Search For Potential Biomarkers Research Articles

The vaginal metabolomics profile with features of polycystic ovary syndrome: a pilot investigation in China.

Polycystic ovary syndrome (PCOS) is the most common metabolic disorder and reproductive endocrine disease, posing an elevated risk to women of reproductive age. Although metabolism differences in serum, amniotic fluid and urine have been documented in PCOS, there remains a paucity of evidence for vaginal fluid. This study aimed to identify the metabolic characteristics and potential biomarkers of PCOS in Chinese women of reproductive age. We involved ten newly diagnosed PCOS women who attended gynecology at Zhongda Hospital and matched them with ten healthy controls who conducted health check-up programs at Gulou Maternal and Child Health Center in Nanjing, China from January 1st, 2019 to July 31st, 2020. Non-targeted metabolomics based on ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) was applied to differentially screen vaginal metabolites between PCOS group and healthy controls. Principal component analysis (PCA), orthogonal partial least-squares discriminant analysis (OPLS-DA) and enrichment analysis were used to observe differences, search for potential biomarkers and enrich related pathways. Among the 20 participants, a total of 195 different metabolites were detected between PCOS group and healthy control group. PCOS and control groups were effectively separated by vaginal fluid. Lipids and lipid-like molecules constituted the majority of differential metabolites. Notably, dopamine exhibited an increased trend in PCOS group and emerged as the most significant differential metabolite, suggesting its potential as a biomarker for identifying PCOS. The application of UHPLC-MS/MS based vaginal metabolomics methods showed significant differences between PCOS and non-PCOS healthy control groups, especially linoleic acid metabolism disorder. Most differential metabolites were enriched in pathways associated with linoleic acid metabolism, phenylalanine metabolism, tyrosine metabolism, nicotinate and nicotinamide metabolism or arachidonic acid metabolism. In this pilot investigation, significant metabolomics differences could be obtained between PCOS and healthy control groups. For PCOS women of reproductive age, vaginal metabolism is a more economical, convenient and harmless alternative to provide careful personalized health diagnosis and potential targets for therapeutic intervention.

Histone-modifying enzymes and gastric cancer: Search for potential biomarkers and therapeutic targets based on Mendelian randomization

Gastric cancer, a common and severe malignancy, is associated with unfavorable outcomes and limited therapeutic options. The exploration of the potential link between plasma histone-modifying enzymes and gastric cancer through Mendelian randomization (MR) analysis offers an opportunity to identify new therapeutic targets and biomarkers. In this study, data on plasma histone-modifying enzymes were obtained from the International Working Unit Open genome-wide association studies project, and summary statistics of gastric cancer from the FinnGen study were analyzed. Forward and inverse MR were performed to determine the causal relationship between plasma histone-modifying enzymes and gastric cancer. The principal methodology for MR is the inverse variance weighted (IVW) method. Additionally, a sensitivity analysis was performed to determine the robustness of the findings. Finally, bioinformatics was used for the preliminary functional analysis. Our forward MR analysis revealed that the plasma Set1/Ash2 histone methyltransferase complex subunit ASH2 (ASH2L) was positively associated with gastric cancer risk, and the histone-lysine N-methyltransferase SETMAR (SETMAR) was negatively associated. Inverse MR analysis revealed that gastric cancer incidence was negatively correlated with the expression of plasma histone acetyltransferase KAT6A (KAT6A). These findings were consistent across different statistical methods and were deemed unlikely to have been distorted by horizontal pleiotropy. Furthermore, bioinformatics analysis indicated that ASH2L, SETMAR, and KAT6A are differentially expressed in various tumors and are significantly correlated with both the prognosis of gastric cancer and the infiltration of various immune cells. Thus, plasma histone-modifying enzymes may be causally linked to gastric cancer, and ASH2L, SETMAR, and KAT6A could play crucial roles as biomarkers and therapeutic targets in managing gastric cancer.

Disulfideptosis-associated lncRNAs reveal features of prognostic, immune escape, tumor mutation, and tumor malignant progression in renal clear cell carcinoma.

