Potential Early Diagnostic Biomarker Research Articles

A novel near-infrared polymethine dye biosensor for rapid and selective detection of lithocholic acid

Lithocholic acid (LCA), a secondary bile acid, has emerged as a potential early diagnostic biomarker for various liver diseases. In this study, we introduce a novel near-infrared (NIR) polymethine dye-based biosensor, capable of sensitive and selective detection of LCA in phosphate buffer and artificial urine (AU) solutions. The detection mechanism relies on the formation of J-aggregates resulting from the interplay of 3,3-Diethylthiatricarbocyanine iodide (DiSC2(7)) dye molecules and LCA, which induces a distinctive red shift in both absorption and fluorescence spectra. The biosensor demonstrates a detection limit for LCA of 70 μM in PBS solution (pH 7.4), while in AU solution, it responds to an LCA concentration as low as ∼60 μM. Notably, the proposed biosensor exhibits outstanding selectivity for LCA, effectively distinguishing it from common interferents such as uric acid, ascorbic acid, and glucose. This rapid, straightforward, and cost-effective spectrometer-based method underscores its potential for early diagnosis of liver diseases by monitoring LCA concentrations.

Serum GSDMD for Early Diagnosis of Bloodstream Infection and Differentiating Bacterial from Fungal Infections.

The role of Gasdermin D (GSDMD) in bloodstream infection (BSI) diagnosis is unknown. Serum GSDMD levels were measured in BSI patients. Endothelial cells and PBMCs were isolated, infected with bacteria/fungi, and intracellular/extracellular GSDMD concentrations were measured. An animal model was established to investigate the association between serum GSDMD levels and BSI incidence/progression. ROC curve analysis indicated that GSDMD could be a potential early diagnostic biomarker for BSI (AUC = 0.9885). Combining GSDMD with procalcitonin (PCT) improved the differential diagnosis of Gram-positive and Gram-negative bacteria (AUC = 0.6699, 66.15% specificity), and early diagnosis of Gram-positive bacteria (98.46% sensitivity), while PCT was not significantly elevated. The combined GSDMD and G-test had higher sensitivity (AUC = 0.7174) for differential diagnosis of bacterial and fungal infections, and early detection of fungal infections (98.44% sensitivity). In vitro and in vivo experiments confirmed that GSDMD levels increased significantly within 2 hours, peaked at 16 hours, and exhibited a time-dependent upward trend. Serum GSDMD, alone or combined with other biomarkers, has potential for early diagnosis and differential diagnosis of BSI caused by various pathogens. This finding offers a new strategy for early detection and treatment of BSI.

Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset

Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers.

The Role of Mucin Expression in the Diagnosis of Oesophago-Gastric Cancer: A Systematic Literature Review

Survival in oesophago-gastric cancer (OGC) is poor due to early diagnostic challenges. Non-invasive risk stratification may identify susceptible patients with pre-malignant or benign disease. Following diagnostic confirmation with endoscopic biopsy, early OGC may be treated sooner. Mucins are transmembrane glycoproteins implicated in OGC with potential use as biomarkers of malignant transformation. This systematic review defines the role of mucins in OGC diagnosis. A literature search of MEDLINE, Web of Science, Embase and Cochrane databases was performed following PRISMA protocols for studies published January 1960–December 2022. Demographic data and data on mucin sampling and analysis methods were extracted. The review included 124 studies (n = 11,386 patients). Gastric adenocarcinoma (GAc) was the commonest OG malignancy (n = 101) followed by oesophageal adenocarcinoma (OAc, n = 24) and squamous cell carcinoma (OSqCc, n = 10). Mucins MUC1, MUC2, MUC5AC and MUC6 were the most frequently implicated. High MUC1 expression correlated with poorer prognosis and metastases in OSqCc. MUC2 expression decreases during progression from healthy mucosa to OAc, causing reduced protection from gastric acid. MUC5AC was upregulated, and MUC6 downregulated in GAc. Mucin expression varies in OGC; changes may be epigenetic or mutational. Profiling upper GI mucin expression in OGC, with pre-malignant, benign and healthy controls may identify potential early diagnostic biomarkers.

