Changes In Biomarker Concentrations Research Articles

Changes and associations between synovial fluid and magnetic resonance imaging markers of osteoarthritis after high tibial osteotomy

BackgroundMechanobiological mechanisms of osteoarthritis (OA) are unclear. Our objectives were to explore: 1) changes in knee joint physiology using a large panel of synovial fluid biomarkers from before to one year after high tibial osteotomy (HTO) surgery, and 2) the association of changes in the synovial fluid biomarkers with the changes in MRI measures of knee effusion-synovitis and articular cartilage composition.MethodsTwenty-six patients with symptomatic knee OA and varus alignment underwent synovial fluid aspirations and 3 T MRI before and one year after medial opening wedge HTO. Cytokine and growth factor levels in synovial fluid were measured with multiplex assays. Ontology and pathway enrichment was assessed using data protein sets with gene set enrichment analysis (GSEA), and analyzed using linear mixed effects models. MRIs were analyzed for effusion-synovitis and T2 cartilage relaxation time using manual segmentations. Changes in biomarker concentrations were correlated to changes in MRI effusion-synovitis volume and articular cartilage T2 relaxation times.ResultsDecreased enrichment in Toll-like receptor and TNF-α signalling was detected one year after HTO. The leading contributors to this reduction included IL-6, TNF-α and IL-1β, whereas the highest contributors to positive enrichment were EGF, PDGF-BB and FGF-2. Effusion-synovitis volume decreased (mean [95%CI]) one year after HTO (-2811.58 [-5094.40, -528.76mm3]). Effusion-synovitis volume was moderately correlated (r [95% CI]) with decreased MMP-1 (0.44 [0.05; 0.71]), IL-7 (0.41 [0.00; 0.69]) and IL-1β (0.59 [0.25; 0.80]) and increased MIP-1β (0.47 [0.10; 0.73]). Medial tibiofemoral articular cartilage T2 relaxation time decreased (mean [95% CI]) one year after HTO (-0.33 [-2.69; 2.05]ms). Decreased T2 relaxation time was moderately correlated to decreased Flt-3L (0.61 [0.28; 0.81]), IL-10 (0.47 [0.09; 0.73]), IP-10 (0.42; 0.03–0.70) and increased MMP-9 (-0.41 [-0.7; -0.03]) and IL-18 (-0.48 [-0.73; -0.10]).ConclusionsDecreased aberrant knee mechanical loading in patients with OA is associated with decreased biological and imaging measures of inflammation (measured in synovial fluid and on MRI) and increased anabolic processes. These exploratory findings suggest that improvement in knee loading can produce long-term (one year) improvement in joint physiology.

Ultra-sensitive Two-dimensional Photonic Crystal Biosensor for Oral Cancerous Cell Detection

Background & Objectives: Over the past two decades, biophotonic sensors based on two-dimensional (2D) photonic crystals (PhCs) have garnered significant attention in cancer diagnosis. This technology has become a crucial tool in early cancer detection and treatment response monitoring due to its ability to detect minute changes in biomarker concentrations and molecular interactions. The development of these sensors through advanced nano and microfabrication techniques has significantly improved diagnostic accuracy and speed, promising substantial enhancements in therapeutic outcomes for cancer patients. Materials & Methods: A biosensor based on a 2D PhC was designed and simulated for the detection of oral cancer cells in a sample. The biosensor, structured with silicon rods in air using the Finite-Difference Time-Domain tool, utilizes five rods as an analyte for detecting normal and cancerous cells, thereby evaluating the sensor’s performance. Results: The variation in the transmission spectrum was studied to detect the presence of malignant cells in the test sample. The sensor’s structural parameters were carefully adjusted to enhance its sensitivity, a crucial factor in the accurate detection of cancerous cells. Two critical parameters, Q-factor and sensitivity, were derived from the results. The sensor achieved a sensitivity of 1148 nm/RIU with a Q-factor of 193. Conclusion: The designed biosensor demonstrates superior accuracy and sensitivity in identifying both malignant and normal cells in the test sample, making it suitable for real- time deployment in point-of-care applications.

Efficacy and Safety of Ketogenic Diet Treatment in Pediatric Patients with Mitochondrial Disease.

