Systematic assessment of serum i-tRF-AsnGTT in gastric cancer: a potential clinical biomarker.

Since gastric cancer shows no apparent signs in its early stages, most patients are diagnosed later with a poor prognosis. We therefore seek more sensitive and specific GC biomarkers. Small RNAs formed from tRNAs represent a novel class of non-coding RNAs that are highly abundant in bodily fluids and essential to biological metabolism. This study explores the potential of i-tRF-AsnGTT in gastric cancer diagnostics. To begin with, we sequenced i-tRF-AsnGTT using high-throughput methods. i-tRF-AsnGTT expression levels in GC were determined using real-time fluorescence PCR. Agarose gel electrophoresis, Sanger sequencing, and repeated freezing and thawing were performed to verify molecular properties. A correlation was found between clinical and pathological parameters and i-tRF-AsnGTT expression levels through the χ² test, and ROC was used to analyze its diagnostic value in GC. In serum, i-tRF-AsnGTT has a low and stable expression level. It can differentiate between patients with gastric cancer and gastritis and healthy donors with better diagnostic efficacy. In combination with clinicopathological parameters, i-tRF-AsnGTT correlates with tumor differentiation, infiltration depth of tumors, TNM stage, lymph node metastases, and neural/vascular invasion. Serum i-tRF-AsnGTT expression is low in GC patients. Serum from postoperative patients shows increased i-tRF-AsnGTT expression levels. Potentially, this could be used as a biomarker to help diagnose gastric cancer and monitor its prognosis.

Differential profiles of serum cytokines in Parkinson's disease according to disease duration.

OBJECTIVE: Neurodegeneration and neuroinflammation are two intertwined mechanisms contributing to the pathophysiology of Parkinson's disease. Whether circulating biomarkers reflecting those two processes differ according to disease duration remains to be established. The present study was conducted to characterize the biomarkers individuals with PD with short (≤5 years) or long disease duration (>5 years). METHODS: We consecutively enrolled 104 patients with Parkinson's disease and evaluated them using validated clinical scales (MDS-UPDRS, Hoehn and Yahr staging, MMSE). Serum samples were assayed for the following biomarkers: neurofilament light chain (NfL), brain-derived neurotrophic factor (BDNF), interleukin (IL-) 1ß, 4, 5, 6, 10, 17, interferon-γ, and tumor necrosis factor α. RESULTS: Mean age of participants was 66.0 ± 9.6 years and 45 (34%) were women. The average disease duration was 8 ± 5 years (range 1 to 19 years). Patients with short disease duration (≤ 5 years) showed a pro-inflammatory profile, with significantly higher levels of pro-inflammatory IL-1ß and lower concentrations of IL-5, IL-10 and IL-17 (p < 0.05). NfL serum levels showed a positive correlation with disease duration and age (respectively rho = 0.248, p = 0.014 and rho = 0.559, p < 0.001) while an opposite pattern was detected for BDNF (respectively rho -0,187, p = 0.034 and rho = -0.245, p = 0.014). CONCLUSIONS: Our findings suggest that a pro-inflammatory status may be observed in PD patients in the early phases of the disease, independently from age.

Association of serum biomarkers with radiographic knee osteoarthritis, knee pain and function in a young, male, trauma-exposed population - Findings from the ADVANCE study.

