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Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

Objectives: With the aging population worldwide, the octogenarians are becoming a substantial group and since cancer incidence increases by age, this group of patients is becoming more affected. Ho...

The interaction between gut microbes and gastrointestinal (GI) tract carcinogenesis has always attracted researchers' attention to identify therapeutic targets or potential prognostic biomarkers. Various studies have suggested that the microbiota do show inflammation and immune dysregulation, which led to carcinogenesis in GI tract. In this review, we have focused on the role of microbes present in the gut, intestine, or faeces in GI tract cancers, including esophageal cancer, gastric cancer, and colorectal cancer. Herein, we have discussed the importance of the microbes and their metabolites, which could serve as diagnostic biomarkers for cancer detection, especially in the early stage, and prognostic markers. To maximize the effect of the treatment strategies, an accurate evaluation of the prognosis is imperative for clinicians. There is a vast difference in the microbiota profiles within a population and across the populations depending upon age, diet, lifestyle, genetic makeup, use of antibiotics, and environmental factors. Therefore, the diagnostic efficiency of the microbial markers needs to be further validated. A deeper understanding of the GI cancer and the host microbiota is needed to acquire pivotal information about disease status.

Objective To investigate whether epileptiform discharge burden can identify those at risk for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). Methods Retrospective analysis of 113 moderate to severe grade SAH patients who had continuous EEG (cEEG) recordings during their hospitalization. We calculated the burden of epileptiform discharges (ED), measured as number of ED per hour. Results We find that many SAH patients have an increase in ED burden during the first 3–10 days following rupture, the major risk period for DCI. However, those who develop DCI have a significantly higher hourly burden from days 3.5–6 after SAH vs. those who do not. ED burden is higher in DCI patients when assessed in relation to the onset of DCI (area under the receiver operator curve 0.72). Finally, specific trends of ED burden over time, assessed by group-based trajectory analysis, also help stratify DCI risk. Conclusions These results suggest that ED burden is a useful parameter for identifying those at higher risk of developing DCI after SAH. The higher burden rate associated with DCI supports the theory of metabolic supply-demand mismatch which contributes to this complication. Significance ED burden is a novel biomarker for predicting those at high risk of DCI.

Background Tuberculosis (Tb) is a disease with worldwide presence and a major cause of death in several developing countries. Current diagnostic methodologies often lack specificity and sensitivity, whereas a long time is needed to obtain a conclusive result. Material and methods In an effort to develop better diagnostic methods, this study aimed at the discovery of a biomarker signature for Tb diagnosis using a Nuclear Magnetic Resonance based metabolomics approach. In this study, we acquired 1H NMR spectra of blood serum samples of groups of healthy subjects, individuals with latent Tb and of patients with pulmonary and extra-pulmonary Tb. The resulting data were treated with uni- and multivariate statistical analysis. Results/Conclusion Six metabolites (inosine, hypoxanthine, mannose, asparagine, aspartate and glutamate) were validated by an independent cohort, all of them related with metabolic processes described as associated with TB infection. The findings of the study are according with the WHO Target Product Profile recommendations for a triage test to rule-out active TB.

Background Whether the anti-gp210 antibody can be used as a biomarker in patients with primary biliary cholangitis (PBC) remains controversial. Aims We aimed to investigate the association between anti-gp210 antibodies and prognosis in ursodeoxycholic acid (UDCA)-treated PBC patients. Methods We conducted a retrospective cohort study of 180 UDCA-treated PBC patients to assess the prognostic value of anti-gp210 antibodies using the Kaplan–Meier method and Cox proportional hazard regression analysis. Results Of the patients included in our analysis, 50 (27.8%) were anti-gp210 positive, and 130 (72.2%) were anti-gp210 negative. The incidence of liver-related death or transplantation was more common in the anti-gp210 + group (22.0 vs. 9.2%, P=0.022). The five-year transplant-free survival rates of anti-gp210-positive patients vs. anti-gp210-negative patients were 77.0% and 90.3%, respectively. We found that the probability of transplant-free survival was significantly lower in the anti-gp210-positive patients than in the anti-gp210-negative patients (log-rank P=0.004). After adjusting for potential confounders using multivariable Cox regression model, positivity for anti-gp210 antibody (hazard ratio: 4.619, 95% confidence interval: 1.895–11.261, P=0.001) was found to be independently associated with an increase in liver-related mortality or transplantation. Conclusion In this cohort of UDCA-treated PBC patients, positivity for anti-gp210 antibody was independently associated with a higher risk of liver-related death or transplantation.

Abstract. Because its secretion is changed in cerebrospinal fluid and peripheral blood, the neuronal polypeptide VGF (nonacronymic) has been discussed as a biomarker for neuropsychiatric disorders. We have shown an enhanced VGF expression by T-cells from Alzheimer’s disease (AD) patients. In this study, we investigated the VGF expression by peripheral monocytes in 38 AD patients, 5 patients with vascular dementia (VD), and 20 neuropsychiatrically healthy individuals using flow cytometry. We determined an enhanced number of VGF-expressing monocytes in VD patients compared to AD patients. VGF+CD14+ monocytes were not correlated with age, body mass index, Mini-Mental State Examination (MMSE), or Q albumin. These preliminary data support findings indicating that VGF might play a role as a peripheral biomarker in VD.