The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review

Background: Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this systematic review aimed to investigate the diagnostic and prognostic value of salivary orosomucoid 1 (ORM1) in patients with that mentioned disease. Methods: The sources included were original articles published from 2013 until 2023 (last date searched, January 2023) from 4 databases (ProQuest, Google Scholar, Springer, and ScienceDirect). The inclusion criteria were original research articles (observational cohort or diagnostic studies). Other article reviews, meta-analyses, non-comparative research, and in silico, in vitro and in vivo studies, technical reports, editor responses, conference abstracts, non-English, non-full-text, and irrelevant articles that were not related to either salivary ORM1, or hepatocellular carcinoma, hepatitis B, or kidney failure were excluded. Then, the ROBINS-I taken was used to assess bias. The result was constructed with PICOS criteria within the table created in the Google spreadsheet. This systematic review followed the PRISMA guidelines. Results: Five diagnostic studies with 533 samples conducted in China and Japan. Limited original studies with homogenous PICO were a limitation, but the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker can detect the prognosis of individuals with the disease with or without chemotherapy. It is because level of salivary ORM1 related to liver damage, the higher the level of ORM1, the more liver damage occurs which leads to a poorer prognosis. Conclusions: Salivary ORM1 is a potential early diagnostic biomarker of HCC related to hepatitis B and a biomarker of the disease prognosis. Registration: Open Science Framework (OSF) (March 16, 2023).

Soluble TNFR1 Levels in Type 2 Diabetes and its Association with Stages of Proteinuria.

Early identification of at-risk individuals for diabetic nephropathy would help in preventing or delaying end-stage renal failure. We measured the levels of circulating soluble tumor necrosis factor receptor 1 (sTNFR1) in various stages of proteinuria (MAC) to determine the association of this marker with diabetic nephropathy. The study was performed on 160 subjects, and a case-control methodology was employed. Type 2 diabetic subjects were recruited based on albuminuria and were grouped as (1) normoalbuminuria (NA); (2) microalbuminuria (MIC); (3) MAC; (4) normal glucose tolerance (NGT) subjects who served as healthy controls. sTNFR1 levels were measured by quantitative enzyme-linked immunosorbent assay (ELISA). Soluble tumor necrosis factor receptor 1 (sTNFR1) levels were highest in the MAC group, followed by the microMAC group. The sTNFR1 levels were not statistically different between the NGT and NA groups. On regression models, sTNFR1 was associated with MIC [odds ratio (OR)- 6.491, 95% confidence interval (CI)-1.868-22.55] and MAC (OR per standard deviation-15.28; 95% CI-3.76-62.15; p < 0.001) even after controlling for all the possible confounding factors. Receiver operator curve (ROC) analysis revealed sTNFR1 cut-point of 1832 pg/mL had a C-statistic of 0.685 to discriminate MI from NA with 52% sensitivity. Whereas the sTNFR1 cut-point of 2050 pg/mL with a C-statistic of 0.8177 had 77% sensitivity for identifying MAC. Soluble tumor necrosis factor receptor 1 (sTNFR1) is significantly associated with MIC and MAC group in type 2 diabetes, and this suggests a potential early diagnostic biomarker role of sTNFR1 for MAC among Asian Indians.

Olink proteomics profiling platform reveals non-invasive inflammatory related protein biomarkers in autism spectrum disorder.

Owing to the lack of valid biomarkers, the diagnosis of autism spectrum disorder (ASD) diagnosis relies solely on the behavioral phenotypes of children. Several researchers have suggested an association between ASD and inflammation; however, the complex relationship between the two is unelucidated to date. Therefore, the current study aims to comprehensively identify novel circulating ASD inflammatory biomarkers. Olink proteomics was applied to compare the plasma inflammation-related protein changes in a group of the healthy children (HC, n = 33) and another with ASD (n = 31). The areas under the receiver operating characteristic curves (AUCs) of the differentially expressed proteins (DEPs) were calculated. The functional analysis of the DEPs was performed using Gene Ontology and Kyoto Encyclopedia Genes and Genomes. Pearson correlation tests were used employed to analyze the correlation between the DEPs and clinical features. A total of 13 DEPs were significantly up-regulated in the ASD group compared with the HC group. The four proteins, namely, STAMBP, ST1A1, SIRT2, and MMP-10 demonstrated good diagnostic accuracy with the corresponding AUCs (95% confidence interval, CI) of 0.7218 (0.5946-0.8489), 0.7107 (0.5827-0.8387), 0.7016 (0.5713-0.8319), and 0.7006 (0.568-0.8332). Each panel of STAMBP and any other differential protein demonstrated a better classification performance [AUC values from 0.7147 (0.5858-0.8436, STAMBP/AXIN1) to 0.7681 (0.6496-0.8867, STAMBP/MMP-10)]. These DEP profiles were enriched in immune and inflammatory response pathways, including TNF and NOD-like receptor signaling pathways. The interaction between STAMBP and SIRT2 (R = 0.97, p = 8.52 × 10-39) was found to be the most significant. In addition, several DEPs related to clinical features in patients with ASD, particularly AXIN1 (R = 0.36, p = 0.006), SIRT2 (R = 0.34, p = 0.010) and STAMBP (R = 0.34, p = 0.010), were positively correlated with age and parity, indicating that older age and higher parity may be the inflammation-related clinical factors in ASD. Inflammation plays a crucial role in ASD, and the up-regulated inflammatory proteins may serve as potential early diagnostic biomarkers for ASD.