OBJECTIVE: The ArmeD SerVices TrAuma RehabilitatioN OutComE (ADVANCE) study is investigating long-term combat-injury outcomes; this sub-study aims to understand the association of osteoarthritis (OA) biomarkers with knee radiographic OA (rOA), pain and function in this high-risk population for post-traumatic OA. DESIGN: ADVANCE compares combat-injured participants with age, rank, deployment and job-role frequency-matched uninjured participants. Post-injury immunoassay-measured serum biomarkers, knee radiographs, Knee Injury and Osteoarthritis Outcome Scale, and six-minute walk tests are reported. The primary analysis, adjusted for age, body mass, socioeconomic status, and ethnicity, was to determine any differences in biomarkers between those with/without combat injury, rOA and pain. Secondary analyses were performed to compare post-traumatic/idiopathic OA, painful/painfree rOA and injury patterns. RESULTS: A total of 1145 male participants were recruited, aged 34.1 ± 5.4, 8.9 ± 2.2 years post-injury (n = 579 trauma-exposed, of which, traumatic-amputation n = 161) or deployment (n = 566 matched). Cartilage oligomeric matrix protein (COMP) was significantly higher in the combat-injured group compared to uninjured (p = 0.01). Notably, COMP was significantly lower in the traumatic-amputation group compared to non-amputees (p < 0.001), decreasing relative to number of amputations (p < 0.001). Leptin was higher (p = 0.005) and adiponectin lower (p = 0.017) in those with v without knee pain, associated with an increased risk of 22% and 17% for pain, and 46% and 34% for painful rOA, respectively. There were no significant differences between trauma-exposed and unexposed participants with rOA. CONCLUSIONS: The most notable findings of this large, unique study are the similarities between those with rOA regardless of trauma-exposure, the injury-pattern and traumatic-amputation-associated differences in COMP, and the relationship between adipokines and pain.

Performance of serum biomarkers reflective of different pathogenic processes in systemic sclerosis-associated interstitial lung disease.

OBJECTIVE: Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). METHODS: Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. RESULTS: Serum levels of KL-6 [MD 35.67 (95% CI 22.44-48.89, P < 0.01)], SP-D [81.13 (28.46-133.79, P < 0.01)], CCL18 [17.07 (6.36-27.77, P < 0.01)], YKL-40 [22.81 (7.19-38.44, P < 0.01)] and MMP-7 [2.84 (0.88-4.80, P < 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53-1.00, P' <0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01-1.61, P' =0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52-9.03, P < 0.01)] or SP-D [OR 2.00 (1.06-3.78, P = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665-1.554, P < 0.01)] showed improved performance compared with KL-6 and SP-D alone. CONCLUSION: All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression.

Novel prediction model of early screening lung adenocarcinoma with pulmonary fibrosis based on haematological index.

BACKGROUND: Lung cancer (LC), a paramount global life-threatening condition causing significant mortality, is most commonly characterized by its subtype, lung adenocarcinoma (LUAD). Concomitant with LC, pulmonary fibrosis (PF) and interstitial lung disease (ILD) contribute to an intricate landscape of respiratory diseases. Idiopathic pulmonary fibrosis (IPF) in association with LC has been explored. However, other fibrotic interrelations remain underrepresented, especially for LUAD-PF and LUAD-ILD. METHODS: We analysed data with statistical analysis from 7,137 healthy individuals, 7,762 LUAD patients, 7,955 ILD patients, and 2,124 complex PF patients collected over ten years. Furthermore, to identify blood indicators related to lung disease and its complications and compare the relationships between different indicators and lung diseases, we successfully applied the naive Bayes model for a biomarker-based prediction of diagnosis and development into complex PF. RESULTS: Males predominantly marked their presence in all categories, save for complex PF where females took precedence. Biomarkers, specifically AGR, MLR, NLR, and PLR emerged as pivotal in discerning lung diseases. A machine-learning-driven predictive model underscored the efficacy of these markers in early detection and diagnosis, with NLR exhibiting unparalleled accuracy. CONCLUSIONS: Our study elucidates the gender disparities in lung diseases and illuminates the profound potential of serum biomarkers, including AGR, MLR, NLR, and PLR in early lung cancer detection. With NLR as a standout, therefore, this study advances the exploration of indicator changes and predictions in patients with pulmonary disease and fibrosis, thereby improving early diagnosis, treatment, survival rate, and patient prognosis.

Aspirin for evidence-based preeclampsia prevention trial: effects of aspirin on maternal serum pregnancy-associated plasma protein A and placental growth factor trajectories in pregnancy.