Mitochondrial diseases (MDs) are a heterogeneous group of disorders resulting from abnormal mitochondrial function. Currently, there is no causal treatment for MDs. The aim of the study was to assess the effectiveness and safety of the ketogenic diet (KD) in patients with MD and to analyse selected biochemical and clinical parameters evaluating the effectiveness of KD treatment in patients with MDs. A total of 42 paediatric patients were assigned to four groups: group 1-patients with MD in whom KD treatment was started (n = 11); group 2-patients with MD remaining on an ordinary diet (n = 10); group 3-patients without MD in whom KD treatment was initiated (n = 10), group 4-patients without MD on a regular diet (n = 11). Clinical improvement was observed in 9/11 patients with MD treated with KD. Among patients with MD without KD, the clinical condition deteriorated in 7/10 patients, improved in 2/10 patients, and remained unchanged in one patient. Adverse events of KD occurred with a comparable frequency in groups 1 and 3. There was no significant difference in changes in biomarker concentrations over the course of the study among patients treated and untreated with KD.

Longitudinal AD biomarkers in monozygotic twins: genetic contribution to AD biomarker concentrations over time

AbstractBackgroundUnderstanding the earliest pathophysiological changes in Alzheimer’s disease (AD) is important for development of therapeutic intervention strategies. Studying genetically identical twins provides unique information on genetic and environmental influences on development of AD. Here we studied change in AD biomarkers amyloid β1‐42 (aβ42), amyloid β1‐40 (aβ40), phosphorylated tau181 (p‐tau) and total tau (t‐tau) in CSF over time in a cohort of older cognitively normal monozygotic twins and tested the genetic contribution to biomarker concentrations at baseline and to change of biomarker concentrations over time.MethodWe included 103 twins (npairs = 42) from the EMIF‐AD preclinAD study with 2‐4 repeated CSF sampling available across a time period of 4.47±2 years (mean±SD age: 68.8±7 years, 54 (52%) female). We measured aβ42, aβ40, p‐tau and t‐tau using the Lumipulse platform (Fujirebio Diagnostics, Inc.). We used linear mixed models to investigate change in biomarker concentrations over time. We used twin‐pair intraclass correlation (ICC) analysis to estimate the genetic contribution to biomarker concentrations at baseline and at repeated measurements, and to annual change in biomarker concentrations.ResultAt baseline, 25 (24%) individuals had an abnormal aβ42/aβ40 ratio, 27 (26%) abnormal p‐tau and 35 (34%) abnormal t‐tau, and at last measurement respectively 34 (33%), 38 (37%) and 45 (44%). Across the group, aβ42/aβ40 decreased (β±SE ‐0.001±0, p‐value<0.001), and p‐tau and t‐tau increased over time (respectively 1.37±0.3, p‐value<0.001; 6.58±2.3, p‐value = 0.004). Increases in p‐tau levels were most pronounced in amyloid positive individuals (2.72±0.38, p‐value<0.001) compared to amyloid negative individuals (0.65±0.24, p‐value = 0.007; p‐value interaction<0.001). At baseline, the genetic contribution to biomarker concentrations was lowest for t‐tau (ICC = 0.5, p<0.001) and highest for aβ40 (ICC = 0.79, p<0.001). ICC’s remained similar at repeated measurements (table 1). Annual changes of aβ40 and p‐tau showed significant twin‐pair correlations (resp. ICC’s: 0.58 and 0.42; p‐values <0.01; Figure 1), indicating a genetic contribution to change in these concentrations over time.ConclusionIn this sample of older cognitively normal monozygotic twins, we found that AD biomarkers became increasingly abnormal over time. Our unique twin design further indicates that these very early pathophysiological changes are under moderate to high genetic influence, which also indicates a role of environmental factors.

Calorie restriction reduces biomarkers of cellular senescence in humans.

Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young-to-middle-aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an adlibitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Proteome-Wide Changes in Blood Biomarkers During Hemodialysis

IntroductionDuring hemodialysis, proteins in the blood can decrease in concentration due to diffusion, convective clearance, dialyzer adsorption, or cellular uptake, while others may increase in concentration due to production, cellular release, secretion, or ultrafiltration of water. We examined the impact of hemodialysis on blood protein concentrations on a proteome-wide scale. MethodsA nested cohort of 44 patients (25 male, 19 female) including 29 with intradialytic hypotension were selected from the prospective Hemodialysis Outcomes and SympToms assessment (HOST) cohort. 1,163 proteins were measured before and after a hemodialysis treatment using Olink. Pre- and post-dialysis concentrations were compared, and the impact of protein characteristics and intradialytic hypotension on protein concentration was evaluated. Results189 proteins (16%) significantly decreased and 54 (5%) significantly increased in concentration. Change in concentration was associated with protein molecular weight (r = 0.37, P = 2.8 x 10-16), isoelectric point (r = -0.26, P = 6.4 x 10-14), and pre-dialysis concentration (r = -0.21, P = 3.0 x 10-9). There was enrichment for cardiovascular biomarkers in those nominally associated with a drop in systolic blood pressure during treatment (P = 2.8 x 10-8). ConclusionsChanges in the blood proteome are detectable during hemodialysis on a high throughput scale. Protein properties and intradialytic hypotension events appear associated with changes in biomarker concentration. Larger proteome-wide biomarker studies may identify measures of dialysis adequacy and reveal pathological processes contributing to adverse effects of dialysis.

Immune biomarkers in non-treatment-seeking heavy drinkers who used a probiotic supplement for 30 days: An open-label pilot study

Alcohol use disorder (AUD) is associated with significant psychological and economic burdens, as well as physical comorbidities that can lead to death. Previous research has found that probiotics may reduce inflammatory biomarkers in persons with AUD and comorbid conditions such as cirrhosis of the liver. This relationship has not been explored in heavy drinkers without comorbid conditions. In a proof-of-concept study, individuals who were heavy drinkers without known comorbidities received a 30-day course of a daily probiotic supplement in an open-label pilot trial. Eligible participants (N = 16) met NIAAA guidelines for heavy alcohol use and did not report any preexisting medical problems. Blood samples were taken at four timepoints: prior to the probiotic course, at the midpoint, at the end, and after a washout period of at least one month. Immunoassays were conducted on plasma samples to quantify the following inflammatory biomarkers: IL-6, IL-8, IL-10, LBP, MCP-1, sCD14, sCD163, and TNF-α. Linear mixed models were used to test within-subjects changes in biomarker concentrations over the study period, with alcohol use included as a time-varying covariate. Biomarker concentrations did not change significantly. A higher number of heavy drinking days was statistically associated with higher concentrations of IL-6 (F(1,8) = 6.66, p = 0.0326) and IL-8 (F(1,17) = 6.38, p = 0.0218). Greater days since last drink was associated with a lower concentration of MCP-1 (F(1,17) = 5.77, p = 0.028). In summary, biomarker trajectories were associated with alcohol consumption variables, but not probiotic use, in this open-label pilot study. Randomized controlled trials are needed to evaluate fully the potential benefits of probiotics in heavy drinkers without known comorbidities and under conditions of non-abstinence.

Quintuply-fortified salt for the improvement of micronutrient status among women of reproductive age and preschool-aged children in Punjab, India: protocol for a randomized, controlled, community-based trial