The role of salivary orosomucoid 1 as an early diagnostic and prognostic biomarker of hepatocellular carcinoma related to Hepatitis B: A systematic review

Background: Salivary orosomucoid 1 (ORM1) is highly increased in hepatocellular carcinoma related to hepatitis B. Thus, this study aims to investigate the role of salivary ORM1 as an early diagnostic and prognostic biomarker of HCC related to hepatitis B. Methods: The sources included were original articles published from 2013 until 2023 (last date searched, January 2023) from ProQuest, Google Scholar, Springer, and ScienceDirect. The inclusion criteria were original research articles (observational cohort or diagnostic studies). Other article reviews, meta-analyses, non-comparative research, and in silico, in vitro and in vivo studies, technical reports, editor responses, conference abstracts, non-English, non-full-text, and irrelevant articles that were not related to either salivary ORM1, or hepatocellular carcinoma, hepatitis B, or kidney failure were excluded. Then, the ROBINS-I took was used to assess bias . The result was constructed with PICOS criteria within the table created in the google spreadsheet. This systematic review followed the PRISMA guidelines. Results: We included five diagnostic studies with 533 samples conducted in China and Japan. Even though limited original studies with homogenous PICO was a limitation, the evidence output of this study can still be well presented. Salivary ORM1 may be useful to detect early cancer diagnosis as rapidly increased levels of ORM1 can be observed in the early stages of HCC (four times higher than usual) and the biomarker has a sensitivity of 81.67% and a specificity of 77.5%. This biomarker is also able to detect the prognosis of individuals with the disease with or without chemotherapy because the higher the level of ORM1, the more liver damage occurs that leads to a poorer prognosis. Conclusions: Salivary ORM1 is a potential early diagnostic biomarker of HCC related to hepatitis B and a biomarker of the disease prognosis. Registration: Open Science Framework (OSF) (March 16, 2023).

LncRNA HIF1A-AS2: a potential biomarker for early diagnosis of acute myocardial infarction and predictor of left ventricular dysfunction

BackgroundRapid diagnosis of acute myocardial infarction (AMI) is the subject of many clinical studies as it enables an effective therapy, preventing adverse progression of AMI and increasing survival rates. Recent studies have revealed that specific blood-based long non-coding RNAs (lncRNAs) are deregulated in patients with AMI and serve as promising diagnostic and prognostic tools. The current study aimed to determine the potential role of a hypoxia-responsive lncRNA, hypoxia-inducible factor 1A antisense RNA 2 (HIF1A-AS2), as a biomarker for early diagnosis and predictor of left ventricular dysfunction (LVD).MethodsThis study was carried out on 48 patients with AMI and 50 age-and sex-matched controls. The relative quantification of HIF1A-AS2 expression was done using reverse transcription real‐time polymerase chain reaction.ResultsCompared to the control group, HIF1A-AS2 were significantly higher in MI patients (P < 0.001). Interestingly, patients presenting within 3 h of chest pain onset had elevated levels of HIF1A‐AS2 as compared to patients with late presentation. The ROC curve was constructed to assess HIF1A-AS2 as an early marker. It demonstrated higher sensitivity (94%) and specificity (86%). Moreover, the multivariate regression analysis revealed that HIF1A‐AS2 was significantly associated with LVD in the patient group after 6 months follow up (p = 0.018).ConclusionOur study suggests that HIF1A‐AS2 may be a potential early diagnostic biomarker of AMI with high sensitivity. In addition, it might have a promising role as a predictor of left ventricular dysfunction.

