Biomarker For Distinguishing Patients Research Articles

STREM2 is a plasma biomarker for human NASH and promotes hepatocyte lipid accumulation.

Pathogenetic mechanisms of the progression of NAFL to advanced NASH coupled with potential noninvasive biomarkers and novel therapeutic targets are active areas of investigation. The recent finding that increased plasma levels of a protein shed by myeloid cells -soluble Triggering Receptor Expressed on Myeloid cells 2 (sTREM2) -may be a biomarker for NASH has received much interest. We aimed to test sTREM2 as a biomarker for human NASH and investigate the role of sTREM2 in the pathogenesis of NASH. We conducted studies in both humans (comparing patients with NASH vs. NAFL) and in mice (comparing different mouse models of NASH) involving measurements of TREM2 gene and protein expression levels in the liver as well as circulating sTREM2 levels in plasma. We investigated the pathogenetic role of sTREM2 in hepatic steatosis using primary hepatocytes and bone marrow derived macrophages. RNA sequencing analysis of livers from patients with NASH or NAFL as well as livers from 2 mouse models of NASH revealed elevated TREM2 expression in patients/mice with NASH as compared with NAFL. Plasma levels of sTREM2 were significantly higher in a well-characterized cohort of patients with biopsy-proven NASH versus NAFL (area under receiver-operating curve 0.807). Mechanistic studies revealed that cocultures of primary hepatocytes and macrophages with an impaired ability to shed sTREM2 resulted in reduced hepatocyte lipid droplet formation on palmitate stimulation, an effect that was counteracted by the addition of exogenous sTREM2 chimeric protein. Conversely, exogenous sTREM2 chimeric protein increased lipid droplet formation, triglyceride content, and expression of the lipid transporter CD36 in hepatocytes. Furthermore, inhibition of CD36 markedly attenuated sTREM2-induced lipid droplet formation in mouse primary hepatocytes. Elevated levels of sTREM2 due to TREM2 shedding may directly contribute to the pathogenesis of NAFLD by promoting hepatocyte lipid accumulation, as well as serving as a biomarker for distinguishing patients with NASH versus NAFL. Further investigation of sTREM2 as a clinically useful diagnostic biomarker and of the therapeutic effects of targeting sTREM2 in NASH is warranted.

Cerebral Small Vessel Disease Burden: An Independent Biomarker for Anomia Treatment Responsiveness in Chronic Stroke Patients With Aphasia

ObjectiveTo determine whether MRI-based cerebral small vessel disease (cSVD) burden predicts treatment-induced aphasia recovery in chronic stroke patients above and beyond initial aphasia severity and stroke-lesion volume. DesignRetrospective. Four cSVD neuroimaging markers were rated using validated visual scales: white matter hyperintensities, enlarged perivascular spaces, lacunes, and global cortical atrophy. We also calculated a cSVD total score. We employed linear regression models to model treatment response as a function of cSVD burden. We also ran correlation analyses to determine the association among cSVD burden and pre-treatment linguistic and non-linguistic cognition. SettingResearch clinic. ParticipantsThe study includes data from 30 chronic stroke patients with aphasia who received treatment for word finding difficulties and completed additional pre-treatment neuroimaging and behavioral assessments (N=30). Interventions120-minute sessions of anomia treatment 2 times per week for up to 12 weeks. Main Outcome MeasuresChange in accuracy on the treatment probes measured as a percentage (ie, change in accuracy percentage score=post-treatment accuracy percentage minus pre-treatment accuracy percentage). ResultsBaseline cSVD burden predicted response to anomia treatment independently from demographic and stroke-related factors. Patients with lower cSVD burden exhibited enhanced rehabilitation response compared with those with higher cSVD burden (β=-6.816e-02, P=.019). cSVD burden was highly associated with nonverbal executive function at baseline (r=-0.49, P=.005): patients with lower cSVD burden exhibited higher performance on nonverbal executive function tasks compared with participants with higher cSVD burden. No association was observed among cSVD burden and performance on language tasks at the baseline. ConclusionscSVD, a marker of brain reserve and a robust risk factor for post-stroke dementia, may be used as a biomarker for distinguishing patients who are more likely to respond to anomia therapy from those who are less likely to do so and for individualizing treatment parameters (eg, targeting both linguistic and nonlinguistic cognition in severe cSVD).

Biomarkers of disease activity in patients with chronic spontaneous urticaria.