BackgroundMultiple micronutrient (MN) deficiencies remain highly prevalent among women of reproductive age (WRA) and preschool-aged children (PSC) in many areas within India. Salt is an attractive vehicle for MN fortification in this context, as it is universally consumed in fairly consistent amounts and coverage of iodized salt (IS) is 94%. The overall objective of this trial is to evaluate the nutritional impact of quintuply-fortified salt with iron in the form of encapsulated ferrous fumarate, zinc, vitamin B12, folic acid, and iodine (eFF-Q5S) vs. quintuply-fortified salt with iron in the form of ferric pyrophosphate plus EDTA, zinc, vitamin B12, folic acid, and iodine (FePP-Q5S) vs. IS for the improvement of MN status among non-pregnant WRA and PSC.MethodsThe study is a community-based, randomized, controlled trial that will be conducted in Punjab, India. 780 non-pregnant WRA 18–49 years old and 468 PSC 12–59 months old will be enrolled and assigned to one of three intervention groups. Salt will be provided to participants monthly for 12 months. Primary outcomes include changes in mean concentration of biomarkers of iron, zinc, vitamin B12, folate and iodine. Secondary outcomes include changes in the composition of the gut microbiome, and discretionary salt intake of PSC.DiscussionIf proven efficacious, multiply-fortified salt (MFS) has the potential to drastically reduce the burden of MN deficiencies in India, and around the world. Although effectiveness research will be needed to examine the impact of MFS under programmatic conditions, salt fortification will piggy-back on existing platforms to produce IS and doubly-fortified salt (DFS), making it possible to scale-up the intervention quickly.Trial registrationClinicaltrials.gov: NCT05166980; date of registration: December 22, 2021. Clinical Trials Registry-India: CTRI/2022/040332 and CTRI/2022/02/040333; date of registration: February 15, 2022.

Effect of Player Position on Serum Biomarkers during Participation in a Season of Collegiate Football.

This prospective cohort study examined the relationship between a panel of four serum proteomic biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], total Tau, and neurofilament light chain polypeptide [NF-L]) in 52 players from two different cohorts of male collegiate student football athletes from two different competitive seasons of Division I National Collegiate Athletic Association Football Bowl Subdivision. This study evaluated changes in biomarker concentrations (as indicators of brain injury) over the course of the playing season (pre- and post-season) and also assessed biomarker concentrations by player position using two different published classification systems. Player positions were divided into: 1) speed (quarterbacks, running backs, halfbacks, fullbacks, wide receivers, tight ends, defensive backs, safety, and linebackers) versus non-speed (offensive and defensive linemen), and 2) "Profile 1" (low frequency/high strain magnitudes positions including quarterbacks, wide receivers, and defensive backs), "Profile 2" (mid-range impact frequency and strain positions including linebackers, running backs, and tight ends), and "Profile 3" (high frequency/low strains positions including defensive and offensive linemen). There were significant increases in GFAP 39.3 to 45.6 pg/mL and NF-L 3.5 to 5.4 pg/mL over the course of the season (p < 0.001) despite only five players being diagnosed with concussion. UCH-L1 decreased significantly, and Tau was not significantly different. In both the pre- and post-season blood samples Tau and NF-L concentrations were significantly higher in speed versus non-speed positions. Concentrations of GFAP, Tau, and NF-L increased incrementally from "Profile 3," to "Profile 2" to "Profile 1" in the post-season. UCH-L1 did not. GFAP increased (by Profiles 3, 2, 1) from 42.4 to 49.6 to 78.2, respectively (p = 0.051). Tau increased from 0.37 to 0.61 to 0.67, respectively (p = 0.024). NF-L increased from 3.5 to 4.9 to 8.2, respectively (p < 0.001). Although GFAP and Tau showed similar patterns of elevations by profile in the pre-season samples they were not statistically significant. Only NF-L showed significant differences between profiles 2.7 to 3.1 to 4.2 in the pre-season (p = 0.042). GFAP, Tau, and NF-L concentrations were significantly associated with different playing positions with the highest concentrations in speed and "Profile 1" positions and the lowest concentrations were in non-speed and "Profile 3" positions. Blood-based biomarkers (GFAP, Tau, NF-L) provide an additional layer of injury quantification that could contribute to a better understanding of the risks of playing different positions.

Characterization of Platelet Biologic Markers in the Early Pathogenesis of Postoperative Acute Respiratory Distress Syndrome.