Investigating the role of lncRNAs associated with the latest cell death mode (Disulfideptosis) in renal clear cell carcinoma, as well as their correlation with tumor prognosis, immune escape, immune checkpoints, tumor mutational burden, and malignant tumor progression. Searching for potential biomarkers and targets for renal clear cell carcinoma. Downloaded the expression profile data and clinical data of 533 cases of renal clear cell carcinoma from the TCGA database, and randomly divided them into a test set (267 cases) and a validation set (266 cases). Based on previous research, 13 genes associated with Disulfideptosis were obtained. Using R software, lncRNAs with a differential expression that is related to the prognosis of renal clear cell carcinoma and associated with Disulfideptosis were screened out. After univariate Cox regression analysis, Lasso regression analysis, and multivariate Cox regression analysis, lncRNAs with independent predictive ability were obtained. A predictive risk model was established based on the risk scores. Verification was carried out between the obtained high-risk and low-risk groups and their subgroups (including Age, Gender, tumor mutational burden (TMB), tumor grading, and staging). Subsequently, a nomogram was established, and a calibration curve was generated for verification. Performed GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) functional enrichment analyses. Downloaded the values of Tumor Immune Dysfunction and Exclusion (TIDE) for all samples and calculated the difference between the high and low-risk groups. Selected human renal tumor cell lines (786-O, OS-RC-2, A-498, ACHN) and human renal cortex proximal tubule epithelial cell line (HK-2). The RNA expression levels of the above lncRNAs in each cell line were analyzed using RT-qPCR (Real-time Quantitative PCR Detecting System). Used siRNA (small interfering RNA) to knock down FAM225B in 786-O and OS-RC-2 cell lines, and then performed in vitro cell experiments to validate the functional characteristics of FAM225B. Our constructed predictive model includes 5 lncRNAs with an independent predictive ability (FAM225B, ZNF503-AS1, SPINT1-AS1, WWC2-AS2, LINC01338), which can effectively distinguish between patients in high and low-risk groups and their subgroups. The 1, 3, and 5-year AUC (Area Under the ROC Curve) values of the established nomogram are 0.756, 0.752, and 0.781, respectively. The 5-year AUC value is higher compared to other clinical characteristics (Age: 0.598, Gender: 0.488, Grade: 0.680, Stage: 0.717). After the knockdown of FAM225B, the proliferation, migration, and invasion abilities of renal cancer cell lines OS-RC-2 and 786-O all decreased. We have constructed and validated a prognostic model based on Disulfideptosis-associated lncRNAs. This model can effectively predict the high or low risk of patient prognosis and can distinguish the tumor cell mutational burden and immune escape capabilities among high-risk and low-risk patients. This predictive model can serve as an independent prognostic factor for renal clear cell carcinoma, providing a new direction for personalized treatment of patients with renal clear cell carcinoma.

Heat Shock Proteins (HSPs) and Cardiovascular Complications of Obesity: Searching for Potential Biomarkers.

Heat shock proteins (HSPs), a family of proteins that support cellular proteostasis and perform a protective function under various stress conditions, such as high temperature, intoxication, inflammation, or tissue hypoxia, constitute a promising group of possible biochemical markers for obesity and cardiovascular diseases. HSP27 is involved in essential cellular processes occurring in conditions of obesity and its cardiometabolic complications; it has protective properties, and its secretion may indicate a cellular response to stress. HSP40 plays a controversial role in the pathogenesis of obesity. HSP60 is involved in various pathological processes of the cardiovascular, immune, excretory, and nervous systems and is associated with obesity and concomitant diseases. The hypersecretion of HSP60 is associated with poor prognosis; hence, this protein may become a target for further research on obesity and its cardiovascular complications. According to most studies, intracellular HSP70 is an obesity-promoting factor, whereas extracellular HSP70 exhibited inconsistent dynamics across different patient groups and diagnoses. HSPs are involved in the pathogenesis of cardiovascular pathology. However, in the context of cardiovascular and metabolic pathology, these proteins require further investigation.