OBJECTIVE Mild traumatic brain injury (mTBI) is a major cause of emergency room (ER) admission. Thirty percent of mTBI patients have postconcussion syndrome (PCS), and 15% have symptoms for over a year. This population is underdiagnosed and does not receive appropriate care. The authors proposed a fast and inexpensive fluorometric measurement of circulating cell-free DNA (cfDNA) as a biomarker for PCS. cfDNA is a proven, useful marker of a variety of acute pathological conditions such as trauma and acute illness. METHODS Thirty mTBI patients were recruited for this prospective single-center trial. At admission, patients completed questionnaires and blood was drawn to obtain cfDNA. At 3–4 months after injury, 18 patients returned for cognitive assessments with questionnaires and the Color Trails Test (CTT). The fast SYBR Gold assay was used to measure cfDNA. RESULTS Seventeen men and 13 women participated in this trial. The mean ± SD age was 50.9 ± 13.9 years. Of the 18 patients who returned for cognitive assessment, one-third reported working fewer hours, 4 (22.2%) changed their driving patterns, and 5 (27.7%) reduced or stopped performing physical activity. The median cfDNA level of the mTBI group was greater than that of the matched healthy control group (730.5 vs 521.5 ng/ml, p = 0.0395). Admission cfDNA concentration was negatively correlated with performance on the CTT1 and CTT2 standardized tests (r = −0.559 and −0.599), meaning that greater cfDNA level was correlated with decreased cognitive performance status. The performance of the patients with normal cfDNA level included in the mTBI group was similar to that of the healthy participants. In contrast, the increased cfDNA group (> 800 ng/ml) had lower scores on the CTT tests than the normal cfDNA group (p < 0.001). Furthermore, patients with moderate/severe cognitive impairment according to CTT1 results had a greater median cfDNA level than the patients with scores indicating mild impairment or normal function (1186 vs 473.5 ng/ml, p = 0.0441, area under the receiver operating characteristic curve = 0.8393). CONCLUSIONS The data from this pilot study show the potential to use cfDNA, as measured with a fast test, as a biomarker to screen for PCS in the ER. A large-scale study is required to establish the value of cfDNA as an early predictor of PCS.

BACKGROUND: Neurodevelopmental impairment is a significant consequence for survivors of surgery for critical congenital heart disease. This study sought to determine if intraoperative methylprednisolone during neonatal cardiac surgery is associated with neurodevelopmental outcomes at 12 months of age and to identify early prognostic variables associated with neurodevelopmental outcomes. METHODS: A planned secondary analysis of a two-center, double-blind, randomized, placebo-controlled trial of intraoperative methylprednisolone in neonates undergoing cardiac surgery was performed. A brain injury biomarker was measured perioperatively. Bayley Scales of Infant and Toddler Development-III (BSID-III) were performed at 12 months of age. Two sample t-tests and generalized linear models were used. RESULTS: There were 129 participants (n=61 methylprednisolone, n=68 placebo). There were no significant differences in BSID-III scores and brain injury biomarker levels between the two treatment groups. Participants who underwent a palliative (vs. corrective) procedure had lower mean BSID-III cognitive (101±15 vs. 106±14, p=0.03) and motor scores (85±18 vs. 94±16, p

Responsive assessment of disease activity in patients who have rheumatoid arthritis (RA) is necessary to evaluate therapeutic efficacy and guide treatment. We compared the utility of the multibiomarker disease activity (MBDA) score in the assessment of RA disease activity with that of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) score and the Clinical Disease Activity Index (CDAI) in a multicenter, randomized, placebo-controlled trial of repository corticotropin injection (RCI) in patients with persistently active RA.Patients received 80 units of RCI twice weekly during a 12-week open-label period; those who experienced low disease activity at week 12 were randomly assigned to receive either 80 units of RCI or placebo twice weekly during a 12-week double-blind period. Changes in disease activity (measured by DAS28-ESR, CDAI, and MBDA scores) and correlations between MBDA scores and both DAS28-ESR and CDAI scores were assessed.Changes from baseline in DAS28-ESR and CDAI scores suggested that RCI therapy led to clinically meaningful improvements in disease activity, but improvements from baseline in MBDA scores were below the minimally important difference threshold. For the DAS28-ESR and CDAI, correlations with total MBDA and individual component scores were generally low (r ≤ 0.3) and occasionally moderate (r 0.3 but r 0.5).The results of the present study suggest overall MBDA scores are not sufficiently responsive for assessing RA disease activity after RCI therapy. These findings are consistent with those seen with other RA drugs and, although they are from a clinical trial, suggest the MBDA should not be a preferred disease activity measure in clinical practice.

To determine the optimal combination of imaging and biochemical biomarkers for use in the prediction of knee osteoarthritis (OA) progression.The present study was a nested case-control trial from the Foundation of the National Institutes of Health OA Biomarkers Consortium that assessed study participants with a Kellgren/Lawrence grade of 1-3 who had complete biomarker data available (n = 539 to 550). Cases were participants' knees that had radiographic and pain progression between 24 and 48 months compared to baseline. Radiographic progression only was assessed in secondary analyses. Biomarkers (baseline and 24-month changes) that had a P value of0.10 in univariate analysis were selected, including quantitative cartilage thickness and volume on magnetic resonance imaging (MRI), semiquantitative MRI markers, bone shape and area, quantitative meniscal volume, radiographic progression (trabecular bone texture [TBT]), and serum and/or urine biochemical markers. Multivariable logistic regression models were built using 3 different stepwise selection methods (complex models versus parsimonious models).Among baseline biomarkers, the number of locations affected by osteophytes (semiquantitative), quantitative central medial femoral and central lateral femoral cartilage thickness, patellar bone shape, and semiquantitative Hoffa-synovitis predicted OA progression in most models (C statistic 0.641-0.671). In most models, 24-month changes in semiquantitative MRI markers (effusion-synovitis, meniscal morphologic changes, and cartilage damage), quantitative central medial femoral cartilage thickness, quantitative medial tibial cartilage volume, quantitative lateral patellofemoral bone area, horizontal TBT (intercept term), and urine N-telopeptide of type I collagen predicted OA progression (C statistic 0.680-0.724). A different combination of imaging and biochemical biomarkers (baseline and 24-month change) predicted radiographic progression only, which had a higher C statistic of 0.716-0.832.The present study highlights the combination of biomarkers with potential prognostic utility in OA disease-modifying trials. Properly qualified, these biomarkers could be used to enrich future trials with participants likely to experience progression of knee OA.

Aims The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. Methods and results We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of ‘T-cell costimulation’ and ‘response to interferon-gamma/positive regulation of interferon-gamma production’ showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. Conclusions We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.