Single-cell RNA sequencing highlights the functional role of human endogenous retroviruses in gallbladder cancer.

Gallbladder cancer (GBC), the most common malignancy of the biliary tract, shows late diagnosis and low survival rate and requires continued search for new diagnostic biomarkers and therapeutic targets. Human endogenous retroviruses (HERVs) are specifically prone to be reactivated in diverse cancers and are implicated in cancer progression and immunotherapy. Single-cell RNA sequencing was performed on tumor tissues and paired adjacent tissues from 4 GBC patients. Dual-luciferase reporter assay was applied to measure enhancer activity of HERV sequences. We dissected the cellular diversity and described the HERV transcriptomic landscape for GBC. We found that HERVs were transcribed in a cell type-specific manner and different HERV families were associated with diverse biological effects. HERVs could function as enhancers, presumably causing altered expression of neighboring genes. The transcription level of HERVH was gradually elevated with the malignant transformation of epithelial cells, suggesting HERVH may be a potential early diagnostic biomarker of GBC. HHLA2, a newly emerging immune checkpoint, was derived by HERVH, exhibited an expressional correlation with HERVH, and was identified as a promising target for immunotherapy. Exploring the transcriptional landscape and potential functional impact of HERVs highlights the important role of HERVs in GBC and provides a fresh perspective on managing GBC. This study was supported by the National Natural Science Foundation of China (31970176, 81972256) and the research grants from the Innovation Capacity Building Project of Jiangsu province (BM2020019).

Serum IgG N-glycans enable early detection and early relapse prediction of colorectal cancer.

Colorectal cancer (CRC) develops mainly from colorectal advanced adenomas (AA), which are considered precancerous lesions. Novel early diagnostic biomarkers are urgently needed to distinguish CRC and AA from healthy control (HC). Alternative glycosylation of serum IgG has been shown to be closely associated with CRC. We aimed to explore the potential of IgG N-glycan as biomarkers in the early differential diagnosis of CRC. The study population was strictly matched to the exclusion criteria process. Serum IgG N-glycan profiles were analyzed by a robust and reliable relative quantitative method based on ultra-performance liquid chromatography (UPLC). Relative quantification and classification performance of IgG N-glycans were evaluated by Mann-Whitney U tests and ROC curve based on directly detected and derived glycan traits, respectively. Six and 14 directly detected glycan traits were significantly changed in AA and CRC, respectively, compared with HC. GP1 and GP3 were able to accurately distinguish AA from HC for early precancerous lesions screening. GP4 and GP14 provided a high value in discriminating CRC from HC. A novel combined index named GlycoF, including GP1, GP3, GP4, GP14 and CEA was developed to provide a potential early diagnostic biomarker in discriminating simultaneously AA (AUC=0.847) and CRC (AUC=0.844) from HC. GlycoF also demonstrated a superior CRC detection rate across CRC all stages and conspicuous prediction ability of risk of relapse. Serum IgG N-glycans analysis provided powerful early screening biomarkers that can efficiently differentiate CRC and AA from HC.

Atrophic gastritis and gastric cancer tissue miRNome analysis reveals hsa-miR-129-1 and hsa-miR-196a as potential early diagnostic biomarkers.