BACKGROUND: The exact mechanism by which aspirin prevents preeclampsia remains unclear. Its effects on serum placental biomarkers throughout pregnancy are also unknown. OBJECTIVE: To investigate the effects of aspirin on serum pregnancy-associated plasma protein A and placental growth factor trajectories using repeated measures from women at increased risk of preterm preeclampsia. STUDY DESIGN: This was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-based Preeclampsia Prevention trial using repeated measures of pregnancy-associated plasma protein A and placental growth factor. In the trial, 1620 women at increased risk of preterm preeclampsia were identified using the Fetal Medicine Foundation algorithm at 11 to 13+6 weeks of gestation, of whom 798 were randomly assigned to receive aspirin 150 mg and 822 to receive placebo daily from before 14 weeks to 36 weeks of gestation. Serum biomarkers were measured at baseline and follow-up visits at 19 to 24, 32 to 34, and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effect of aspirin on biomarker trajectories over time. RESULTS: Overall, there were 5507 pregnancy-associated plasma protein A and 5523 placental growth factor measurements. Raw pregnancy-associated plasma protein A values increased over time, and raw placental growth factor increased until 32 weeks of gestation followed by a decline. The multiple of the median mean values of the same biomarkers were consistently below 1.0 multiple of the median, reflecting the high-risk profile of the study population. Trajectories of mean pregnancy-associated plasma protein A and placental growth factor multiple of the median values did not differ significantly between the aspirin and placebo groups (aspirin treatment by gestational age interaction P values: .259 and .335, respectively). CONCLUSION: In women at increased risk of preterm preeclampsia, aspirin 150 mg daily had no significant effects on pregnancy-associated plasma protein A or placental growth factor trajectories when compared to placebo.

The non-invasive serum biomarkers contributes to indicate liver fibrosis staging and evaluate the progress of chronic hepatitis B.

BACKGROUND: This study aimed to evaluate the diagnostic abilities of the non-invasive serum biomarkers to predict liver fibrosis staging and evaluate the progress of hepatitis B. METHODS: We enrolled 433 patients with chronic HBV infection had complete medical data available for the study, who underwent percutaneous liver biopsy. The extent of fibrosis was assessed using the modified METAVIR score. The predictive values of the non-invasive serum biomarkers were evaluated by the areas under the receiving operator characteristics curves (AUROCs) with 95% confidence intervals. RESULTS: The proportion of males with progressive stages of liver fibrosis was relatively larger, and the average age of patients with cirrhosis stages is older than the non-cirrhotic stages. We found PLT, GGT, ALP, TB, FIB4 and GPR to be significantly associated with liver fibrosis in our cohort. GGT showed a sensitivity of 71.4% and specificity of 76.7% in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3), with an AUROC of 0.775 (95%CI 0.711-0.840).The AUROCs of the GPR in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3) was 0.794 (95%CI 0.734-0.853), but it had a lower sensitivity of 59.2%. Additionally, GGT, FIB4, and GPR could differentiate advanced fibrosis (F3-4) from non-advanced fibrosis (F1-2) among individuals with chronic hepatitis B, with AUROCs of 0.723 (95%CI 0.668-0.777), 0.729 (95%CI 0.675-0.782), and 0.760 (95%CI: 0.709-0.811) respectively. CONCLUSIONS: GGT was a better biomarker to distinguish cirrhosis (F4) from non-cirrhotic stages (F1-3), while GPR was a better biomarker to identify advanced fibrosis (F3-4) and non-advanced fibrosis (F1-2) in patients with chronic hepatitis B.

"Biomarkers in severe traumatic brain injury: enhancing prognostic accuracy and therapeutic strategies".

This study examines the emerging role of biomarkers in the prognosis and management of severe traumatic brain injury (sTBI). Key findings highlight the significance of serum RIP-3, STC1, Nrf2, and cerebrospinal fluid galectin-3 and cytokines in predicting disease severity, mortality, and functional outcomes in sTBI patients. Elevated levels of RIP-3 and STC1 were linked to poor prognosis and increased mortality, with RIP-3 associated with necroptosis and inflammation, and STC1 with neuroprotective properties. Nrf2 was found to correlate with oxidative stress and adverse outcomes, while elevated CSF galectin-3 and IL-6 indicated neuroinflammation and neurodegeneration. These biomarkers show promise not only as prognostic tools but also as potential therapeutic targets. The study suggests further validation through multicenter research to enhance clinical applications and improve treatment strategies for sTBI.

First-trimester serum biomarkers in twin pregnancies and adverse obstetric outcomes-a single center cohort study.