IntroductionPrevious studies have examined biomarkers of coagulation, inflammation and immunity in chronic spontaneous urticaria (CSU), but no recommended biomarkers for disease activity have been established yet.AimTo find the relationship between certain laboratory parameters and disease activity in patients with CSU.Material and methodsSerum concentrations of D-dimer, C-reactive protein (CRP), C3, C4, and prothrombin time (PT), activated partial thromboplastin time (aPTT) values were measured in 44 CSU patients and compared with 33 healthy controls. Correlation between biomarkers and urticaria activity score during 7 consecutive days (UAS7) was calculated.ResultsOur study included 44 CSU patients (38 females and 6 males), mean age of 50.4 years and the average disease duration of 3.1 years. Based on UAS7, 23 (52.3%) CSU patients had mild urticaria, 8 (18.2%) well-controlled, 7 (15.9%) moderate and 6 (13.6%) severe urticaria. Fourteen (31.8%) patients had elevated CRP, 21 (47.7%) had elevated D-dimer and 14 (13.6%) CSU patients had elevated C4 levels. Patients with CSU had statistically significant elevated D-dimer, CRP and PT as compared with controls (p = 0.007, p = 0.005 and p = 0.029, respectively). There was no correlation between PT, aPTT, D-dimer, CRP, C3 and disease activity. Statistically significant differences in C4 levels between patients with severe and well-controlled, mild, moderate urticaria were determined (p = 0.003).ConclusionsCRP, D-dimer, and PT may be considered as biomarkers for distinguishing patients with CSU from controls. The C4 levels correlate with disease activity and may be useful as a potential biomarker of disease activity.

Serum progranulin irrelated with Breg cell levels, but elevated in RA patients, reflecting high disease activity.

Soluble progranulin (PGRN) is known to directly regulate regulatory T cells; however, whether PGRN levels are elevated in patients with rheumatoid arthritis and affect the regulatory subsets of B cells remain unknown. In this study, a total of 80 RA patients and 60 healthy controls were studied. Serum progranulin levels were determined using enzyme-linked immune-sorbent assay. A receiver operating characteristic (ROC) curve was used to evaluate the feasibility of serum PGRN as a biomarker for distinguishing patients with RA. CD19(+)CD5(+)GrB(+) B cells were analyzed by flow cytometry in peripheral blood mononuclear cells (PBMCs). Serum progranulin levels in RA patients (median, 59.4 ng/mL) and in RA patients DAS28 > 5.1 (median, 71.98 ng/mL) were much higher than those in normal controls (median, 46.3 ng/mL; P < 0.001). The area under the ROC curve for progranulin levels was 0.705 for RA versus normal controls and the area under the ROC curve for progranulin levels in RA patients DAS28 > 5.1 was 0.977 versus normal controls (P < 0.001). Interestingly, serum progranulin and DAS28, CRP, ESR were all positively correlated in RA patients (P < 0.001). The number of CD19(+)CD5(+)GrB(+) B cells was significantly higher in RA patients (P < 0.05); however, the level of Breg cells was not related to PGRN (P > 0.05). Our findings indicated that induction of PGRN expression may play a role in RA immune reaction and PGRN levels could be a useful biomarker in RA inflammatory response, but irrelated with Breg cell levels.

Diagnostic Potential of Zymogen Granule Glycoprotein 2 Antibodies as Serologic Biomarkers in Chinese Patients With Crohn Disease.

The need for reliable biomarkers for distinguishing Crohn disease (CD) from ulcerative colitis (UC) is increasing. This study aimed at evaluating the diagnostic potential of anti-GP2 antibodies as a biomarker in Chinese patients with CD. In addition, a variety of autoantibodies, including anti-saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibodies (PANCA), anti-intestinal goblet cell autoantibodies (GAB), and anti-pancreatic autoantibodies (PAB), were evaluated.A total of 91 subjects were prospectively enrolled in this study, including 35 patients with CD, 35 patients with UC, 13 patients with non-IBD gastrointestinal diseases as disease controls (non-IBD DC), and 8 healthy controls (HC). The diagnosis of IBD was determined based on the Lennard-Jones criteria, and the clinical phenotypes of the IBD patients were determined based on the Montreal Classification.Anti-GP2 IgG antibodies were significantly elevated in patients with CD, compared with patients with UC (P = 0.0038), HC (P = 0.0055), and non-IBD DC (P = 0.0063). The prevalence of anti-GP2 IgG, anti-GP2 IgA and anti-GP2 IgA, or IgG antibodies in patients with CD was 40.0%, 37.1%, and 54.3%, respectively, which were higher than those in non-IBD DC (anti-GP2 IgG, 15.4%; anti-GP2 IgA, 7.7%; and anti-GP2 IgA or IgG, 23.1%) and those in patients with UC (anti-GP2 IgG, 11.4%; anti-GP2 IgA, 2.9%; and anti-GP2 IgA or IgG, 14.3%). For distinguishing CD from UC, the sensitivity, specificity, positive predictive value (PPV) and positive likelihood ratios (LR+) were 40%, 88.6%, 77.8%, and 3.51 for anti-GP2 IgG, 37.1%, 97.1%, 92.9%, and 13.0 for anti-GP2 IgA, and 54.3%, 85.3%, 79.2%, and 3.69 for anti-GP2 IgA or IgG. For CD diagnosis, the combination of anti-GP2 antibodies with ASCA IgA increased the sensitivity to 68.6% with moderate loss of specificity to 74.3%. Spearman's rank of order revealed a significantly positive correlation of anti-GP2 IgG with ileocolonic location of disease (L3) (P = 0.043) and a negative correlation of anti-GP2 IgA with biologic therapy (P = 0.012).Our findings suggest that anti-GP2 antibodies could serve as a biomarker for distinguishing patients with CD from patients with UC, and the combination of anti-GP2 antibodies with ASCA IgA may improve the predictive power.