BACKGROUNDGastric cancer (GC) is one of the most frequently diagnosed tumor globally. In most cases, GC develops in a stepwise manner from chronic gastritis or atrophic gastritis (AG) to cancer. One of the major issues in clinical settings of GC is diagnosis at advanced disease stages resulting in poor prognosis. MicroRNAs (miRNAs) are small noncoding molecules that play an essential role in a variety of fundamental biological processes. However, clinical potential of miRNA profiling in the gastric cancerogenesis, especially in premalignant GC cases, remains unclear.AIMTo evaluate the AG and GC tissue miRNomes and identify specific miRNAs’ potential for clinical applications (e.g., non-invasive diagnostics).METHODSStudy included a total of 125 subjects: Controls (CON), AG, and GC patients. All study subjects were recruited at the Departments of Surgery or Gastroenterology, Hospital of Lithuanian University of Health Sciences and divided into the profiling (n = 60) and validation (n = 65) cohorts. Total RNA isolated from tissue samples was used for preparation of small RNA sequencing libraries and profiled using next-generation sequencing (NGS). Based on NGS data, deregulated miRNAs hsa-miR-129-1-3p and hsa-miR-196a-5p were analyzed in plasma samples of independent cohort consisting of CON, AG, and GC patients. Expression level of hsa-miR-129-1-3p and hsa-miR-196a-5p was determined using the quantitative real-time polymerase chain reaction and 2-ΔΔCt method.RESULTSResults of tissue analysis revealed 20 differentially expressed miRNAs in AG group compared to CON group, 129 deregulated miRNAs in GC compared to CON, and 99 altered miRNAs comparing GC and AG groups. Only 2 miRNAs (hsa-miR-129-1-3p and hsa-miR-196a-5p) were identified to be step-wise deregulated in healthy-premalignant-malignant sequence. Area under the curve (AUC)-receiver operating characteristic analysis revealed that expression level of hsa-miR-196a-5p is significant for discrimination of CON vs AG, CON vs GC and AG vs GC and resulted in AUCs: 88.0%, 93.1% and 66.3%, respectively. Compar-ing results in tissue and plasma samples, hsa-miR-129-1-3p was significantly down-regulated in GC compared to AG (P = 0.0021 and P = 0.024, tissue and plasma, respectively). Moreover, analysis revealed that hsa-miR-215-3p/5p and hsa-miR-934 were significantly deregulated in GC based on Helicobacter pylori (H. pylori) infection status [log2 fold change (FC) = -4.52, P-adjusted = 0.02; log2FC = -4.00, P-adjusted = 0.02; log2FC = 6.09, P-adjusted = 0.02, respectively].CONCLUSIONComprehensive miRNome study provides evidence for gradual deregulation of hsa-miR-196a-5p and hsa-miR-129-1-3p in gastric carcinogenesis and found hsa-miR-215-3p/5p and hsa-miR-934 to be significantly deregulated in H. pylori carrying GC patients.

Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer

BackgroundCA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer.MethodsIn the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer.ResultsNine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancer-free. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9–18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone.ConclusionUsing pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0–9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125.

Pyroptosis inhibition improves the symptom of acute myocardial infarction

Acute myocardial infarction (AMI), the leading cause of mortality worldwide, is a rapidly developing and irreversible disease. Therefore, proper prompt intervention at the early stage of AMI is crucial for its treatment. However, the molecular features in the early stage have not been clarified. Here, we constructed mouse AMI model and profiled transcriptomes and proteomes at the early stages of AMI progress. Immune system was extensively activated at 6-h AMI. Then, pyroptosis was activated at 24-h AMI. VX-765 treatment, a pyroptosis inhibitor, significantly reduced the infarct size and improved the function of cardiomyocytes. Besides, we identified that WIPI1, specifically expressed in heart, was significantly upregulated at 1 h after AMI. Moreover, WIPI1 expression is significantly higher in the peripheral blood of patients with AMI than healthy control. WIPI1 can serve as a potential early diagnostic biomarker for AMI. It likely decelerates AMI progress by activating autophagy pathways. These findings shed new light on gene expression dynamics in AMI progress, and present a potential early diagnostic marker and a candidate drug for clinical pre-treatment to prolong the optimal cure time.

A Four-MicroRNA Panel in Peripheral Blood Identified as an Early Biomarker to Diagnose Acute Myocardial Infarction.

Objective: This study aimed to evaluate suitable circulating microRNAs (miRNAs) as diagnostic biomarkers of acute myocardial infarction (AMI).Methods: Patients with AMI were enrolled as study participants. All patients with AMI coming from the Second Affiliated Hospital of Nantong University between October 1, 2017 and May 31, 2019 were screened. At the same time, 80 patients with coronary angiographic stenosis <50% during the same period were selected as the control group. Peripheral blood samples were collected at different time points (0, 6, 12, and 24 h after disease onset) to detect the expression of a previously identified promising four-microRNA panel. The expression levels of miRNAs were tested by real-time polymerase chain reaction (RT-PCR), and the receiver operating characteristic curve (ROC) was used to analyze the diagnostic value of circulating miRNAs.Results: Based on the inclusion and exclusion criteria, 80 patients with AMI and 80 controls were enrolled in this study. The expression of circulating miR-1291, miR-217, miR-455-3p, and miR-566 was significantly downregulated in patients with AMI compared with controls. The area under the ROC curve (AUC) of circulating miR-1291, miR-217, miR-455-3p, and miR-566 were 0.82, 0.79, 0.82, and 0.83, respectively. The AUC of these four miRNAs was 0.87 with 83% sensitivity and 87% specificity. The expression peaks of these four miRNAs occurred earlier than those of cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB). Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the targets of these four miRNAs were significantly enriched in several signaling pathways associated with AMI progression.Conclusion: Circulating miR-1291, miR-217, miR-455-3p, and miR-566 expression levels were significantly lower in patients with AMI; and combined, this panel of four miRNAs acted as a novel and potential early diagnostic biomarker of AMI.