PURPOSE: This study aimed to determine the association of first-trimester maternal serum biomarkers with preterm birth (PTB), fetal growth restriction (FGR) and hypertensive disorders of pregnancy (HDP) in twin pregnancies. METHODS: This is a retrospective cohort study of twin pregnancies followed at Maternidade Dr. Alfredo da Costa, Lisbon, Portugal, between January 2010 and December 2022. We included women who completed first-trimester screening in our unit and had ongoing pregnancies with two live fetuses, and delivered after 24 weeks. Maternal characteristics, pregnancy-associated plasma protein-A (PAPP-A) and ß-human chorionic gonadotropin (ß-hCG) levels were analyzed for different outcomes: small for gestational age (SGA), gestational hypertension (GH), early and late-onset pre-eclampsia (PE), as well as the composite outcome of PTB associated with FGR and/or HDP. Univariable, multivariable logistic regression analyses and receiver-operating characteristic curve were used. RESULTS: 466 twin pregnancies met the inclusion criteria. Overall, 185 (39.7%) pregnancies were affected by SGA < 5th percentile and/or HDP. PAPP-A demonstrated a linear association with gestational age at birth and mean birth weight. PAPP-A proved to be an independent risk factor for SGA and PTB (< 34 and < 36 weeks) related to FGR and/or HDP. None of the women with PAPP-A MoM > 90th percentile developed early-onset PE or PTB < 34 weeks. CONCLUSION: A high serum PAPP-A (> 90th percentile) ruled out early-onset PE and PTB < 34 weeks. Unless other major risk factors for hypertensive disorders are present, these women should not be considered candidates for aspirin prophylaxis. Nevertheless, close monitoring of all TwP for adverse obstetric outcomes is still recommended.

High triglyceride-glucose index at admission is a predictor of post-stroke cognitive impairment in patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a very common complication of ischemic stroke (IS). Triglyceride-glucose (TyG) index was an effective alternative marker of insulin resistance (IR). This prospective study was designed to explore the correlation between TyG index and PSCI. METHODS: Between January 1 2021 to June 30 2022, consecutive patients with first onset IS were enrolled prospectively. Baseline information was collected at admission and fasting blood was drawn the next morning. Montreal Cognitive Assessment (MoCA) was used to evaluate cognitive function at three months after stroke. Multiple regression analysis was used to explore the correlation between PSCI and TyG. Receiver operating characteristic (ROC) was performed to evaluate the predictive ability. RESULTS: Ultimately, 313 patients were enrolled in this study. The TyG index was higher in patients with PSCI than those without PSCI (8.99 (8.55, 9.54) vs. 8.61(8.25, 8.87), P<0.001). The spearman correlation analysis indicated that TyG index was negatively correlated with MoCA score (r=-0.272, P<0.001). The multivariate logistic regression analysis demonstrated that TyG index was correlated with PSCI independently (P<0.001) regardless of whether the patients had diabetes or not. The area under curve (AUC) of the ROC was 0.684 (95%CI=0.635-0.768, P<0.001). The optimal cutoff value of TyG index for predicting PSCI was 8.81, with a sensitivity of 61.7% and a specificity of 73.6%. CONCLUSION: A higher TyG index level at admission was independently correlated with increased risk of PSCI three months later and could be used as a predictor.

Cholestatic HCV Cryoglobulinemia: A New Clinical and Pathological Entity before and after Direct-Acting Antiviral Therapies-A Case-Control Study.

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC- patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35-77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients' follow-up after antiviral therapies.

MIND Diet Impact on Multiple Sclerosis Patients: Biochemical Changes after Nutritional Intervention.