Background: Identifying metastatic melanoma in the sentinel lymph node (SLN) is important because 80% of SLN biopsies are negative and 11% of patients develop complications. The neutrophil-to-lymphocyte ratio (NLR), a biomarker of micrometastatic disease, could improve prediction models for SLN status. We externally validated existing models and developed ‘MelRisk’ prognostic score to better predict SLN metastasis. Methods: The models were externally validated using data from a multicenter cohort study of 1,251 adults. Additionally, we developed and internally validated a new prognostic score `MelRisk’, using candidate predictors derived from the extant literature. Results: The Karakousis model had a C-statistic of 0.58 (95% CI, 0.54–0.62). The Sondak model had a C-statistic of 0.57 (95% CI 0.53–0.61). The MIA model had a C-statistic of 0.60 (95% CI. 0.56–0.64). Our ‘MelRisk’ model (which used Breslow thickness, ulceration, age, anatomical site, and the NLR) showed an adjusted C-statistic of 0.63 (95% CI, 0.56–0.64). Conclusion: Our prediction tool is freely available in the Google Play Store and Apple App Store, and we invite colleagues to externally validate its performance.

Research question Whether extracellular vesicle-derived lncRNAs could serve as promising circulating biomarkers for endometriosis? Design To obtain novel diagnostic markers, we enrolled 85 patients with endometriosis as the endometriosis group and 86 unaffected participants as the control group. RNA sequencing was performed to identify exosomal long non-coding RNAs (lncRNAs) that are differentially expressed between women with endometriosis (n=5) and unaffected participants (n=6). Messenger RNA and lncRNA sequences of the plasma exosomes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. LncRNA expression levels were further validated using quantitative reverse transcriptase polymerase chain reaction. Moreover, receiver operating characteristic curve analysis was performed to determine the diagnostic value of candidate lncRNAs. Clinical features were correlated to the expression levels of candidate lncRNAs. Results We found that 210 lncRNAs were significantly dysregulated; among these, expression of LINC01569, RP3-399L15.2, FAM138B, and CH507-513H4.6 was significantly decreased, whereas expression of RP11-326N17.2, KLHL7-AS1, and MIR548XHG was increased, in the plasma of patients with endometriosis. Combined expression level of RP3-399L15.2 and CH507-513H4.6 was used to distinguish patients with endometriosis from control participants; the results revealed a sensitivity of 80.00% and specificity of 85.45% at the cutoff point, and an area under the ROC curve of 0.9045. Our findings demonstrated the potential of these two lncRNAs as diagnostic biomarkers for endometriosis. Moreover, CH507-513H4.6 alone may be useful to detect early-stage endometriosis lesions. Conclusions The combination of RP3-399L15.2 and CH507-513H4.6 can be potential candidates for endometriosis biomarkers.

Active lesions in the small bowel (SB) have been independently associated with poorer prognoses in patients with Crohn's disease (CD)1; however, there has been a lack of accurate and convenient screening methods. Past studies have found that serum levels of the glycoprotein leucine-rich α2 glycoprotein (LRG) correlates with endoscopic activity in ulcerative colitis,2,3 and this is now available for routine clinical use as a biomarker in patients with inflammatory bowel disease in Japan. LRG has not yet been thoroughly verified in CD, and we investigated whether it can be used as a serum biomarker for detecting SB mucosal activity in patients with CD.

BACKGROUND: Breast cancer (BC) is one of the most life-threatening cancer types among women. Despite major developments in medical sciences and technologies, the incidence and mortality rates of BC cases are still increasing. One of the reasons for this increase is the absence of an easy to perform early-diagnostic tool. Although there are defined BC biomarkers routinely used for diagnostic and prognostic purposes, none of these biomarkers is useful for early diagnosis. Therefore, early diagnosis of BC remains an important challenge and there is a great need for the early-diagnostic biomarker(s). OBJECTIVE: In this study, we aimed to evaluate the diagnostic and prognostic values of glycerol-3-phosphate dehydrogenase (GPD1) and monoacylglycerol lipase (MAGL) proteins as non-invasive serum biomarkers. METHODS: GPD1 and MAGL serum levels were determined by ELISA for BC patients (n= 100) from five different subtypes, and healthy controls (n= 20), and a comparative analysis was performed to determine statistically significant expression differences among the groups. RESULTS: The results provided evidence that GPD1 acted as a diagnostic biomarker in distinguishing triple-negative breast cancer (TNBC) patients from other subtypes, and MAGL acted as a diagnostic biomarker in distinguishing healthy individuals from BC patients. CONCLUSION: GPD1 and MAGL might be proposed as non-invasive diagnostic biomarkers for BC with high sensitivity and specificity.

Emerging evidence has revealed a relationship between lamin B1 (LMNB1) and several cancers such as cervical cancer, liver cancer, and prostate cancer. But no systematic pan-cancer analysis is available. Little is known about the clinical significance and biomarker utility of LMNB1. In this study, we first revealed the key role of LMNB1 in esophageal carcinoma (ESCA) through weighted gene co-expression network analysis (WGCNA) and disease-free survival (DFS) analysis. Based on this result and the datasets of the cancer genome atlas (TCGA), we explored the biomarker utility of LMNB1 across thirty-three tumors. We found that LMNB1 was highly expressed in most of the cancers and significant associations existed between LMNB1 expression and prognosis of cases of nearly half of the cancers. We also found that LMNB1 expression was associated with the infiltration level of Macrophages M1 and T cells CD4 memory activated in some cancers. Moreover, LMNB1 was mainly involved in the functional mechanisms of MRNA binding, olfactory transduction, and gene silencing. Our study first provides a pan-cancer study of LMNB1, thereby offering a relatively comprehensive understanding of the biomarker utility of LMNB1 across thirty-three tumors.