The objective of this study was to characterize the role of platelets in a postoperative ARDS model through an analysis of two platelet-specific biologic markers: thromboxane A2 (TxA2) and soluble CD-40-ligand (sCD40L). This was a nested case-control study of ARDS cases matched to non-ARDS controls. Blood samples were collected from a cohort of 500 patients undergoing thoracic, aortic vascular, or cardiac surgery that placed them at high-risk of developing postoperative ARDS. TxA2 and sCD40L were analyzed at baseline (prior to surgical incision) as well as 2 hours and 6 hours after the key intraoperative events believed to be associated with increased risk of postoperative ARDS. Of 500 patients enrolled, 20 ARDS cases were matched 1:2 to non-ARDS controls based on age, sex, surgical procedure, and surgical lung injury prediction score. Those who developed ARDS had longer surgeries, greater fluid administration, and higher peak inspiratory pressures. There were no significant differences in levels of TxA2 or sCD40L at baseline, at 2 hours, or at 6 hours. There was also no difference in the change in biomarker concentration between baseline and 2 hours or baseline and 6 hours. Two novel platelet-associated biologic markers (TxA2 and sCD40L) were not elevated in patients who developed ARDS in a postoperative ARDS model. Although limited by the relatively small study size, these results do not support a clear role for platelets in the early pathogenesis of postoperative ARDS.

Evaluation of new and old biomarkers in dogs with degenerative mitral valve disease

BackgroundDogs with degenerative mitral valve disease are commonly presented to small animal clinicians. Diagnosis, clinical staging, and therapeutic design are based on a combination of clinical examination, radiography, and echocardiography. To support diagnosis and clinical monitoring, a multi-marker-based approach would be conceivable. The aim of this study was to investigate the suitability of Galectin-3 and interleukin-1 receptor-like 1 protein (ST2) in dogs with degenerative mitral valve disease in accordance with N-terminal-prohormone-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI). For this purpose, serum concentrations of Galectin-3 and ST2 of 64 dogs with different stages of mitral valve disease and 21 dogs without cardiac disease were analyzed at the first examination and six months later. Echocardiography, blood cell count and clinical chemistry were performed and established biomarkers NT-proBNP and cTnI were measured additionally. Differences in the biomarker concentrations between all groups at both timepoints and the change in biomarker concentrations from first to second evaluation was investigated. Furthermore, correlations of each biomarker, between biomarkers and echocardiographic measurements, were calculated. Finally, the receiver-operating characteristic curve and the area under the curve analysis were performed to differentiate between disease stages and controls.ResultsSerum concentrations of Galectin-3 and ST2 were not statistically different between canine patients in the respective stages of mitral valve disease or in comparison to dogs in the control group at any timepoint. A significant increase in ST2 concentrations from the baseline to the follow-up examination was observed in dogs classified as stage B1 and the control group. The concentrations of NT-proBNP and cTnI in stage C dogs were significantly increased in comparison to the other groups.ConclusionsIn this study, no relation between Galectin-3 and ST2 levels to the presence or stage of mitral valve disease could be detected. Nevertheless, considering the increase in ST2 concentrations from the first to second measurement, its value on monitoring disease progress could be feasible. In agreement with previous studies, NT-proBNP and cTnI have once more proven their utility in assessing disease severity. The approach of examining new cardiac biomarkers in dogs is still worth pursuing.

Portable air cleaner use and biomarkers of inflammation: A systematic review and meta-analysis

Fine particulate matter air pollution (PM2.5) is a major contributor to cardiovascular morbidity and mortality, potentially via increased inflammation. PM2.5 exposure increases inflammatory biomarkers linked to cardiovascular disease, including CRP, IL-6 and TNFα. Portable air cleaners (PACs) reduce individual PM2.5 exposure but evidence is limited regarding whether PACs also reduce inflammatory biomarkers. We performed a systematic review and meta-analysis of trials evaluating the use of PACs to reduce PM2.5 exposure and inflammatory biomarker concentrations. We identified English-language articles of randomized sham-controlled trials evaluating high efficiency particulate air filters in non-smoking, residential settings measuring serum CRP, IL-6 and TNFα before and after active versus sham filtration, and performed meta-analysis on the extracted modeled percent change in biomarker concentration across studies. Of 487 articles identified, we analyzed 14 studies enrolling 778 participants that met inclusion criteria. These studies showed PACs reduced PM2.5 by 61.5 % on average. Of the 14 included studies, 10 reported CRP concentrations in 570 participants; these showed active PAC use was associated with 7 % lower CRP (95 % CI: −14 % to 0.0 %, p = 0.05). Nine studies of IL-6, with 379 participants, showed active PAC use was associated with 13 % lower IL-6 (95 % CI: [−23 %, −3 %], p = 0.009). Six studies, with 269 participants, reported TNF-α and demonstrated no statistical evidence of difference between active and sham PAC use. Portable air cleaners that reduce PM2.5 exposure can decrease concentrations of inflammatory biomarkers associated with cardiovascular disease. Additional studies are needed to evaluate clinical outcomes and other biomarkers.

