is longitudinally consistent over years, suggesting it could be a robust long-term biomarker of humoral immune ageing. Finally, we assayed serum from donors with autoimmune disease and found a significant association between “accelerated immune ageing” and autoimmune disease activity.ConclusionsThe circulating antibody repertoire has increased binding to thousands of di-serine peptide containing peptides in older donors, which can be represented as an immune age. Increased immune age is associated with autoimmune disease, acute inflammatory disease severity, and may be a broadly relevant biomarker of immune function in health, disease, and therapeutic intervention.

Differences in biomarkers of inflammation and immune responses in chronic smokers and moist snuff users

BackgroundCigarette smoking is a major risk factor for cancer and other diseases. While smoking induces chronic inflammation and aberrant immune responses, the effects of smokeless tobacco products (STPs) on immune responses is less clear. Here we evaluated markers related to immune regulation in smokers (SMK), moist snuff consumers (MSC) and non-tobacco consumers (NTC) to better understand the effects of chronic tobacco use. Materials and methodsSeveral markers associated with immune regulation were measured in peripheral blood mononuclear cells (PBMCs) from SMK (n = 40), MSC (n = 40), and NTC (n = 40) by flow cytometry. ResultsRelative to NTC, seven markers were significantly suppressed in SMK, whereas in MSC, only one marker was significantly suppressed. In a logistic regression model, markers including granzyme B+ lymphocytes, perforin+ lymphocytes, granzyme B+ CD8+T cells, and KLRB1+ CD8+ T cells remained as statistically significant predictors for classifying the three cohorts. Further, cell-surface receptor signaling pathways and cell–cell signaling processes were downregulated in SMK relative to MSC; chemotaxis and LPS-mediated signaling pathways, were upregulated in SMK compared to MSC. A network of the tested markers was constructed to visualize the immunosuppression in SMK relative to MSC. ConclusionMoist snuff consumption is associated with significantly fewer perturbations in inflammation and immune function biomarkers relative to smoking. ImpactThis work identifies several key immunological biomarkers that differentiate the effects of chronic smoking from the use of moist snuff. Additionally, a molecular basis for aberrant immune responses that could render smokers more susceptible for infections and cancer is provided.

Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Commentaries on Viewpoint: The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies.

Predictors of interleukin-1β and interleukin-1 receptor antagonist in infant saliva.

This study assesses the feasibility of measuring interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1ra) in infant salivary samples as representative of pro- and anti-inflammatory processes, and explores predictors of these biomarkers in a US population. Data were collected from 73 US mother-infant pairs. Salivary samples were collected with an infant swab and analyzed for IL-1β, IL-1ra, and immunoglobulin A (IgA) using ELISA. Household, maternal, infant, and anthropometric predictors were selected using stepwise regression to build final multivariate models. Both IL-1β and IL-1ra can be feasibly measured in infant saliva. The predictors in the final IL-1β model were IL-1ra and reported infant illness. IL-1β, IgA, infant age, household income, maternal BMI, and infant weight-for-age z-score were significant in the final model for IL-1ra. IL-1β and IL-ra are useful biomarkers of immune function for infants. In particular, IL-1ra has the potential to address the relationship between immune function and body composition in the mother-infant dyad.

Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab: Results of the expansion part of a phase I study in patients with metastatic colorectal cancer.

140 Background: Trifluridine/tipiracil (FTD/TPI) is approved for use in patients (pts) with pretreated mCRC. In vivo studies have shown an increase in anti-tumor activity when combining FTD/TPI, oxaliplatin or bevacizumab, and an increase in tumor immunogenicity after treatment with FTD/TPI and oxaliplatin (Ghiringhelli, 2018). The recommended dose for expansion had been defined as FTD/TPI 35 mg/m² bid, days 1–5 q14, together with oxaliplatin 85 mg/m² (day 1). Methods: In addition to FTD/TPI and oxaliplatin, eligible pts received bevacizumab 5 mg/kg (Cohort A) or nivolumab 3 mg/kg (Cohort B) on day 1. Eligibility criteria included measurable disease, performance status (PS) 0-1, normal organ function, progression after &gt; 1 prior anti-tumor therapy (excluding oxaliplatin), and confirmed MSS status (Cohort B). A Bayesian design was used for futility and efficacy assessments. Efficacy endpoints of objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and adverse events (AEs) were assessed for each cohort; biomarkers of immune function including PD-L1 expression for Cohort B. Results: A total of 37 and 17 pts were enrolled in Cohorts A and B respectively; with a median age of 64 years (range 33 to 83 years), 61% and 39% had an PS of 0 and 1. At baseline, no pt showed PD-L1 expression on tumor cells, and only 1 pt on immune cells (5% threshold). At data cutoff, 32 and 12 pts were evaluable for response in Cohorts A and B. In Cohort A, ORR was 13% (1 CR; 3 PR), and DCR was 91%. The mPFS was 6.9 months (95% IC, 4.3-9.3). In Cohort B, ORR was 8% (1 PR), DCR was 67%. The mPFS was 6.5 months (95% IC, 1.8-8.6). Overall, the most common treatment-related AEs (≥20% of pts) included neutropenia, nausea, diarrhoea, and fatigue; only 1 pt reported grade 3 febrile neutropenia; 5 pts discontinued due to AEs and no treatment-related death were reported. Conclusions: In this study, bevacizumab in addition to FTD/TPI and oxaliplatin showed antitumor activity. The cohort of nivolumab was prematurely discontinued due to lack of efficacy. Both cohorts showed an acceptable safety profile in pretreated mCRC pts. Clinical trial information: NCT02848443.