BACKGROUND: Toll-like receptors participate in various biological mechanisms, mainly including the immune response and inflammatory response. Nevertheless, the role of TLRs in STAD remains unclear. OBJECTIVE: We aimed to explore the expression, prognosis performance of TLRs in STAD and their relationship with immune infiltration. METHODS: Student’s t-test was used to evaluate the expression of TLRs between STAD tissues and normal tissues. Kaplan-Meier method was applied to explored the prognosis value of TLRs in STAD. And qRT-PCR validated their expression and prognosis value. Spearman’s correlation analysis and Wilcoxon rank-sum test were used to assess the association between TLRs and immune infiltration in STAD. RESULTS: The mRNA level of TLR3 was downregulated in STAD. We summarized genetic mutations and CNV alteration of TLRs in STAD cohort. Prognosis analysis revealed that STAD patients with high TLR3 expression showed better prognosis in OS, FP and PPS. The result of qRT-PCR suggested that TLR3 expression was decreased in STAD tissues and STAD patients with high TLR3 mRNA level had a better OS. Univariate and multivariate cox regression analysis suggested TLR3 expression and clinical stage as independent factors affecting STAD patients’ prognosis. A positive association existed between TLR3 expression and the abundance of immune cells and the expression of various immune biomarkers. Furthermore, key targets related to TLR3 were identified in STAD, mainly including MIR-129 (GCAAAAA), PLK1, and V$IRF1_01. CONCLUSIONS: Our result demonstrated TLR3 as a prognosis marker and associated with immune infiltration in STAD.

BACKGROUND: Recent reports indicated the importance of chemotractant CXCL-13 in solid tumors and lymphoid malignancies. However, the prognostic value of the mentioned cytokines as biomarkers in chronic lymphocytic leukemia patient’s remains to be identified. Therefore; this study was designed in order to address the relation between CXCL-13 concentrations levels and markers of severity in CLL patients. METHODS: Our study included 150 CLL patients and 20 controls. Serum CXCL-13 was determined by ELISA for CLL patients at diagnosis as well as controls. RESULTS: The serum CXCL-13 levels were significantly higher in CLL patients as compared to controls. The high CXCL-13 concentration levels was significantly associated with high number of smudge cells; high LDH; high grade of Rai stage, short time to first treatment (TTT). Cox regression analysis was conducted for prediction of TTT, using age, gender, WBCs, smudge cells, CXCL-13, LDH, ZAP70, CD38, β2-microglobulin, Rai staging as covariates. High LDH, CXCL-13 and CD38% were significantly independent predictor for shorter TTT. CONCLUSION: High CXCL-13 serum levels at CLL diagnosis is correlated with other markers of disease activity; and could be served as biomarkers that predict CLL patient’s outcome.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. With the expectation of improved survival, tremendous efforts and resources have been invested in the discovery of specific biomarkers for early detection of the disease. Several investigators have reported the presence of cancer-associated autoantibodies in the plasma or serum of lung cancer patients. Previously, we used a monoclonal antibody (mAb) proteomics technology platform for the discovery of novel lung cancer-associated proteins. OBJECTIVE: The identification of specific protein epitopes associated with various cancers is a promising method in biomarker discovery. Here, in a preliminary study, we aimed to detect autoantibody-leucine-rich alpha-2-glycoprotein 1 (LRG1) immunocomplexes using epitope-specific monoclonal antibodies (mAbs). METHODS: We performed sandwich ELISA assays using the LRG1 epitope-specific capture mAbs, Bsi0352 and Bsi0392, and an IgG-specific polyclonal antibody coupled to a reporter system as the detection reagent. We tested the plasma of lung cancer patients and apparently healthy controls. RESULTS: Depending on the epitope specificity of the capture mAb, we were either unable to distinguish the control from LC-groups or showed a higher level of LRG1 and IgG autoantibody containing immunocomplexes in the plasma of non-small cell lung cancer and small cell lung cancer subgroups of lung cancer patients than in the plasma of control subjects. CONCLUSIONS: Our findings underline the importance of protein epitope-specific antibody targeted approaches in biomarker research, as this may increase the accuracy of previously described tests, which will need further validation in large clinical cohorts.

Objectives Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. Methods We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. Results Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. Conclusion Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.

Background: Periprocedural myocardial injury (PMI) is a frequent complication of percutaneous coronary intervention (PCI) associated with poor prognosis. However, no effective method has been found to identify patients at risk of PMI before the procedure. MicroRNA-133a (miR-133a) has been reported as a novel biomarker in various cardiovascular diseases. Herein, it was sought to determine whether circulating miR-133a could predict PMI before the procedure. Methods: Eighty patients with negative preoperative values of cardiac troponin T (cTnT) receiving elective PCI for stable coronary artery disease (CAD) were recruited. Venous serum samples were collected on admission and within 16–24 hours post-PCI for miRNA measurements. PMI was defined as a cTnT value above the 99% upper reference limit (URL) after the procedure. The association between miR-133a and PMI was further assessed. Results: Periprocedural myocardial injury occurred in 48 patients. The circulating level of miR-133a was significantly higher in patients with PMI before and after the procedure (both p < 0.001). Receiver operating characteristic curve analysis of the preoperative miR-133a level revealed an area under the curve (AUC) of 0.891, with a sensitivity of 93.8% and a specificity of 71.9% to predict PMI. Additionally, a decrease was found in fibroblast growth factor receptor 1 (FGFR1) in parallel with an increase in miR-133a levels in patients with PMI. Conclusions: This study demonstrates for the first time that serum miR-133a can be used as a novel biomarker for early identification of stable CAD patients at risk of PMI undergoing elective PCI. The miR-133a-FGFR1 axis may be involved in the pathogenesis of PMI.

BACKGROUND: Effective biomarkers for prediction of recurrence of lung adenocarcinoma cancer (LADC) patients are needed to determine treatment strategies post-surgery to improve outcome. OBJECTIVE: This study evaluates the efficacy of carboxypeptidase E (CPE) mRNA including its splice isoforms, CPE-ΔN, as a biomarker for predicting recurrence in adenocarcinoma patients. METHODS: RNA was extracted from resected tumors from 86 patients with different stages of non-small cell LADC. cDNA was synthesized and qRT-PCR carried out to determine the copy numbers of CPE/CPE-ΔN mRNA. Patients were followed for 7 years post-tumor resection to determine recurrence and death. RESULTS: ROC curve analysis showed the overall AUC for CPE/CPE-ΔN copy number was 0.563 in predicting recurrence and 0.562 in predicting death. Kaplan-Meier survival analysis showed statistical difference (p= 0.018), indicating that patients with high CPE/CPE-ΔN copy numbers had a shorter time of disease-free survival and also shorter time to death (p= 0.035). Subgroup analyses showed that association of disease-free survival time with CPE/CPE-ΔN copy number was stronger among stage I and II LADC patients (p= 0.047). CONCLUSIONS: CPE/CPE-ΔN mRNA is a potentially useful biomarker for predicting recurrence and death in LADC patients, especially in identifying patients at high risk of recurrence at early stages I and II.