Impact of retrograde intrarenal surgery on biomarkers that are associated with renal parenchyma injury, a preliminary study.

The primary objective of this preliminary study was to assess the changes in concentration of biomarkers, which indicate renal injury, after RIRS. Within this prospective study, we included 21 patients with nephrolithiasis requiring treatment with RIRS. From each patient, blood and urine samples were taken at fixed intervals before and after RIRS. Kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), calbindin, albumin, clusterin, gluthation S-transferase-π (GST-π), beta-2-microglobulin (B2M), osteopontin, cystatin c, and trefoil-factor-3 (TFF3) were measured in urine. Creatinine, cystatin c and uric acid were analyzed in the blood samples. A significant increase of the biomarkers clusterin, GST-π, B2M, NGAL and cystatin c was observed after RIRS. However, the biomarkers gradually normalized during the first 14 postoperative days. The parameters surgery time, cumulative stone volume, and BMI did not significantly influence the biomarker concentrations. In the case of GST-π and NGAL a significant positive, yet minuscule effect of age was observed. With our study, we identified 5 out of 12 assessed renal injury biomarkers that showed a significant increase after RIRS. The increase was only temporary and all markers normalized within 14days. Further studies are needed to determine the clinical value of these identified markers to assess the long-term impact of intrarenal pressure elevation during RIRS.

Human Physiological Responses to a Single Deep Helium-Oxygen Diving.

Objective: The objective of this study was to explore whether a single deep helium-oxygen (heliox) dive affects physiological function.Methods: A total of 40 male divers performed an open-water heliox dive to 80 m of seawater (msw). The total diving time was 280 min, and the breathing helium-oxygen time was 20 min. Before and after the dive, blood and saliva samples were collected, and blood cell counts, cardiac damage, oxidative stress, vascular endothelial activation, and hormonal biomarkers were assayed.Results: An 80 msw heliox dive induced a significant increase in the percentage of granulocytes (GR %), whereas the percentage of lymphocytes (LYM %), percentage of intermediate cells (MID %), red blood cell number (RBC), hematocrit (hCT), and platelets (PLT) decreased. During the dive, concentrations of creatine kinase (CK), a myocardial-specific isoenzyme of creatine kinase (CK-MB) in serum and amylase alpha 1 (AMY1), and testosterone levels in saliva increased, in contrast, IgA levels in saliva decreased. Diving caused a significant increase in serum glutathione (GSH) levels and reduced vascular cell adhesion molecule-1 (VCAM-1) levels but had no effect on malondialdehyde (MDA) and endothelin-1 (ET-1) levels.Conclusion: A single 80 msw heliox dive activates the endothelium, causes skeletal-muscle damage, and induces oxidative stress and physiological stress responses, as reflected in changes in biomarker concentrations.

Proinflammatory and Hyperinsulinemic Dietary Patterns Are Associated With Specific Profiles of Biomarkers Predictive of Chronic Inflammation, Glucose-Insulin Dysregulation, and Dyslipidemia in Postmenopausal Women.