There is substantial evidence supporting the neuroprotective effects of the MIND diet in neurodegenerative diseases like Parkinson's and Alzheimer's. Our aim was to evaluate the impact of a nutritional intervention (NI) with this diet on multiple sclerosis (MS) patients. The study was conducted in two stages. In the first stage, two groups were included: MS patients before the NI (group A) and healthy control subjects (group B). In this stage, groups (A) and (B) were compared (case-control study). In the second stage, group (A) was assessed after the NI, with comparisons made between baseline and final measurements (before-and-after study). In the case-control stage (baseline evaluation), we found significant differences in fatigue scores (p < 0.001), adherence to the MIND diet (p < 0.001), the serum levels of brain-derived neurotrophic factor (BDNF) (p < 0.001), and higher oxidative status in the MS group, with lower levels of reduced glutathione (p < 0.001), reduced/oxidised glutathione ratio (p < 0.001), and elevated levels of lipoperoxidation (p < 0.002) and 8-hydroxy-2'-deoxyguanosine (p < 0.025). The before-and-after intervention stage showed improvements in fatigue scores (p < 0.001) and physical quality-of-life scores (MSQOL-54) (p < 0.022), along with decreases in the serum levels of glial-derived neurotrophic factor (GDNF) (p < 0.041), lipoperoxidation (p < 0.046), and 8-hydroxy-2'-deoxyguanosine (p < 0.05). Consumption of the MIND diet is linked to clinical and biochemical improvement in MS patients.

Expression and predictive value of serum core fucosylated low molecular weight kininogen and alpha-galactosylated antibodies in patients with hepatic fibrosis. / è‚çº¤ç»´åŒ–æ‚£è€ è¡€æ¸ æ ¸å¿ƒå²©è—»ç³–åŸºåŒ–ä½Žåˆ†å­é‡æ¿€è‚½åŽŸå’Œα-半乳糖基化抗体的表达及预测价值.

OBJECTIVES: Hepatic fibrosis is a common pathological basis for many chronic liver diseases and can progress to cirrhosis, a leading cause of mortality in liver diseases. Early identification and reversal of hepatic fibrosis are key in the treatment of chronic liver disease. This study aims to compare the expression levels of serum core fucosylated low molecular weight kininogen (LMWK-Fc) and alpha-galactosylated (α-Gal) antibodies in patients with hepatic fibrosis at different stages, and to evaluate their diagnostic efficacy for hepatic fibrosis. METHODS: A retrospective analysis was conducted on 275 patients with chronic liver disease who visited the Department of Infectious Diseases at the Second Xiangya Hospital of Central South University between June 2022 and March 2023. Among these, 115 patients underwent liver biopsy. Based on the extent of collagen deposition and its impact on liver structure and microcirculation, patients were staged from 0 to 4: S0 (no significant collagen deposition in liver tissues; liver structure and microcirculation are normal), S1 (mild collagen deposition in liver tissues, with partial disruption of lobule structure, but microcirculation remains largely normal), S2 (moderate collagen deposition in liver tissues, with partial disruption of lobule structure and microcirculation), S3 (extensive collagen deposition in liver tissues, with substantial disruption of lobule structure and microcirculation), and S4 (development of cirrhosis, with heavy collagen deposition, complete disruption of lobule structure, and severe impairment of microcirculation). Patients were grouped as no fibrosis (S0), fibrosis (S1-S2), and significant fibrosis (S3-S4). For the 160 patients without liver biopsy, they were categorized based on liver stiffness measurement (LSM) value: no fibrosis (F0: LSM<7.3 kPa), fibrosis (F1-F2: LSM 7.3-12.4 kPa), and significant fibrosis (F3-F4: LSM>12.4 kPa). Demographic data (age, gender) and laboratory indicators (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase, alkaline phosphatase, alpha-fetoprotein, platelet count) were collected to calculate the fibrosis-4 index (FIB-4) and aspartate aminotransferase-to-platelet ratio index (APRI). Serum LMWK-Fc and α-Gal antibodies were measured and compared across the groups, and their correlation with fibrosis severity was analyzed. The receiver operating characteristic (ROC) curve was used to assess the predictive value of serum LMWK-Fc and α-Gal antibody levels for hepatic fibrosis. RESULTS: Among the 160 patients without complete liver biopsy, serum α-Gal antibody and LMWK-Fc levels increased progressively from the no fibrosis group to the significant fibrosis group, with statistically significant differences (P<0.05). Among the 115 patients with liver biopsy, serum LMWK-Fc levels were significantly higher in the fibrosis group and the significant fibrosis groups compared with the no fibrosis group, and α-Gal antibody levels were significantly higher in the significant fibrosis group compared with the no fibrosis group and the fibrosis group (P<0.001, P=0.032, respectively). Univariate and multivariate linear regression analyses showed that hepatic fibrosis was correlated with gender and LMWK-Fc levels (both P<0.05), but not with age, α-Gal antibody levels, FIB-4, or APRI (all P>0.05). CONCLUSIONS: The expression levels of serum LMWK-Fc and α-Gal antibodies vary across different stages of hepatic fibrosis, suggesting a potential association with fibrosis progression. LMWK-Fc levels have a certain predictive value for the diagnosis of hepatic fibrosis.