NO BIOMARKER: TRANSMISSION AND EMISSION METHODS FOR ITS POTENTIAL DETECTION IN EXOPLANET ATMOSPHERES WITH SPEKTR-UF (WSO-UV)

Among all habitability factors for terrestrial exoplanets, one of the most important is the presence of a secondary N2–O2 dominant atmosphere in an exoplanet. This factor can potentially indicate the already existing geological and biological processes on the exoplanet. Meanwhile, direct characterization of the N2–O2 atmospheres of terrestrial exoplanets is a difficult observational task. There are only a few indicators (molecules) of such an atmosphere, among which one can single out a potential biomarker – a molecule of nitric oxide NO. The strongest spectral features of this molecule in the ultraviolet range are γ-bands (203–248 nm). An important role in the search for potential biomarkers on exoplanets, including the registration of NO γ‑bands, can be played by planned for the launch WSO-UV space observatory. In the paper estimates of the possibility of detecting the transmission of light in γ-bands in the atmospheres of exoplanets with this observatory are presented. The methods of emission and transmission spectroscopy are compared as applied to the detection of NO. Based on the results of this work, it is shown that there is a potential possibility of detecting a transmission signal in the NO γ-bands in the atmospheres of nearby exoplanets (10 pc) using the LSS spectrograph of the WSO-UV observatory. At the same time, the imposed restrictions for the registration of this signal on more distant exoplanets are presented.

Analysis of the relationship between the component composition of milk and blood biomarkers of Holsteinized cows

The search for potential biomarkers that signal the state of the physiological status of the organism of highly productive cows, which are taken into account in further selection aimed at increasing the quantity and quality of dairy products, is becoming relevant in many countries engaged in dairy cattle breeding. The study was conducted on the basis of the Ladozhsky breeding plant (Krasnodar Krai) — a branch of the L.K. Ernst Federal State Budgetary Institution. Studies of blood samples were carried out on an automatic biochemical and enzyme immunoassay analyzer «Chem Well». The analysis of the expanded component composition of milk was made on the analyzer «Combi Foss 7» (IFS). Based on the results of the studies, we calculated the relationship between the component composition of milk and blood of cows. For daily milk yield, moderate positive correlations were observed with phospholipids r = 0.364, cholesterol r = 0.324, albumin r = 0.316 and magnesium r = 0.309. Moderate relationship between cholesterol and lactose was r = 0.408 and between cholesterol and SOMO r = 0.307. Direct moderate relationship r = 0.376 between lactose and ALT, r = 0.361 — albumin, r = 0.455 — phospholipids. Moderate direct correlation between trans-isomers and alkaline phosphatase was r = 0.309, chlorine — r = 0.259. Moderate inverse correlations appeared in relation to daily milk yield — erythrocytes r = 0.312. Moderate inverse correlations between transisomers and cholesterol r = -0.385, urea r = -0.428. The relationships of other components of milk and blood, both direct and inverse, turned out to be weak and very weak.

Lymphangioleiomyomatosis: Searching for potential biomarkers.

Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers. We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination. A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465-832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314-546) and 427 (365-513) ng/ml, respectively (p < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 (p = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (-6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%). Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.

Метаболомный профиль сыворотки крови у пациентов с язвенным колитом: патофизиологическая роль, диагностическое и терапевтическое значение

The incidence of inflammatory bowel disease (IBD) in both children and adults is increasing worldwide. While Crohn’s disease predominates in the pediatric population, ulcerative colitis (UC) more often affects the elderly. The relevance of metabolomic profiling in IBD has been confirmed in several studies revealing changes in endogenous and microbial metabolism associated with their pathogenesis. The metabolome composition of body fluids depends significantly on sex since sexual dimorphism is a trigger for metabolic differences between organisms. We have previously studied serum metabolic profiles in male patients with UC and identified candidate biomarkers of the disease. Objective. To determine the features of metabolome composition and candidate metabolite biomarkers of UC in women using a non-targeted serum metabolomic analysis. Patients and methods. This study included 10 women with active UC (moderately severe and severe attacks; a study group) aged 23 to 61 years (mean age: 35.2 ± 13.5 years) and 10 age-matched healthy volunteers (a control group) without IBD. Serum metabolites were analyzed by gas chromatography-mass spectrometry. Sample classification and search for potential biomarkers were performed using a partial least squares-discriminant analysis (PLS-DA), support vector machines (SVM), and a naïve Bayes classifier. ROC curves and areas under correlated curves were used to compare the success of different methods. Results. In serum samples from patients with UC and healthy volunteers, up to 90 low molecular weight compounds with different mass spectra and retention times were identified. The analysis revealed 25 compounds whose concentrations in the blood differed significantly between the study group and the comparison group (p &lt;0.05). Six of the 25 compounds (adipic acid, β-glycerophosphate, glyceric acid, 2-hydroxybutyric acid, squalene, 2-palmitoylglycerol) were among the most significant 15 compounds detected by two classifiers at once (PLS-DA and SVM). Of these 15 compounds, only 7 were identical to the compounds that significantly altered in men: 2-hydroxybutyric acid, creatinine, β-glycerophosphate, α-glycerophosphate, trans-palmitoleic acid, palmitic acid, and squalene. Some of these compounds, just as in men, were associated with lipid metabolism disorders and glycolysis regulation (α-glycerophosphate), as well as with impaired osteogenesis (β-glycerophosphate). Conclusion. Significant differences were found between serum metabolomic profiles in women with UC and healthy volunteers. About half of the most significant compounds detected in the study group were identical to the compounds that were significantly altered in men with UC. In future investigations, the results obtained by non-targeted metabolomics, as well as the exact mechanisms of metabolic changes in UC patients, should be confirmed and clarified using targeted metabolomics and other omics. Key words: inflammatory bowel disease, ulcerative colitis, metabolome, biomarkers, gas chromatography-mass spectrometry