Hepatocellular carcinoma (HCC) is a cancer with relatively high mortality, yet little attention has been devoted for related prognostic biomarkers. This study analyzed differential expression of m5C RNA methyltransferase-related genes in normal samples and tumors samples in TCGA-LIHC using Wilcoxon test. K-means consensus clustering analysis was implemented to subdivide samples. Independent prognostic factors were screened by univariate and multivariate Cox regression analyses. KEGG pathway enrichment analysis was performed on the screened independent prognostic factor using GSEA tools. qPCR was conducted to test mRNA expression of key m5C RNA methyltransferase-related genes in tissues and cells. There were 7 m5C RNA methyltransferase-related genes (NOP2, NSUN4, etc.) differentially expressed in HCC tumor tissues. HCC samples were classified into 3 subgroups through clustering analysis according to the expression mode of m5C RNA methyltransferase-related genes. It was also discovered that patients in different subgroups presented significant differences in survival rate and distribution of grade. Additionally, NOP2, NSUN4 and NSUN5 expression notable varied in different grades. Through regression analyses combined with various clinical pathological factors, it was displayed that NSUN4 could work as an independent prognostic factor. KEGG analysis showed that NSUN4 mainly enriched in signaling pathways involved in ADHERENS JUNCTION, RNA DEGRADATION, MTOR SIGNALING PATHWAY, COMPLEMENT and COAGULATION CASCADES. As examined by qPCR, NSUN4 was conspicuously upregulated in HCC patient’s tissues and cells. Altogether, our study preliminarily developed a novel biomarker that could be independently used in prognosis of HCC, which may provide a new direction for the study of related molecular mechanism or treatment regimen.

Bipolar androgen therapy (BAT) is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively identified patients with mCRPC that achieved deep PSA responses to BAT. All patients with available next-generation molecular sequencing harbored pathogenic mutations in TP53 and/or a homologous recombination DNA repair gene. BACKGROUND: Bipolar androgen therapy (BAT) is an emerging treatment strategy for men with metastatic castration resistant prostate cancer (mCRPC) whereby serum testosterone is cycled from supraphysiologic to near-castrate levels each month. BAT has been shown to induce clinical responses in a significant proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of patients with mCRPC who achieved deep responses to BAT. METHODS: We conducted a retrospective analysis of patients with mCRPC treated with BAT at Johns Hopkins. We identified 22 of 114 (19%) patients with mCRPC who achieved ≥70% PSA reductions upon treatment with BAT. All patients were treated using 400 mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Clinical-grade DNA sequencing was obtained using commercially available assays. RESULTS: Somatic next-generation sequencing was obtained for 15 of 22 (68%) patients. Of these 15 extreme PSA responders with sequencing data available, All 15 of 15 (100%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among the subset of patients with measureable disease (N = 15), 10 patients (67%) achieved an objective response including one patient with a complete response. The median radiographic progression-free survival of these deep PSA responders was 11.3 months (95% CI, 7.9–25.0 months). CONCLUSIONS: We observed an enrichment of TP53 and HRD mutations in mCRPC patients with extreme PSA responses to BAT, with durability lasting about a year. These data support the hypothesis that BAT may most benefit patients with DNA repair-deficient mCRPC. Further studies of BAT in biomarker-selected mCRPC populations (ie, TP53/HRD-mutated) are warranted.

Aims: Given the reversibility of methylation, biomarkers with discriminating ability are of great interest for targeted therapeutic sites. Materials & methods: Methylation array data of 461 lung adenocarcinoma (LUAD) patients comprising of 458 tumor and 32 LUAD paracancerous samples were compared using partial least squares discrimination analysis and receiver operating characteristics analysis. Results: A six-DNA methylation signature (corresponding to five genes) was found to significantly discriminate normal and LUAD samples. Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of methylation sites in the Wnt pathway in LUAD compared with controls. Conclusion: This six-DNA methylation signature demonstrated potential as a novel biomarker for diagnosis and therapeutic targets. Further, inhibition of Wnt signaling pathway may be an important step in LUAD progression.

Background Inappropriate and excessive activation of type I interferon (IFN) system is a key feature of systemic lupus erythematosus (SLE), and its targeting has led to important achievements in the development of novel drugs for SLE. Aim of the work To evaluate the serum levels of interferon lambda IFNλ3 (IL28B) in Egyptian patients with SLE and investigate its potential relation with different clinical and laboratory parameters. Patients and methods The study included 40 SLE patients and 40 controls. The SLE disease activity index (SLEDAI) was assessed. The measurement of serum levels of IFNλ3 was performed in all participants using enzyme linked immunosorbent assay (ELISA). Results The mean age of the patients was 26.8 ± 7.8 years with disease duration 5.1 ± 4.5 years and they were 35 females and 5 males. The serum levels of IFNλ3 were significantly higher in SLE patients (9.7 ± 12.47 pg/mL) compared to the control (5.13 ± 1.63 pg/mL)(p = 0.02). Significant correlations were observed between serum IFNλ3 and serositis (r = 0.35,p = 0.03), C3 consumption (r −0.33, p = 0.04) and SLEDAI (r 0.34, p = 0.03). On multivariate regression analysis, serositis and SLEDAI (but not C3) were significant independent predictors of IFNλ3 levels (β = 0.08, p = 0.037 and β = 0.06, p = 0.014 respectively). Conclusion The results support a possible role of IFNλ3/IL28B in the immunopathogenesis of SLE. The significant association of serum IFNλ3 with disease activity highlights the utility of IFNλ3 as a novel biomarker for monitoring disease activity and predicting severity in SLE. Further studies on IFNλ3 in SLE could be promising in the development of personalized therapy for lupus patients.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.