Optimizing a Diagnostic Model of Periodontitis by Using Targeted Proteomics.

Periodontitis (PD), a widespread chronic infectious disease, compromises oral health and is associated with various systemic conditions and hematological alterations. Yet, to date, it is not clear whether serum protein profiling improves the assessment of PD. We collected general health data, performed dental examinations, and generated serum protein profiles using novel Proximity Extension Assay technology for 654 participants of the Bialystok PLUS study. To evaluate the incremental benefit of proteomics, we constructed two logistic regression models assessing the risk of having PD according to the CDC/AAP definition; the first one contained established PD predictors, and in addition, the second one was enhanced by extensive protein information. We then compared both models in terms of overall fit, discrimination, and calibration. For internal model validation, we performed bootstrap resampling (n = 2000). We identified 14 proteins, which improved the global fit and discrimination of a model of established PD risk factors, while maintaining reasonable calibration (area under the curve 0.82 vs 0.86; P < 0.001). Our results suggest that proteomic technologies offer an interesting advancement in the goal of finding easy-to-use and scalable diagnostic applications for PD that do not require direct examination of the periodontium.

A targeted antibody-based array reveals a serum protein signature as biomarker for adolescent idiopathic scoliosis patients.

BACKGROUND: Evident adolescent idiopathic scoliosis (AIS) incurs high treatment costs, low quality of life, and many complications. Early screening of AIS is essential to avoid progressing to an evident stage. However, there is no valid serum biomarker for AIS for early screening. METHODS: Antibody-based array is a large-scale study of proteins, which is expected to reveal a serum protein signature as biomarker for AIS. There are two segments of the research, including biomarkers screening and validation. In the biomarkers screening group, a total of 16 volunteers participated in this study, and we carried out differentially expressed proteins screening via protein array assay between No-AIS group and the AIS group, through which GeneSet enrichment analysis was performed. In the validation group with a total of 62 volunteers, the differentially expressed proteins from screening group were verified by Enzyme-Linked immunosorbent assay (ELISA), and then multiple regression analysis. RESULTS: In our study, there were twenty-nine differentially expressed proteins in AIS, through Protein array assay and GeneSet enrichment analysis in the biomarkers screening group. Then the expression of FAP, CD23 and B2M decreased as the degree of AIS increased via ELISA in validation group (FAP, p < 0.0001; CD23, p = 0.0002; B2M, p < 0.0001). Further, the results of multiple regression analysis showed that FAP, CD23 are linked to Cobb angle, whereas B2M were excluded because of multicollinearity. CONCLUSIONS: Altogether, we found that serum protein FAP and CD23 are intimately related to AIS, suggesting FAP and CD23 are expected to serve as the serum biomarkers, which significantly facilitate frequent longitudinal monitoring as to keep track of disease progression and tailor treatment accordingly.

A Prospective Cohort Study of Novel Markers of Hepatitis B Virus Replication in Human Immunodeficiency Virus Coinfection.