Towards the Search for Potential Biomarkers in Osteosarcoma: State-of-the-Art and Translational Expectations.

Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in children, adolescents and young adults under 20 years of age. It also presents another peak of incidence in people over 50 years of age and is associated with rheumatic diseases. Numerous environmental risk factors, such as bone diseases, genetics and a history of previous neoplasms, have been widely described in the literature, which allows monitoring a certain group of patients. Diagnosis requires numerous imaging tests that make it possible to stratify both the local involvement of the disease and its distant spread, which ominously determines the prognosis. Thanks to various clinical trials, the usefulness of different chemotherapy regimens, radiotherapy and surgical techniques with radical intent has now been demonstrated; these represent improvements in both prognosis and therapeutic approaches. Osteosarcoma patients should be evaluated in reference centres by multidisciplinary committees with extensive experience in proper management. Although numerous genetic and rheumatological diseases and risk factors have been described, the use of serological, genetic or other biomarkers has been limited in clinical practice compared to other neoplasms. This limits both the initial follow-up of these patients and screening in populations at risk. In addition, we cannot forget that the diagnosis is mainly based on the direct biopsy of the lesion and imaging tests, which illustrates the need to study new diagnostic alternatives. Therefore, the purpose of this study is to review the natural history of the disease and describe the main biomarkers, explaining their clinical uses, prognosis and limitations.

Predicting AT(N) pathologies in Alzheimer's disease from blood-based proteomic data using neural networks.

Blood-based biomarkers represent a promising approach to help identify early Alzheimer's disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In the current study, we aim to harness the power of state-of-the-art deep learning neural networks (NNs) to identify plasma proteins that predict amyloid, tau, and neurodegeneration (AT[N]) pathologies in AD. We measured 3,635 proteins using SOMAscan in 881 participants from the European Medical Information Framework for AD Multimodal Biomarker Discovery study (EMIF-AD MBD). Participants underwent measurements of brain amyloid β (Aβ) burden, phosphorylated tau (p-tau) burden, and total tau (t-tau) burden to determine their AT(N) statuses. We ranked proteins by their association with Aβ, p-tau, t-tau, and AT(N), and fed the top 100 proteins along with age and apolipoprotein E (APOE) status into NN classifiers as input features to predict these four outcomes relevant to AD. We compared NN performance of using proteins, age, and APOE genotype with performance of using age and APOE status alone to identify protein panels that optimally improved the prediction over these main risk factors. Proteins that improved the prediction for each outcome were aggregated and nominated for pathway enrichment and protein-protein interaction enrichment analysis. Age and APOE alone predicted Aβ, p-tau, t-tau, and AT(N) burden with area under the curve (AUC) scores of 0.748, 0.662, 0.710, and 0.795. The addition of proteins significantly improved AUCs to 0.782, 0.674, 0.734, and 0.831, respectively. The identified proteins were enriched in five clusters of AD-associated pathways including human immunodeficiency virus 1 infection, p53 signaling pathway, and phosphoinositide-3-kinase-protein kinase B/Akt signaling pathway. Combined with age and APOE genotype, the proteins identified have the potential to serve as blood-based biomarkers for AD and await validation in future studies. While the NNs did not achieve better scores than the support vector machine model used in our previous study, their performances were likely limited by small sample size.