As the most common cause of dementia, the study of Alzheimer’s disease (AD) faces challenges in terms of understanding the cause, monitoring the pathogenesis, and developing early diagnosis and effective treatment. Rapid and accurate identification of AD biomarkers in the brain is critical to provide key insights into AD and facilitate the development of early diagnosis methods. In this work, we developed a platform that enables a rapid screening of AD biomarkers by employing graphene-assisted Raman spectroscopy and machine learning interpretation in AD transgenic animal brains. Specifically, we collected Raman spectra on slices of mouse brains with and without AD and used machine learning to classify AD and non-AD spectra. By contacting monolayer graphene with the brain slices, the accuracy was significantly increased from 77% to 98% in machine learning classification. Further, using linear supporting vector machine (SVM), we identified a spectral feature importance map that reveals the importance of each Raman wavenumber in classifying AD and non-AD spectra. Based on this spectral feature importance map, we identified AD biomarkers including Aβ and tau proteins, and other potential biomarkers, such as triolein, phosphatidylcholine, and actin, which have been confirmed by other biochemical studies. Our Raman-machine learning integrated method with interpretability is promising to greatly accelerate the study of AD and can be extended to other tissues, biofluids, and for various other diseases.

Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.

In the past decade, there has been an increasing awareness that traumatic brain injury (TBI) and concussion substantially increase the risk for developing psychiatric disorders. Even mild TBI increases the risk for depression and anxiety disorders such as posttraumatic stress disorder by two- to threefold, predisposing patients to further functional impairment. This strong epidemiological link supports examination of potential mechanisms driving neuropsychiatric symptom development after TBI. One potential mechanism for increased neuropsychiatric symptoms after TBI is via inflammatory processes, as central nervous system inflammation can last years after initial injury. There is emerging preliminary evidence that TBI patients with posttraumatic stress disorder or depression exhibit increased central and peripheral inflammatory markers compared with TBI patients without these comorbidities. Growing evidence has demonstrated that immune signaling in animals plays an integral role in depressive- and anxiety-like behaviors after severe stress or brain injury. In this review, we will 1) discuss current evidence for chronic inflammation after TBI in the development of neuropsychiatric symptoms, 2) highlight potential microglial activation and cytokine signaling contributions, and 3) discuss potential promise and pitfalls for immune-targeted interventions and biomarker strategies to identify and treat TBI patients with immune-related neuropsychiatric symptoms.

Background Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. Methods All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. Results Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4–9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. Conclusions Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.

Background Non-invasive clinical algorithms for the detection of liver fibrosis (LF) can reduce the need for liver biopsy (LB). We explored the implementation of two serum biomarkers, enhanced liver fibrosis (ELF) and Mac-2 binding protein glycosylation isomer (M2BPGi), in clinical algorithms for LF in chronic hepatitis B (CHB) patients. Methods Two clinical algorithms were applied to 152 CHB patients: (1) transient elastography (TE) followed by biomarkers (TE/ELF and TE/M2GPGi); (2) biomarker test followed by TE (ELF/TE and M2BPGi/TE). Using the cut-off value or index for the detection of advanced LF (TE≥F3; 9.8 in ELF and 3.0 in M2BPGi), LB was expected to be performed in cases with discordant TE and biomarker results. Results In both algorithms, the expected number of LBs was lower when using M2BPGi than when using ELF (TE/ELF or ELF/TE, 13.2% [N=20]; TE/M2BPGi or M2BPGi/TE, 9.9% [N=15]), although there was no statistical difference (P=0.398). In the TE low-risk group (TE≤F2), the discordance rate was significantly lower in the TE/M2BPGi approach than in the TE/ELF approach (1.5% [2/136] vs. 11.0% [15/136], P=0.002). In the biomarker low-risk group, there was no significant difference between the ELF/TE and M2BPGi/TE approaches (3.9% [5/126] vs. 8.8% [13/147], P=0.118). Conclusions Both ELF and M2BPGi can be implemented in non-invasive clinical algorithms for assessing LF in CHB patients. Given the lowest possibility of losing advanced LF cases in the low-risk group when using the TE/M2BPGi approach, this combination seems useful in clinical practice.

Research question: Do women with laparoscopically confirmed endometriosis have higher plasma concentrations of circulating cell-free DNA (cirDNA) than those without endometriosis? Design: This prospective study recruited women aged 18-45 years undergoing benign gynaecological laparoscopy at two tertiary hospitals. Venous blood was collected immediately prior to surgery, and women were allocated to the endometriosis or control groups based on surgical findings. Total plasma cirDNA and cirDNA integrity were measured by qPCR targeting short (115 bases) and long (247 bases) ALU segments, while endometrial-derived cirDNA was measured by qPCR of bisulfite treated cirDNA using primers selective for a FAM101A sequence uniquely unmethylated in endometrial tissue. Five cirDNA parameters were compared between the control and endometriosis cohorts: total cirDNA concentration, long-stranded cirDNA concentration, integrity ratio, endometrial cirDNA concentration and endometrial cirDNA proportion. Results: Twenty-eight endometriosis and 15 control samples were included in analysis. Women with and without endometriosis had cirDNA concentrations of 2.24 ± 0.89 ng/mL and 2.56 ± 0.92 ng/mL respectively. Analysis by phenotype of endometriosis revealed a significantly higher endometrial cirDNA concentration in women with superficial disease (n = 10) compared to deep endometriosis (n = 18) (mean difference 0.14 ng/mL; 95% confidence interval 0.15-0.26; p = 0.025), but not compared to controls. Conclusions: There were no significant differences in any of the cirDNA parameters between women with and without endometriosis. The low statistical power and heterogenous pelvic pathology in the control group render it difficult to determine whether the negative results demonstrated in this study reflect a true lack of increase in cirDNA in endometriosis.

Considerable advancements have been made in the quantification of biofluid-based biomarkers for traumatic brain injury (TBI), which provide a clinically accessible window to investigate disease mechanisms and progression. Methods with improved analytical sensitivity compared with standard immunoassays are increasingly used, and blood tests are being used in the diagnosis, monitoring, and outcome prediction of TBI. Most work to date has focused on acute TBI diagnostics, while the literature on biomarkers for long-term sequelae is relatively scarce. In this review, we give an update on the latest developments in biofluid-based biomarker research in TBI and discuss how acute and prolonged biomarker changes can be used to detect and quantify brain injury and predict clinical outcome and neuropsychiatric sequelae.