N-Terminal Pro-B-Type Natriuretic Peptide in Patients with Hypertensive Heart Disease

N-Terminal Pro-B-Type Natriuretic Peptide in Patients with Hypertensive Heart DiseasePatients with hypertensive heart disease have elevated concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The aim of our study was to evaluate NT-proBNP in patients with long-standing hypertension and in patients with signs of hypertensive cardiomyopathy. The study included three groups of 50 subjects: healthy persons (Control Group), patients with hypertension and normal left ventricular systolic function (Group 1) and patients with longstanding hypertension and signs of hyper tensive cardiomyopathy with impaired left ventricular systolic function (Group 2). Our results show a very good correlation (Pearson's test) between NT-proBNP in Group 1 and Group 2 and C-reactive protein (Group 1: r = 0.8424; Group 2: r = 0.6650), systolic blood pressure (Group 1: r = 0.7213; Group 2: r = 0.4856), diastolic blood pressure (Group 1: r = 0.4282; Group 2: r = 0.3989) and ejection fraction (Group 1: r = -0.7390; Group 2: r = 0.9111). ROC analysis revealed that the AUC between the Control Group and Group 1 for NT-proBNP (0.912) was not significantly different (p&gt;0.05) from the AUC for systolic (0.924) and diastolic pressure (0.937). A cut-off value for NT-proBNP of 5.89 pmol/L can be used to reliably distinguish patients of Group 1 from the Control Group, and a cut-off value of 21.67 pmol/L reliably separates patients from Group 1 and Group 2 (in both cases, the AUC is 1.000). Patients in Group 2 who belonged to the II and III New York Heart Association (NYHA) class had significantly higher levels of NT-proBNP than those in NYHA class I (ANOVA test, p=0.001). These data suggest that NT-proBNP is a useful biomarker for distin guishing patients with long-standing hypertension who are at risk of heart failure, allowing optimization and proper treatment of these patients.

Plasma soluble human leukocyte antigen-G expression is a potential clinical biomarker in patients with hepatitis B virus infection

The significance of upregulated soluble human leukocyte antigen-G (sHLA-G) expression under various pathologic conditions has been discussed. In this study, we evaluated the potential significance of plasma sHLA-G expression in patients with hepatitis B virus (HBV) infection. The study included 90 acute hepatitis B patients (AHB), 131 chronic hepatitis B patients (CHB), 152 resolved hepatitis B individuals (RHB), and 129 normal controls. sHLA-G were determined using enzyme-linked immunosorbent assay. A receiver operating characteristic (ROC) curve was used to evaluate the feasibility of plasma sHLA-G as a biomarker for distinguishing patients with HBV infection. sHLA-G levels in AHB (median, 193.1 U/mL; p < 0.001), CHB (median, 324.6 U/mL; p < 0.001), and RHB (median, 14.8 U/mL; p = 0.006) patients was much higher than that in normal controls (median, 9.0 U/mL). A significant difference for sHLA-G levels was also observed between patients with HBV infection (AHB vs CHB, AHB vs RHB, and CHB vs RHB; all p < 0.001). The area under the ROC curve for sHLA-G levels was 1.000 (p < 0.001) for AHB, 0.993 (p < 0.001) for CHB, and 0.604 (p = 0.003) for RHB patients versus normal controls, respectively. Data also indicated that the percentage of CD4(+)CD25(+)FoxP3(+) T regulatory cells and HLA-G(+)CD14(+) monocytes was significantly increased in AHB and CHB patients compared with normal controls (all p < 0.001). Our findings indicated that induction of HLA-G expression may play a role in HBV immune evasion and sHLA-G levels could be a useful biomarker in HBV infection.