BACKGROUND & AIMS: The contribution of the novel biomarkers, hepatitis B virus (HBV) RNA and HBV core-related antigen (HBcrAg), to characterization of HBV-human immunodeficiency virus (HIV) coinfection is unclear. We evaluated the longitudinal dynamics of HBV RNA and HBcrAg and their association with classical HBV serum biomarkers and liver histology and viral staining. METHODS: HBV-HIV co-infected adults from 8 North American centers entered a National Institutes of Health-funded prospective cohort study. Demographic, clinical, serological, and virological data were collected at entry and every 24 to 48 weeks for up to 192 weeks. Participants with HBV RNA and HBcrAg measured ≥2 times (N = 95) were evaluated; 56 had paired liver biopsies obtained at study entry and end of follow-up. RESULTS: Participants had a median age of 50 years; 97% were on combination anti-viral therapy. In hepatitis B e antigen (HBeAg)+ participants, there were significant declines in HBV RNA and HBcrAg over 192 weeks that tracked with declines in HBeAg, hepatitis B surface antigen, HBV DNA, and hepatitis B core antigen (HBcAg) hepatocyte staining grade (all P < .05). In HBeAg- participants, there were not significant declines in HBV RNA (P = .49) and HBcrAg (P = .63), despite modest reductions in hepatitis B surface antigen (P < .01) and HBV DNA (P = .03). HBV serum biomarkers were not significantly related to change in hepatic activity index, Ishak fibrosis score, or hepatocyte HBcAg loss (all P > .05). CONCLUSIONS: In HBV-HIV coinfected adults on suppressive dually active antiviral therapy, the use of novel HBV markers reveals continued improvement in suppression of HBV transcription and translation over time. The lack of further improvement in HBV serum biomarkers among HBeAg- patients suggests limits to the benefit of combination anti-viral therapy and provide rationale for additional agents with distinct mechanisms of action.

Human immunodeficiency virus coinfection differentially impacts hepatitis B virus viral markers based on hepatitis Be antigen status in patients with suppressed viremia.

Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg), reflecting transcriptional activity of covalently closed circular DNA, are gaining traction as important markers to assess viral activity. Whether their expression differs under viral suppression by HIV co-infection status is unknown. Among adults with chronic HBV on antiviral therapy, we sought to determine if the expression of HBV markers (specialized and well-established) differs between HBV-HIV co-infection vs. HBV mono-infection. We compared HBV marker levels among 105 participants in the Hepatitis B Research Network (HBRN) HBV-HIV Ancillary Study and 105 participants in the HBRN mono-infected Cohort Study, matched for HBeAg status and HBV DNA suppression on therapy. Among HBeAg+ participants (N = 58 per group), after adjusting for age, sex, race, ALT and HBV DNA, viral markers were higher (p < .05) in the HBV-HIV versus the HBV-only sample (HBeAg: 1.05 vs. 0.51 log10 IU/mL; HBsAg: 3.85 vs. 3.17 log10 IU/mL; HBV RNA: 5.60 vs. 3.70 log10 U/mL; HBcrAg: 6.59 vs. 5.51 log10 U/mL). Conversely, among HBeAg(-) participants (N = 47 per group), HBsAg (2.00 vs. 3.04 log10 IU/mL) and HBV RNA (1.87 vs. 2.66 log10 U/mL) were lower (p < .05) in HBV-HIV vs. HBV-only; HBcrAg levels were similar (4.14 vs. 3.64 log10 U/mL; p = .27). Among adults with chronic HBV with suppressed viremia on antiviral therapy, viral markers tracked with HIV co-infection status and associations differed inversely by HBeAg status. The greater sensitivity and specificity of HBV RNA compared to HBcrAg allows for better discrimination of transcriptional activity regardless of HBeAg status.

Orthogonal proteomics methods warrant the development of Duchenne muscular dystrophy biomarkers.