Circulating tumour cells (CTCs) are cancer cells released by cancer into the peripheral circulation. Haematogenous tumour spread is a hallmark of metastatic malignancy and a key factor in cancer recurrence and prognosis. CTCs have diagnostic and prognostic significance for a number of adenocarcinomas and melanoma. A review of the published peer-reviewed literature was performed to determine the clinical relevance of CTCs as a biomarker in the management of oral squamous cell carcinoma (OSCC). Fourteen studies met the eligibility criteria. With regard to patients with OSCC, this review found the following: (1) CTCs have been detected using multiple techniques; (2) the presence of CTCs does not appear to be related to tumour differentiation or size; (3) CTCs may be detected without lymph node involvement; (4) the detection of CTCs may be prognostic for both disease-free survival and overall survival; (5) quantification of CTCs may reflect the efficacy of therapy; (6) CTCs may be of value for ongoing patient monitoring. Preliminary evidence suggests that CTCs have diagnostic and prognostic potential as a biomarker for oral cancer management and warrant further investigation to determine their appropriate place in the management of OSCC patients.

Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability.All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients.The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P.001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve,0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices.The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

Background Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED. Methods This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses. Results Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P Conclusions NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

Purpose Cardiac myxoma (CM), the most common cardiac tumor in adults, accounts for 50–75% of benign cardiac tumors. The diagnosis of CM is often elusive, especially in young stroke survivors and transthoracic echocardiography (TTE) is the initial technique for the differential diagnostics of CM. Less invasive cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are not available for the majority of cardiac patients. Here, a robust imaging approach, ortho-Positronium (o-Ps) imaging, is presented to determine cardiac myxoma extracted from patients undergoing urgent cardiac surgery due to unexpected atrial masses. We aimed to assess if the o-Ps atom, produced copiously in intramolecular voids during the PET imaging, serves as a biomarker for CM diagnosing. Methods Six perioperative CM and normal (adipose) tissue samples from patients, with primary diagnosis confirmed by the histopathology examination, were examined using positron annihilation lifetime spectroscopy (PALS) and micro-CT. Additionally, cell cultures and confocal microscopy techniques were used to picture cell morphology and origin. Results We observed significant shortening in the mean o-Ps lifetime in tumor with compare to normal tissues: an average value of 1.92(02) ns and 2.72(05) ns for CM and the adipose tissue, respectively. Microscopic differences between tumor samples, confirmed in histopathology examination and micro-CT, did not influenced the major positronium imaging results. Conclusions Our findings, combined with o-Ps lifetime analysis, revealed the novel emerging positronium imaging marker (o-PS) for cardiovascular imaging. This method opens the new perspective to facilitate the quantitative in vivo assessment of intracardiac masses on a molecular (nanoscale) level.

Objectives: Fetal growth restriction is associated with chronic fetal hypoxia, poor perinatal outcome and increased perinatal mortality. There are no reliable methods to detect cell damage in the central nervous system (CNS) in these patients. The findings of increased an acidic calcium-binding protein (S100B) concentration in biological fluids of infants after brain injury have supported the use of S100B as a biochemical marker of CNS damage. The purpose of the study was to assess blood S100B concentrations in small for gestational age (SGA) and appropriate for gestational age (AGA) newborns and to evaluate the usefulness of S100B for early detection of hypoxia. Material and methods: The investigation was carried out between November 2011 and April 2014. Serum S100B protein level was assessed in cord blood collected from newborns after birth. Medical records of mothers of neonates studied were reviewed for pregnancy induced hypertension (PIH), preeclampsia, maternal smoking during pregnancy and abnormalities in umbilical artery (UA) Doppler ultrasound examination. Results: The study was carried out in 88 SGA neonates and 80 AGA neonates. The median value of S100B protein concentration in the SGA study group was significantly higher than in AGA controls (p < 0.001). Cord blood serum S100B concentration in SGA neonates with prenatal normal UA Doppler ultrasound findings (n = 32) did not differ from that SGA neonates with abnormal prenatal UA Doppler findings (n = 25) (p = 0.74), but was significantly higher than in AGA newborns (p < 0.001). Conclusions : Elevated S100B protein levels in cord blood collected from SGA newborns may be helpful in detecting infants at higher risk of postnatal neurologic disturbances at an early stage.

Neurodegenerative processes in the brain are reflected by structural retinal changes. As a possible biomarker of cognitive state in prodromal α-synucleinopathies, we compared melanopsin-mediated post-illumination pupil response (PIPR) with cognition (CERAD-plus) in 69 patients with isolated REM-sleep behavior disorder. PIPR was significantly correlated with cognitive domains, especially executive functioning (r = 0.417, p

BACKGROUND: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat.OBJECTIVES: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort.METHODS: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors.RESULTS: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned.CONCLUSIONS: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.

Background: Colorectal cancer (CRC) is an important global burden, and the discovery of biomarkers for screening and monitoring is a current challenge. The present study aimed to determine the serum concentration of ROBO4 and CLEC14A in CRC patients and assess the clinical value of these diagnostic and progression biomarkers in CRC.Methods: Serum samples were collected from 32 patients with operable colorectal cancer and from 16 healthy individuals. Blood serum of CRC patients were tested at two time points (before and after surgery). Serum concentration of ROBO4 and CLEC14A were measured using ELISA tests.Results: The serum concentrations of ROBO4 and CLEC14A were significantly higher in CRC patients than non-cancer controls; the concentrations were already higher in TNM stage I + II CRC patients. The sensitivitiy and specificity of ROBO4 and CLEC14A in distiguishing cancer patients form controls ranged from 71.9–100% and from 84.5–100%, respectively. The serum ROBO4 concentration was associated with the TNM stage, depth of invasion, and lymph node and distant metastases. No significant relationship was observed between the CLEC14A concentration and the tumor site or the N and M stages. The level of ROBO4 was statistically lower 3 months after the surgery, compared to the level noted prior to the operation. The concentration of CLEC14A decreased in the postoperative period, compared to preoperative one; however, the decline was not statistically significant.Conclusion: Our preliminary study has provided evidence that ROOB4 and CLEC14A seem to be suitable biomarkers for clinical diagnostic purposes. However, ROOB4 appears to be more appropriate for assessment of CRC progression.