Continuous Moderate-Intensity but Not High-Intensity Interval Training Improves Immune Function Biomarkers in Healthy Young Men.

Khammassi, M, Ouerghi, N, Said, M, Feki, M, Khammassi, Y, Pereira, B, Thivel, D, and Bouassida, A. Continuous moderate-intensity but not high-intensity interval training improves immune function biomarkers in healthy young men. J Strength Cond Res 34(1): 249-256, 2020-Effects of endurance running methods on hematological profile are still poorly known. This study aimed to compare the effects of 2 training regimes; high-intensity interval training (HIIT) and moderate-intensity continuous training (MCT) performed at the same external load on hematological biomarkers in active young men. Sixteen men aged 18-20 years were randomly assigned to HIIT or MCT group. Aerobic capacity and hematological biomarkers were assessed before and after 9 weeks of interventions. At baseline, aerobic and hematological parameters were similar for the 2 groups. After intervention, no significant change was observed in maximal aerobic velocity and estimated VO2max in both groups. Leukocyte (p < 0.01), lymphocyte (p < 0.05), neutrophil (p < 0.05), and monocyte (p < 0.01) count showed significant improvements in response to the MCT compared with the HIIT intervention. The MCT intervention favored an increase in the number of immune cells, whereas the opposite occurred as a result of the HIIT intervention. These findings suggest that MCT interventions might be superior to HIIT regimes in improving immune function in active young men.

Alterações agudas induzidas por uma prova de triathlon longo em diferentes biomarcadores enzimáticos e da função imune

Objectivo: Analisar as alterações hematológicas agudas induzidas por uma prova de triathlon longo. Avaliou-se o comportamento de diversos biomarcadores enzimáticos e da função imune em atletas portugueses masculinos de triathlon. Métodos: 10 atletas seniores masculinos (31,5 ± 1,2 anos; 69,3 ± 1,9 kg; 177,7 ± 1,4 cm; 22,0 ± 0,8 de IMC e 10,1 ± 2,2 % GC) divididos em grupos elite e não-elite. Foram recolhidas amostras de sangue venoso periférico antes e imediatamente após as provas. Utilizou-se estatí­stica descritiva, testes não-paramétricos de Wilcoxon e Mann-Whitney e coeficiente de correlação de Spearman. Resultados: Verificou-se o aumento da actividade das enzimas CK e AST (p &lt; 0,05) em ambos os grupos. O aumento da actividade da enzima GGT (p &lt; 0,05) ocorreu somente no grupo elite. Foi constatado, em ambos os grupos, um aumento da contagem leucocitária, fundamentalmente expressa pelo aumento da contagem de neutrófilos (p &lt; 0,05). Após a prova, registou-se a diminuição da relação CD4/CD8 e aumento das concentrações dos linfócitos T CD3+CD8+, T CD4+reg e T CD4+CD69+ nos atletas dos grupos não-elite. Conclusão: Os resultados encontrados sugerem que a intensidade e a duração da prova de triathlon condicionam as respostas dos diversos biomarcadores analisados em função do ní­vel de treino dos atletas.Palavras-chave: triathlon, treino, actividade enzimática, sistema imune, linfócitos.

Cancer Immune Control Dynamics (CICD): A clinical data driven model of systemic immunity.

e21058 Background: Recent clinical advances in cancer immuno-therapeutics underscore the need for improved understanding of the complex relationship between cancer and the multiple, multi-functional, inter-dependent, cellular and humoral mediators/regulators of the human immune system. This will lead to improvements in the efficacy of existing immune therapies (patient selection; drug combinations) and insight into new therapeutic targets that may significantly reduce the time to new therapeutics discoveries capable of meaningful clinical impacts. Methods: A systems analysis approach (Cancer Immune Control Dynamics, CICD) attempts to identify the differences between systemic immune homeostasis of healthy volunteers versus patients with metastatic malignant melanoma based on serial measurements of a set of conventional peripheral blood biomarkers of immune function (15 cell subsets and 35 cytokines) assessed daily over 7-10 days. The modeling strategy takes aerospace engineering control theory and system identification algorithms to analyze the state of an individual’s immune system based on the biomarkers’ dynamic non-linear oscillatory behaviors. The analysis framework builds on the classical predator-prey equations commonly used to model biological system dynamics. Tens of thousands of biologically possible biomarker interactions are modeled by a set of matrix equations that creates a system interaction model. CICD quantifies the system equations with biomarker values and solves it to measure the interactions. Results: Quantification of thousands of unique biomarker relationships per participant enables classification based on their immune profile rather than their clinical diagnosis and a basis for a visualization of a person’s immunity state. Conclusions: Results provide initial evidence that a model-based analysis of serially collected biomarker data can lead to biological insights into human immunity, of potential benefit in clinical decisions. It is anticipated that CICD-based capabilities will provide tools to specifically address cancer and treatment modulated (immune checkpoint inhibitors) parameters of human immunity, revealing clinically relevant biological interactions.