Distinct cerebral perfusion patterns in FTLD and AD

We examined the utility of distinguishing between patients with frontotemporal lobar degeneration (FTLD) and Alzheimer disease (AD) using quantitative cerebral blood flow (CBF) imaging with arterial spin labeled (ASL) perfusion MRI. Forty-two patients with FTLD and 18 patients with AD, defined by autopsy or CSF-derived biomarkers for AD, and 23 matched controls were imaged with a continuous ASL method to quantify CBF maps covering the entire brain. Patients with FTLD and AD showed distinct patterns of hypoperfusion and hyperperfusion. Compared with controls, patients with FTLD showed significant hypoperfusion in regions of the frontal lobe bilaterally, and hyperperfusion in posterior cingulate and medial parietal/precuneus regions. Compared with controls, patients with AD showed significant hypoperfusion in the medial parietal/precuneus and lateral parietal cortex, and hyperperfusion in regions of the frontal lobe. Direct comparison of patient groups showed significant inferior, medial, and dorsolateral frontal hypoperfusion in FTLD, and significant hypoperfusion in bilateral lateral temporal-parietal and medial parietal/precuneus regions in AD. Doubly dissociated areas of hypoperfusion in FTLD and AD are consistent with areas of significant histopathologic burden in these groups. ASL is a potentially useful biomarker for distinguishing patients with these neurodegenerative diseases.

Urine macrophage migration inhibitory factor (MIF) in children with urinary tract infection: a possible predictor of acute pyelonephritis

Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine expressed at sites of inflammation. We have assessed this factor (MIF) in urinary tract infections with the aim of determining a non-invasive and sensitive method to differentiate upper and lower renal involvement. Thirty-three pediatric patients with urinary track infection (25 with acute pyelonephritis, eight with acute cystitis) and 40 healthy subjects were recruited for this prospective case-control study. Pyelonephritis was differentiated from cystitis by dimercaptosuccinic acid (DMSA) scan. Urinary MIF concentration was determined using an enzyme-linked immunosorbent assay method. The urine MIF/creatinine (Cr) ratio was significantly higher in pyelonephritis patients than in those with acute cystitis and the control group (P < 0.001). The optimal cut-point of 4.90 pg/micromol Cr for the urine MIF/Cr ratio has the potential to be a biomarker for distinguishing patients with acute pyelonephritis from those with acute cystitis. Determination of the urinary MIF was also useful in selecting the patients at risk of permanent renal damage. Of those patients with pyelonephritis, based on the DMSA scan at the time of infection, scarring on follow-up DMSA scan 9-12 months later occurred in patients with the highest urinary MIF/Cr ratios. We conclude that the urine MIF/Cr ratio is a sensitive test for differentiating acute pyelonephritis from acute cystitis and also for detecting children with acute pyelonephritis who are at a higher risk for permanent renal scars in the future.

Chemokine markers predict biochemical recurrence of prostate cancer following prostatectomy.

Stratifying patients who have a high risk of prostate cancer recurrence following prostatectomy can potentiate the use of adjuvant therapy at an early stage. Inflammation has emerged as a mediator of prostate cancer metastatic progression. We hypothesized that chemokines can be biomarkers for distinguishing patients with high risk for biochemical recurrence of prostate cancer. In a nested case-control study, 82 subjects developed biochemical recurrence within 5 years of prostatectomy. Prostate tissues from 98 age-matched subjects who were recurrence-free following prostatectomy in the same period were the controls. A high-throughput lectin-based enrichment of prostate tissue enabled multiplex ELISA to identify the expression of three chemokines to discriminate the two patient populations. The expression of CX3CL1 and IL-15 in prostate tissue was associated with 5-year biochemical recurrence-free survival following prostatectomy. However, the expression of chemokine ligand 4 (CCL4) was associated with biochemical recurrence. Multivariable logistic regression model combining preoperative prostate-specific antigen, Gleason score, surgical margin, and seminal vesicle status with the three chemokines doubled the specificity of prediction at 90% sensitivity compared with use of the clinicopathologic variables alone (P < 0.0001). Survival analysis yielded a nomogram that supported the use of CX3CL1, IL-15, and CCL4 in predicting 1-, 3-, and 5-year recurrence-free survival after prostatectomy. Each of the three chemokines can serve as independent predictors of biochemical recurrence. However, the combination of chemokine biomarkers plus clinicopathologic variables discriminated prostatectomy subjects for the probability of biochemical recurrence significantly better than clinicopathologic variables alone.