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

Immune effector cell (IEC) therapies have revolutionized our approach to relapsed B-cell malignancies, and interest in the investigational use of IECs is rapidly expanding into other diseases. Current challenges in the analysis of IEC therapies include small sample sizes, limited access to clinical trials and a paucity of predictive biomarkers of efficacy and toxicity associated with IEC therapies. Retrospective and prospective multi-center cell therapy trials can assist in overcoming these barriers through harmonization of clinical endpoints and correlative assays for immune monitoring, allowing additional cross-trial analysis to identify biomarkers of failure and success. The Consortium for Pediatric Cellular Immunotherapy (CPCI) offers a unique platform to address the aforementioned challenges by delivering cutting-edge cell and gene therapies for children through multi-center clinical trials. Here the authors discuss some of the important pre-analytic variables, such as biospecimen collection and initial processing procedures, that affect biomarker assays commonly used in IEC trials across participating CPCI sites. The authors review the recent literature and provide data to support recommendations for alignment and standardization of practices that can affect flow cytometry assays measuring immune effector function as well as interpretation of cytokine/chemokine data. The authors also identify critical gaps that often make parallel comparisons between trials difficult or impossible.

Background Immune checkpoint inhibitors (ICIs) have shown numerous clinical benefits in multiple cancer types, but good predictive biomarkers are severely lacking. Although increasing evidence has linked Hedgehog (Hh) signaling pathway with tumor development, a systematic investigation for its potential as a biomarker remains elusive. Methods We collected and analyzed the transcriptional data and clinical outcomes of diverse cancers from the Cancer Genome Atlas and four published ICI datasets. Hh activity was estimated by conducting a single‐sample gene‐set enrichment analysis (ssGSEA) for the Hh‐related genes and calculating the ssGSEA score in each tumor sample. Results Our findings suggest that tumors with high Hh activity displayed multiple immunosuppressive characteristics, including lack of anti‐tumor response pathways, downregulation of immune effectors, enrichment of immunosuppressive cells and chemokines, and activation of immunosuppressive signaling. Notably, patients in the non‐response group had enriched Hh activity and showed worse overall survival (OS; pooled HR = 1.50, 95% CI = 1.02–2.21, p = 0.039). In the subgroup of high programmed cell death ligand 1 (PD‐L1) expression, patients who harbored high Hh activity displayed a dramatically lower response rate to ICIs and a strikingly worse OS (pooled HR = 2.89, 95% CI = 1.53–5.49, p

Bladder cancer is the most common malignant tumours with high morbidity, mortality and recurrence. However, currently developed detection methods for bladder cancer-associated urine biomarkers are hindered by their extremely low abundance. Hence, the exploration of a highly sensitive and selective approach for the detection of trace bladder cancer-associated biomarkers in human urine is of vital importance for the diagnosis of bladder cancer. Herein, we developed a highly reliable indium gallium zinc oxide field effect transistor (IGZO FET) biosensor for the detection of bladder cancer-related biomarker microRNA. The single-stranded DNA-functionalized IGZO FET biosensors exhibit high sensing reproducibility and stability with an ultralow detection limit of 19.8 amol/L. The device could also be used for quantitative detection of trace microRNA in human urine samples and can effectively distinguish bladder cancer patients from healthy donors. The development of high performance IGZO FET biosensors presents new opportunities for the achievement of early-stage diagnosis of bladder cancer.

As a biomarker for liver disease, bilirubin has been utilized in prognostic scoring systems for cirrhosis. While laboratory-based methods are used to determine bilirubin levels in clinical settings, they do not readily lend themselves to applications outside of hospitals. Consequently, bilirubin monitoring for cirrhotic patients is often performed only intermittently; thus, episodes requiring clinical interventions could be missed. This work investigates the feasibility of measuring bilirubin concentration in whole porcine blood samples using dual-wavelength transmission measurement. A compact and low-cost dual-wavelength transmission measurement setup is developed and optimized to measure whole blood bilirubin concentrations. Using small volumes of whole porcine blood (72 µL), we measured the bilirubin concentration within a range corresponding to healthy individuals and cirrhotic patients (1.2-30 mg/dL). We demonstrate that bilirubin levels can be estimated with a positive correlation (R-square0.95) and an accuracy of ±1.7 mg/dL, with higher reliability in cirrhotic bilirubin concentrations (4 mg/dL) - critical for high-risk patients. The optical and electronic components utilized are economical and can be readily integrated into a miniature, low-cost, and user-friendly system. This could provide a pathway for point-of-care monitoring of blood bilirubin outside of medical facilities (e.g., patient's home).

To investigate the prognostic value of dual-energy CT (DECT) based radiomics to predict disease-free survival (DFS) and overall survival (OS) for patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC).From January 2014 to December 2018, a total of 156 AGC patients were enrolled and randomly allocated into a training cohort and a testing cohort at a ratio of 2:1. Volume of interest of primary tumor was delineated on eight image series. Four feature sets derived from pre-NAC and delta radiomics were generated for each survival arm. Random survival forest was used for generating the optimal radiomics signature (RS). Statistical metrics for model evaluation included Harrell's concordance index (C-index) and the average cumulative/dynamic AUC throughout follow-up. A clinical model and a combined Rad-clinical model were built for comparison.The pre-IU (derived from iodine uptake images before NAC) RS performed best for DFS and OS in the testing cohort (C-indices, 0.784 and 0.698; the average cumulative/dynamic AUCs, 0.80 and 0.77). When compared with the clinical model, the radiomics model had significantly higher C-index to predict DFS in the testing cohort (0.784 vs. 0.635, p 0.001), but no statistical difference was found for OS (0.698 vs. 0.680, p = 0.473). The combined Rad-clinical models showed improved performance in the testing cohort, with C-indices of 0.810 and 0.710 for DFS and OS, respectively.DECT-derived radiomics serves as a promising non-invasive biomarker to predict survival for AGC patients after NAC, providing an opportunity for transforming proper treatment.