Identification of Early Diagnostic and Prognostic Biomarkers via WGCNA in Stomach Adenocarcinoma.

Stomach adenocarcinoma (STAD) is a leading cause of cancer deaths, and the outcome of the patients remains dismal for the lack of effective biomarkers of early detection. Recent studies have elucidated the landscape of genomic alterations of gastric cancer and reveal some biomarkers of advanced-stage gastric cancer, however, information about early-stage biomarkers is limited. Here, we adopt Weighted Gene Co-expression Network Analysis (WGCNA) to screen potential biomarkers for early-stage STAD using RNA-Seq and clinical data from TCGA database. We find six gene clusters (or modules) are significantly correlated with the stage-I STADs. Among these, five hub genes, i.e., MS4A1, THBS2, VCAN, PDGFRB, and KCNA3 are identified and significantly de-regulated in the stage-I STADs compared with the normal stomach gland tissues, which suggests they can serve as potential early diagnostic biomarkers. Moreover, we show that high expression of VCAN and PDGFRB is associated with poor prognosis of STAD. VCAN encodes a large chondroitin sulfate proteoglycan that is the main component of the extracellular matrix, and PDGFRB encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. Consistently, Gene Ontology (GO) analysis of differentially expressed genes in the STADs indicates terms associated with extracellular matrix and receptor ligand activity are significantly enriched. Protein-protein network interaction analysis (PPI) and Gene Set Enrichment Analysis (GSEA) further support the core role of VCAN and PDGFRB in the tumorigenesis. Collectively, our study identifies the potential biomarkers for early detection and prognosis of STAD.

Identification of Potential Early Diagnostic Biomarkers of Sepsis.

ObjectiveThe goal of this article was to identify potential biomarkers for early diagnosis of sepsis in order to improve their survival.MethodsWe analyzed differential gene expression between adult sepsis patients and controls in the GSE54514 dataset. Coexpression analysis was used to cluster coexpression modules, and enrichment analysis was performed on module genes. We also analyzed differential gene expression between neonatal sepsis patients and controls in the GSE25504 dataset, and we identified the subset of differentially expressed genes (DEGs) common to neonates and adults. All samples in the GSE54514 dataset were randomly divided into training and validation sets, and diagnostic signatures were constructed using least absolute shrink and selection operator (LASSO) regression. The key gene signature was screened for diagnostic value based on area under the receiver operating characteristic curve (AUC). STEM software identified dysregulated genes associated with sepsis-associated mortality. The ssGSEA method was used to quantify differences in immune cell infiltration between sepsis and control samples.ResultsA total of 6316 DEGs in GSE54514 were obtained spanning 10 modules. Module genes were mainly enriched in immune and metabolic responses. Screening 51 genes from among common genes based on AUC > 0.7 led to a LASSO model for the training set. We obtained a 25-gene signature, which we validated in the validation set and in the GSE25504 dataset. Among the signature genes, SLC2A6, C1ORF55, DUSP5 and RHOB were recognized as key genes (AUC > 0.75) in both the GSE54514 and GSE25504 datasets. SLC2A6 was identified by STEM as associated with sepsis-associated mortality and showed the strongest positive correlation with infiltration levels of Th1 cells.ConclusionIn summary, our four key genes may have important implications for the early diagnosis of sepsis patients. In particular, SLC2A6 may be a critical biomarker for predicting survival in sepsis.