Investigation of poor predictive factors in extensive stage small cell lung cancer under etoposide-platinum-atezolizumab treatment.

The phase III trial IMpower133 showed that platinum and etoposide plus atezolizumab was associated with improved overall survival (OS) and progression free-survival (PFS) when compared to the placebo group in treatment-naïve extensive stage (ES) small cell lung cancer (SCLC). Due to superiority in clinical outcomes, combination immunotherapy plus chemotherapy have become mainstay treatment modalities as first-line treatment in ES-SCLC. Nevertheless, real-world data are still lacking and the search for potential biomarkers is essential. This study aimed to evaluate potential predictive biomarkers applicable in ES-SCLC under combination therapy. Patients with ES-SCLC under etoposide-platinum-atezolizumab enrolled from seven university hospitals affiliated to the Catholic University of Korea were evaluated. Pretreatment clinical parameters were evaluated for association with OS and PFS. Adverse events (AEs) during induction and maintenance phases were also evaluated. p-values below 0.05 were considered statistically significant. A total of 41 patients were evaluated. Six-month survival was 68.6%. As best response to treatment, 26 (63.4%) showed partial response, nine (22.0%) showed stable disease, and four (9.8%) showed progressive disease. During the induction phase, grade I-II AEs occurred in 22 (53.7%) patients, and grade III-IV AEs occurred in 26 (63.4%) patients. During the maintenance phase, nine out of 25 (36.0%) patients experienced any grade AEs. In multivariate analysis for OS, lactate dehydrogenase (LDH), c-reactive protein (CRP), and forced vital capacity (%) were significant factors. In multivariate analysis for PFS, sex, and LDH were significant. In ES-SCLC under etoposide-platinum-atezolizumab, pretreatment CRP, LDH and FVC (%) were independent predictive factors.

Elucidating the Role of Innate and Adaptive Immune Responses in the Pathogenesis of Canine Chronic Inflammatory Enteropathy-A Search for Potential Biomarkers.

Simple SummaryCanine chronic inflammatory enteropathy (CIE) is a chronic disease affecting the small or large intestine and, in some cases, the stomach of dogs. This gastrointestinal disorder is common and is characterized by recurrent vomiting, diarrhea, and weight loss in affected dogs. The pathogenesis of IBD is not completely understood. Similar to human IBD, potential disease factors include genetics, environmental exposures, and dysregulation of the microbiota and the immune response. Some important components of the innate and adaptive immune response involved in CIE pathogenesis have been described. However, the immunopathogenesis of the disease has not been fully elucidated. In this review, we summarized the literature associated with the different cell types and molecules involved in the immunopathogenesis of CIE, with the aim of advancing the search for biomarkers with possible diagnostic, prognostic, or therapeutic utility.Canine chronic inflammatory enteropathy (CIE) is one of the most common chronic gastrointestinal diseases affecting dogs worldwide. Genetic and environmental factors, as well as intestinal microbiota and dysregulated host immune responses, participate in this multifactorial disease. Despite advances explaining the immunological and molecular mechanisms involved in CIE development, the exact pathogenesis is still unknown. This review compiles the latest reports and advances that describe the main molecular and cellular mechanisms of both the innate and adaptive immune responses involved in canine CIE pathogenesis. Future studies should focus research on the characterization of the immunopathogenesis of canine CIE in order to advance the establishment of biomarkers and molecular targets of diagnostic, prognostic, or therapeutic utility.