BACKGROUND: Molecular components in blood, such as proteins, are used as biomarkers to detect or predict disease states, guide clinical interventions and aid in the development of therapies. While multiplexing proteomics methods promote discovery of such biomarkers, their translation to clinical use is difficult due to the lack of substantial evidence regarding their reliability as quantifiable indicators of disease state or outcome. To overcome this challenge, a novel orthogonal strategy was developed and used to assess the reliability of biomarkers and analytically corroborate already identified serum biomarkers for Duchenne muscular dystrophy (DMD). DMD is a monogenic incurable disease characterized by progressive muscle damage that currently lacks reliable and specific disease monitoring tools. METHODS: Two technological platforms are used to detect and quantify the biomarkers in 72 longitudinally collected serum samples from DMD patients at 3 to 5 timepoints. Quantification of the biomarkers is achieved by detection of the same biomarker fragment either through interaction with validated antibodies in immuno-assays or through quantification of peptides by Parallel Reaction Monitoring Mass Spectrometry assay (PRM-MS). RESULTS: Five, out of ten biomarkers previously identified by affinity-based proteomics methods, were confirmed to be associated with DMD using the mass spectrometry-based method. Two biomarkers, carbonic anhydrase III and lactate dehydrogenase B, were quantified with two independent methods, sandwich immunoassays and PRM-MS, with Pearson correlations of 0.92 and 0.946 respectively. The median concentrations of CA3 and LDHB in DMD patients was elevated in comparison to those in healthy individuals by 35- and 3-fold, respectively. Levels of CA3 vary between 10.26 and 0.36 ng/ml in DMD patients whereas those of LDHB vary between 15.1 and 0.8 ng/ml. CONCLUSIONS: These results demonstrate that orthogonal assays can be used to assess the analytical reliability of biomarker quantification assays, providing a means to facilitate the translation of biomarkers to clinical practice. This strategy also warrants the development of the most relevant biomarkers, markers that can be reliably quantified with different proteomics methods.

MicroRNA-145 and microRNA-486 are potential serum biomarkers for vascular calcification.

INTRODUCTION: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC. METHODS: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non-calcified aortas. Phase 2: miRs with the highest rate of change, plus miR-145 [the most abundant miR in vascular smooth muscle cells (VSMCs)], were validated in aortas and serum from rats with and without VC. Phase 3: the selected miRs were analyzed in epigastric arteries from kidney donors and recipients, and serum samples from general population. Phase 4: VSMCs were exposed to different phosphorus concentrations, and miR-145 and miR-486 were overexpressed to investigate their role in VC. RESULTS: miR-145, miR-122-5p, miR-486 and miR-598-3p decreased in the rat calcified aortas, but only miR-145 and miR-486 were detected in serum. In human epigastric arteries, miR-145 and miR-486 were lower in kidney transplant recipients compared with donors. Both miRs inversely correlated with arterial calcium content and with VC (Kauppila index). In the general population, the severe VC was associated with the lowest serum levels of both miRs. The receiver operating characteristic curve showed that serum miR-145 was a good biomarker of VC. In VSMCs exposed to high phosphorus, calcium content, osteogenic markers (Runx2 and Osterix) increased, and the contractile marker (α-actin), miR-145 and miR-486 decreased. Overexpression of miR-145, and to a lesser extent miR-486, prevented the increase in calcium content induced by high phosphorus, the osteogenic differentiation and the loss of the contractile phenotype. CONCLUSION: miR-145 and miR-486 regulate the osteogenic differentiation of VSMCs, and their quantification in serum could serve as a marker of VC.

Benefits of using exchangeable copper and the ratio of exchangeable copper in a real-world cohort of patients with Wilson disease.

Wilson disease (WD) is a complex disease in which diagnosis and long-term metabolic copper control remains challenging. The absence of accurate biomarkers requires the combination of different parameters to ensure copper homeostasis. Exchangeable copper and its ratio (REC) have been suggested to be useful biomarkers in this setting. We aimed at introducing these measurements and evaluate their performance and accuracy in our real-world cohort of WD patients. Exchangeable copper and REC were measured in 48 WD patients and 56 control individuals by inductively coupled plasma-mass-spectrometry. Demographic and clinical characteristics were collected. REC was shown to be significantly higher among WD patients compared to controls and useful for WD identification by using the previously established cutoffs: 71.4% of WD patients with a recent diagnosis had REC ≥18.5% and 95.1% of long-term treated WD had REC ≥14%; only four patients of the cohort presented discordant levels. Moreover, REC values were below 15% in all the control individuals. Exchangeable copper was significantly higher in WD patients compared to controls and tended to be reduced among WD patients who were compliant to medication. This real-life study confirmed that exchangeable copper and REC are useful serum biomarkers that can be used as complementary tests to ensure WD diagnosis (REC) and copper homeostasis whithin time (exchangeable copper). The desirable target levels for this last objective still needs to be validated in prospective cohorts.