Background: Dietary patterns promoting hyperinsulinemia and chronic inflammation, including the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and cancer. EDIH was developed using plasma C-peptide, whereas EDIP was based on plasma C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha receptor 2 (TNF-αR2). We investigated whether these dietary patterns were associated with a broader range of relevant biomarkers not previously tested.Methods: In this cross-sectional study, we included 35,360 women aged 50–79 years from the Women's Health Initiative with baseline (1993–1998) fasting blood samples. We calculated EDIH and EDIP scores from baseline food frequency questionnaire data and tested their associations with 40 circulating biomarkers of insulin response/insulin-like growth factor (IGF) system, chronic systemic inflammation, endothelial dysfunction, lipids, and lipid particle size. Multivariable-adjusted linear regression was used to estimate the percent difference in biomarker concentrations per 1 standard deviation increment in dietary index. FDR-adjusted p < 0.05 was considered statistically significant.Results: Empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) were significantly associated with altered concentrations of 25 of the 40 biomarkers examined. For EDIH, the percent change in biomarker concentration in the insulin-related biomarkers ranged from +1.3% (glucose) to +8% (homeostatic model assessment for insulin resistance) and −9.7% for IGF-binding protein-1. EDIH impacted inflammation and endothelial dysfunction biomarkers from +1.1% (TNF-αR2) to +7.8% (CRP) and reduced adiponectin by 2.4%; and for lipid biomarkers: +0.3% (total cholesterol) to +3% (triglycerides/total cholesterol ratio) while reducing high-density lipoprotein cholesterol by 2.4%. EDIP showed a similar trend of associations with most biomarkers, although the magnitude of association was slightly weaker for the insulin-related biomarkers and stronger for lipids and lipid particle size.Conclusions: Dietary patterns with high potential to contribute to insulin hypersecretion and to chronic systemic inflammation, based on higher EDIH and EDIP scores, were associated with an unfavorable profile of circulating biomarkers of glucose-insulin dysregulation, chronic systemic inflammation, endothelial dysfunction and dyslipidemia. The broad range of biomarkers further validates EDIH and EDIP as mechanisms-based dietary patterns for use in clinical and population-based studies of metabolic and inflammatory diseases.

Trends in environmental chemical concentrations in the Canadian population: Biomonitoring data from the Canadian Health Measures Survey 2007–2017

Ten years of nationally representative biomonitoring data collected between 2007 and 2017 are available from the Canadian Health Measures Survey (CHMS). These data establish baseline environmental chemical concentrations in the general population. Here we sought to evaluate temporal trends in environmental chemical exposures in the Canadian population by quantifying changes in biomarker concentrations measured in the first five two-year cycles of the CHMS. We identified 39 chemicals that were measured in blood or urine in at least three cycles and had detection rates over 50% in the Canadian population. We calculated geometric mean concentrations for each cycle using the survey weights provided. We then conducted analyses of variance to test for linear trends over all cycles. We also calculated the percent difference in geometric means between the first and most recent cycle measured. Of the 39 chemicals examined, we found statistically significant trends across cycles for 21 chemicals. Trends were decreasing for 19 chemicals from diverse chemical groups, including metals and trace elements, phenols and parabens, organophosphate pesticides, per- and polyfluoroalkyl substances, and plasticizers. Significant reductions in chemical concentrations included di-2-ethylhexyl phthalate (DEHP; 75% decrease), perfluorooctane sulfate (PFOS; 61% decrease), perfluorooctanoic acid (PFOA; 58% decrease), dimethylphosphate (DMP; 40% decrease), lead (33% decrease), and bisphenol A (BPA; 32% decrease). Trends were increasing for two pyrethroid pesticide metabolites, including a 110% increase between 2007 and 2017 for 3-phenoxybenzoic acid (3-PBA). No significant trends were observed for the remaining 18 chemicals that included arsenic, mercury, fluoride, acrylamide, volatile organic compounds, and polycyclic aromatic hydrocarbons. National biomonitoring data indicate that concentrations, and therefore exposures, have decreased for many priority chemicals in the Canadian population. Concentrations for other chemical groups have not changed or have increased, although average concentrations remain below thresholds of concern derived from human exposure guidance values. Continued collection of national biomonitoring data is necessary to monitor trends in exposures over time.

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium

B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear. To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis. We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing. Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid+xanthurenic acid+3-hydroxyanthranilic acid+anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers. Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.