In-Silico Analysis to Identify Differentially Expressed and Methylated Genes in Esophageal Squamous Cell Carcinoma: Search for Potential Biomarkers

Early detection and diagnosis aided by quality treatment and proper patient care is crucial for reducing the overwhelming cancer burden. Esophageal Squamous Cell Carcinoma (ESCC) is a highly aggressive cancer of esophageal epithelial cells and it is associated with high mortality rates, poor prognosis, differences in patient response to specific treatment modalities, and metastatic potential. Despite various therapeutic interventions, there have not been any remarkable results in parameters like increase in prognosis, and 5-year survival rates. New diagnostic biomarkers specific to the stage and patient response will provide significant therapeutic targets for ESCC. Differential changes in gene expression and aberrant DNA methylation can be used for elucidating biomarkers for early diagnosis, better prognosis, chemoprevention, and personalized therapy. In this study, integrated bioinformatics analysis has been applied to identify differentially expressed and aberrantly methylated genes in ESCC. For insights into molecular mechanisms and pathogenesis of ESCC, notable pathways associated with ESCC were identified.

РОЛЬ ФАКТОРОВ РОСТА ФИБРОБЛАСТОВ 19, 21 И БЕЛКА KLOTHO В РАЗВИТИИ ИНСУЛИНОРЕЗИСТЕНТНОСТИ И ОЖИРЕНИЯ У ДЕТЕЙ

The incidence of obesity in children, especially in younger schoolchildren aged from 7 to 10 years, is progressively increasing in all countries. This has led to interest in the search for potential biomarkers that can identify individuals at risk of developing metabolic disorders and for whom preventive measures can be adapted. Fibroblast growth factors 19 (FGF-19), 21 (FGF-21) and Klotho protein are regulators of energy homeostasis. However, in the pediatric population, the relationship between obesity, metabolic disorders and the aforementioned factors has not been studied in depth. The literature review presents the main mechanisms of action of FGF-19, FGF-21 and the Klotho protein, expanding our understanding of their role in the development of insulin resistance and obesity, and discusses the scientific basis for further research in pediatrics.

Brevican and Neurocan Cleavage Products in the Cerebrospinal Fluid - Differential Occurrence in ALS, Epilepsy and Small Vessel Disease

The neural extracellular matrix (ECM) composition shapes the neuronal microenvironment and undergoes substantial changes upon development and aging, but also due to cerebral pathologies. In search for potential biomarkers, cerebrospinal fluid (CSF) and serum concentrations of brain ECM molecules have been determined recently to assess ECM changes during neurological conditions including Alzheimer’s disease or vascular dementia. Here, we measured the levels of two signature proteoglycans of brain ECM, neurocan and brevican, in the CSF and serum of 96 neurological patients currently understudied regarding ECM alterations: 16 cases with amyotrophic lateral sclerosis (ALS), 26 epilepsy cases, 23 cerebral small vessel disease (CSVD) patients and 31 controls. Analysis of total brevican and neurocan was performed via sandwich Enzyme-linked immunosorbent assays (ELISAs). Major brevican and neurocan cleavage products were measured in the CSF using semiquantitative immunoblotting. Total brevican and neurocan concentrations in serum and CSF did not differ between groups. The 60 kDa brevican fragment resulting from cleavage by the protease ADAMTS-4 was also found unchanged among groups. The presumably intracellularly generated 150 kDa C-terminal neurocan fragment, however, was significantly increased in ALS as compared to all other groups. This group also shows the highest correlation between cleaved and total neurocan in the CSF. Brevican and neurocan levels strongly correlated with each other across all groups, arguing for a joint but yet unknown transport mechanism from the brain parenchyma into CSF. Conclusively our findings suggest an ALS-specific pattern of brain ECM remodeling and may thus contribute to new diagnostic approaches for this disorder.

Emotional Modulation of Frontal Alpha Asymmetry - a Novel Biomarker of Mild Traumatic Brain Injury.

Objective findings of brain injury or dysfunction are typically lacking in mild traumatic brain injury (MTBI) despite prolonged post-concussion symptoms in some patients. Thus, there is a need for objective biomarkers of MTBI that reflect altered brain physiology underlying subjective symptoms. We have previously reported increased attention to threat-related stimuli in subjects with MTBI, suggesting a physiological vulnerability to depression. Vulnerability to depression has been linked with relatively greater activity of the right than left frontal cortex reflected in inverse pattern in frontal alpha with greater power on the left than right. We investigated whether patients with previous MTBI show this pattern of frontal activity reflected in more negative frontal alpha asymmetry (FAA) scores. Furthermore, in search for potential biomarkers of MTBI, we created a novel index, emotional modulation of FAA (eFAA) and investigated whether it correlates with subjective symptoms. EEG was recorded while subjects with previous MTBI and controls performed a computer-based reaction time task integrating different cognitive executive functions and containing either threat-related or emotionally neutral visual stimuli. Post-concussion symptoms and depression were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Beck’s depression inventory (BDI). Task-induced FAA was assessed and eFAA calculated by subtracting FAA in the context of neutral stimuli from FAA in the context of emotional stimuli. The MTBI group showed FAA scores reflecting relatively greater right-sided frontal activity compared to healthy controls. eFAA differentiated the symptomatic MTBI from non-symptomatic MTBI group and from healthy controls. eFAA also correlated with RPQ and BDI scores. In conclusion, FAA pattern previously linked with vulnerability to depression, was observed in patients with previous MTBI. Furthermore, eFAA has potential as a biomarker of altered affective brain functions in MTBI.

The Analysis of Inflammation-Related Proteins in a Cargo of Exosomes Derived from the Serum of Uveal Melanoma Patients Reveals Potential Biomarkers of Disease Progression.

Simple SummaryUveal melanoma (UM) is the most common intraocular tumour in adults with a poor prognosis and extremely high mortality rate due to the development of metastatic disease. Despite good knowledge of the histological and genetic background of metastases formation, there is still a lack of specific biomarkers which would allow early detection of UM progression. Due to their unique molecular cargo consisting of proteins and nucleic acids, exosomes have been widely studied as carriers of biomarkers for cancer development and progression. In this study, we analyzed the inflammation-related protein cargo of exosomes derived from the serum of primary and metastatic UM patients and healthy donors using multiplex immunoassay technology. We showed a significant correlation between the disease stage and the concentration of inflammation-related proteins from exosomal cargo. Based on the obtained results, we propose the panel of exosomal proteins for early detection of uveal melanoma progression into metastatic disease.Background: Uveal melanoma (UM) is the most common intraocular tumour in adults with a poor prognosis and extremely high mortality rate due to the development of metastatic disease. However, despite relatively good knowledge about the histological and genetic risk factors for metastasis development, there is no specific biomarker that would allow early detection of UM progression. Recently, exosomes and their molecular cargo have been widely studied in the search for potential biomarkers in several cancers. The purpose of this study was to analyze the inflammation-related protein cargo of exosomes derived from the serum of primary and metastatic UM patients and healthy donors. Methods: The exosomes were isolated from the serum of primary and metastatic UM patients and healthy donors. Using multiplex immunoassay technology, we analyzed the concentration of 37 inflammation-related proteins in obtained exosomes. Results: The analysis of protein cargo showed several molecules related to inflammation, such as interferon-gamma, interleukin 2, 22 and 12(p40), Pentraxin-3, TNFSF13B and TNFSF8 which were significantly enriched in metastatic UM exosomes. We showed a significant correlation between the disease stage and the concentration of these inflammation-related proteins from exosomal cargo. Conclusions: Based on the obtained results, we propose the panel of exosomal proteins for early detection of uveal melanoma progression into metastatic disease.

Identification of Potential Diagnostic miRNAs Biomarkers for Alzheimer Disease Based on Weighted Gene Coexpression Network Analysis

Alzheimer disease (AD) is an age-related neurodegenerative disease that accounts for nearly three fourths of dementia cases. Searching for potential biomarkers will help clinicians in the early diagnosis and treatment of AD. Firstly, we downloaded detailed AD data from the Gene Expression Omnibus (GEO) database for identification of differentially expressed microribonucleic acids (DEmiRNAs) and differentially expressed messenger ribonucleic acids (DEmRNAs). Secondly, functional enrichment analysis was used to identify the biological functions of DEmRNAs. Thirdly, weighted gene coexpression network analysis was used to identify important modules and hub miRNAs. In addition, the miRNA-mRNA regulatory network was constructed. Fourthly, the GSE120584 dataset was used for electronic expression verification and diagnostic analysis. Finally, real-time polymerase chain reaction invitro verification was performed. We obtained 1005 DEmiRNAs and 97 DEmRNAs, respectively. Functional enrichment found that DEmRNAs was enriched in the N-glycan biosynthesis pathway, which was associated with AD. In the weighted gene coexpression network analysis, we found that the brown module was the optimal module. Moreover, 11 hub miRNAs were identified. A total of 216 negatively regulated miRNA-mRNA regulation effects are involved. Hub miRNAs were found to have potential diagnostic value in the receiver operating characteristic analysis. Eleven hub miRNAs were identified, andDEmRNAs was found to be significantly enriched in the N-glycan biosynthesis pathway, which contributes to the early diagnosis and treatment of AD.