Circulating biomarkers for monitoring therapy response and detection of disease progression in lung cancer patients

Liquid biopsies have become of interest as minimally invasive ways to monitor treatment response in lung cancer patients. Circulating tumor DNA (ctDNA) and protein biomarkers are evaluated for their added value in monitoring therapy response and early detection of disease progression.Plasma and serum samples of non-small cell or small cell lung cancer patients were analyzed for driver mutations in ctDNA (EGFR, KRAS or BRAF) using droplet digital PCR and protein biomarkers (CA125, CEA, CA15.3, Cyfra 21-1, HE4, NSE, proGRP and SCCA) using electrochemiluminescence immunoassays. Biomarker concentration changes were compared with the outcome of CT-scans during therapy.The median difference of the concentration of ctDNA, CA125 and Cyfra21-1 was significantly lower in patients with partial response (PR) compared to patients with progressive disease (PD) on the first evaluation CT-scan (P<0.001, P=0.042 and P=0.020, respectively). A substantial agreement between ctDNA or CA125 response and radiographic response was observed (k=0.692 and k=0.792, respectively). The median difference of the concentration of ctDNA and Cyfra21-1 was also significantly lower in PR patients compared to PD patients at the last CT-scan during therapy (P<0.001 and P=0.026, respectively). An almost perfect agreement between ctDNA and radiographic response (k=0.827) and a moderate agreement between Cyfra21-1 response and radiographic response was observed (k=0.553).Serial testing of the concentration of ctDNA, Cyfra21-1, and possibly CA125 could be a useful added tool for monitoring therapy response and early detection of disease progression in lung cancer patients.

The multi-biomarker disease activity test for assessing response to treatment strategies using methotrexate with or without prednisone in the CAMERA-II trial

ObjectivesThe CAMERA-II trial compared two tight-control, treat-to-target strategies, initiating methotrexate with prednisone (MTX+pred) or MTX with placebo (MTX+plac), in early RA-patients. The multi-biomarker disease activity (MBDA) blood test objectively measures RA disease activity with a score of 1–100. In CAMERA-II, response profiles of the MBDA score, its individual biomarkers, and DAS28 were assessed.MethodsWe evaluated 92 patients from CAMERA-II of whom clinical data and serum for MBDA testing at baseline and ≥ 1 time-point from months 1, 2, 3, 4, 5, 6, 9, or 12 were available. Changes (∆) from baseline for DAS28 and MBDA score and comparisons of ∆DAS28 and ∆MBDA score over time within the MTX+pred versus the MTX+plac strategy were tested for significance with t tests. Changes in biomarker concentration from baseline to months 1–5 were tested with Wilcoxon signed rank test and tested for difference between treatment arms by Mann-Whitney U test.ResultsMBDA and DAS28 showed similar response profiles, with gradual improvement over the first 6 months in the MTX+plac group, and in the MTX+pred group faster improvement during month 1, followed by gradual improvement. The 12 MBDA biomarkers could be grouped into 4 categories of response profiles, with significant responses for 4 biomarkers during the MTX+plac strategy and 9 biomarkers during the MTX+pred strategy.ConclusionsMBDA tracked treatment response in CAMERA-II similarly to DAS28. More individual MBDA biomarkers tracked treatment response to MTX+pred than to MTX+plac. Four response profiles could be observed.Trial registrationCAMERA-II International Standard Randomised Controlled Trial Number: ISRCTN 70365169. Registered on 29 March 2006, retrospectively registered.

On the Possible Relevance of Bottom-up Pathways in the Pathogenesis of Alzheimer's Disease.

Dementia is an increasing health problem in older aged populations worldwide. Age-related changes in the brain can be observed decades before the first symptoms of cognitive decline appear. Cognitive impairment has chronic inflammatory components, which can be enhanced by systemic immune activation. There exist mutual interferences between inflammation and cognitive deficits. Signs of an activated immune system i.e. increases in the serum concentrations of soluble biomarkers such as neopterin or accelerated tryptophan breakdown along the kynurenine axis develop in a significant proportion of patients with dementia and correlate with the course of the disease, and they also have a predictive value. Changes in biomarker concentrations are reported to be associated with systemic infections by pathogens such as cytomegalovirus (CMV) and bacterial content in saliva. More recently, the possible influence of microbiome composition on Alzheimer's disease (AD) pathogenesis has been observed. These observations suggest that brain pathology is not the sole factor determining the pathogenesis of AD. Interestingly, patients with AD display drastic changes in markers of immune activation in the circulation and in the cerebrospinal fluid. Other data have suggested the involvement of factors extrinsic to the brain in the pathogenesis of AD. However, currently, neither the roles of these factors nor their importance has been clearly defined.