Role of miRNAs in Sigmoid Colon Cancer: A Search for Potential Biomarkers.

Simple SummaryUnderstanding the microRNAs’ role in cancer is challenging, because, in the most cases, the only tissues available are the tumor and its counterpart, the adjacent-to-tumor tissue. Indeed, this scenario could affect our analyses in the cancer field, including to colorectal cancer. Using systematic criteria to select the healthy individuals and sigmoid colon cancer cases, we found that adjacent-to-tumor tissue already has molecular alterations in relation to healthy tissue and to tumor tissue as well. In addition, all miRNAs found showed to be involved in the carcinogenic process, according to the gene enrichment analysis. We suggested that future cancer studies should consider using these three tissues in their analysis, as well as the creation of a database of healthy individuals’ miRNA expression profiles. Using these three tissues, we could better understand the role of adjacent-to-tissue in cancer and other several questions related with clinical aspects.The aberrant expression of microRNAs in known to play a crucial role in carcinogenesis. Here, we evaluated the miRNA expression profile of sigmoid colon cancer (SCC) compared to adjacent-to-tumor (ADJ) and sigmoid colon healthy (SCH) tissues obtained from colon biopsy extracted from Brazilian patients. Comparisons were performed between each group separately, considering as significant p-values < 0.05 and |Log2(Fold-Change)| > 2. We found 20 differentially expressed miRNAs (DEmiRNAs) in all comparisons, two of which were shared between SCC vs. ADJ and SCC vs. SCH. We used miRTarBase, and miRTargetLink to identify target-genes of the differentially expressed miRNAs, and DAVID and REACTOME databases for gene enrichment analysis. We also used TCGA and GTEx databases to build miRNA-gene regulatory networks and check for the reproducibility in our results. As findings, in addition to previously known miRNAs associated with colorectal cancer, we identified three potential novel biomarkers. We showed that the three types of colon tissue could be clearly distinguished using a panel composed by the 20 DEmiRNAs. Additionally, we found enriched pathways related to the carcinogenic process in which miRNA could be involved, indicating that adjacent-to-tumor tissues may be already altered and cannot be considered as healthy tissues. Overall, we expect that these findings may help in the search for biomarkers to prevent cancer progression or, at least, allow its early detection, however, more studies are needed to confirm our results.

Metabolic Pattern of Systemic Sclerosis: Association of Changes in Plasma Concentrations of Amino Acid-Related Compounds With Disease Presentation.

ObjectiveAmino acids (AA) and their derivatives play an integral role in the synthesis of structural and regulatory elements in human organisms and therefore pathologies such as systemic sclerosis that may alter the blood pattern of these compounds. This study aimed to evaluate changes in plasma concentrations of amino acid-related metabolites in systemic sclerosis in a search for potential biomarkers and mechanisms of the disease.MethodsPlasma samples from 42 patients diagnosed with systemic sclerosis (SSc) according to the 2013 American College of Rheumatology and European League Against Rheumatism ACR/EULAR classification criteria were compared to 27 matched healthy controls. Liquid chromatography/mass spectrometry was applied for the analysis of 36 amino acid-related metabolites.ResultsThe analysis of plasma AA metabolite patterns revealed the number of changes including an increase (20%) in concentrations of NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) in SSc vs. healthy subjects. Furthermore, SSc patients had higher glutamine, proline, betaine, 1-methylhistidine, and methylnicotinamide levels, while the concentration of tryptophan was lower. The specific metabolic pattern was identified for several aspects of disease presentation. Most interestingly NOS inhibitor L-NAME was elevated in patients with diffuse systemic sclerosis or telangiectasia.ConclusionsThese results provide further evidence for the involvement of endothelium-dependent pathways in the mechanisms and presentation of SSc. Endothelial dysfunction biomarkers may be useful in the assessment of presentation and prognosis in SSc.