Serum Exo-EphA2 as a Potential Diagnostic Biomarker for Pancreatic Cancer

Pancreatic cancer (PC) is a highly malignant tumor with poor detection sensitivity and specificity in biomarkers and diagnosis. Previous research indicated that serum Ephrin type-A receptor 2 in exosomes (Exo-EphA2) was highly expressed and might have facilitated cell migration in PC cells. However, the dynamics of clinical performance of serum Exo-EphA2 in PC patients are unknown. Thus, this study evaluated serum Exo-EphA2 as a potential diagnostic biomarker in PC. The expressions of serum Exo-EphA2 were assessed by enzyme-linked immunosorbent assay for N = 353 serum samples, including from 204 PC patients, 75 patients with benign pancreatic disease, and 74 healthy control patients. Carbohydrate antigen 19-9 (CA 19-9) and carbohydrate antigen 242 (CA 242) were measured by automated immunoassay. Serum Exo-EphA2 levels were significantly higher in PC patients than in benign pancreatic disease and healthy control patients. Receiver operating characteristic curve analysis suggested that using combined diagnoses of Exo-EphA2 with CA 19-9 and CA 242 was more effective to discriminate early stage (stage I and II) in PC than in healthy controls and benign disease patients. Novel findings suggest that serum Exo-EphA2 is a potential early diagnostic biomarker complementing CA 19-9 and CA 242 in PC.

Identification of key genes and expression profiles in osteoarthritis by co-expressed network analysis

BackgroundThe underlying molecular characteristics of osteoarthritis (OA), a common age-related joint disease, remains elusive. Here, we aimed to identify potential early diagnostic biomarkers and elucidate underlying mechanisms of OA using weighted gene co-expression network analysis (WGCNA). Material and methodsWe obtained the gene expression profile dataset GSE55235, GSE55457, and GSE55584, from the Gene Expression Omnibus. WGCNA was used to investigate the changes in co-expressed genes between normal and OA synovial membrane samples. Modules that were highly correlated to OA were subjected to functional enrichment analysis using the R clusterProfiler package. Differentially expressed genes (DEGs) between the two samples were screened using the “limma” package in R. A Venn diagram was constructed to intersect the genes in significant modules and DEGs. RT -PCR was used to further verify the hub gene expression levels between normal and OA samples. ResultsThe preserved significant module was found to be highly associated with OA development and progression (P < 1e-200, correlation = 0.92). Functional enrichment analysis suggested that the antiquewhite4 module was highly correlated to FoxO signaling pathway, and the metabolism of fatty acids and 2-oxocarboxylic acid. A total of 13 hub genes were identified based on significant module network topology and DEG analysis, and RT-PCR confirmed that these genes were significantly increased in OA samples compared with that in normal samples. ConclusionsWe identified 13 hub genes correlated to the development and progression of OA, which may provide new biomarkers and drug targets for OA.

Plausible diagnostic value of urinary isomeric dimethylarginine ratio for diabetic nephropathy

Altered circulatory asymmetric and symmetric dimethylarginines have been independently reported in patients with end-stage renal failure suggesting their potential role as mediators and early biomarkers of nephropathy. These alterations can also be reflected in urine. Herein, we aimed to evaluate urinary asymmetric to symmetric dimethylarginine ratio (ASR) for early prediction of diabetic nephropathy (DN). In this cross-sectional study, individuals with impaired glucose tolerance (IGT), newly diagnosed diabetes (NDD), diabetic microalbuminuria (MIC), macroalbuminuria (MAC), and normal glucose tolerance (NGT) were recruited from Dr. Mohans’ Diabetes Specialties centre, India. Urinary ASR was measured using a validated high-throughput MALDI-MS/MS method. Significantly lower ASR was observed in MIC (0.909) and MAC (0.741) in comparison to the NGT and NDD groups. On regression models, ASR was associated with MIC [OR: 0.256; 95% CI: 0.158–0.491] and MAC [OR 0.146; 95% CI: 0.071–0.292] controlled for all the available confounding factors. ROC analysis revealed ASR cut-point of 0.95 had C-statistic of 0.691 (95% CI: 0.627-0.755) to discriminate MIC from NDD with 72% sensitivity. Whereas, an ASR cut-point of 0.82 had C-statistic of 0.846 (95% CI: 0.800 - 0.893) had 91% sensitivity for identifying MAC. Our results suggest ASR as a potential early diagnostic biomarker for DN among the Asian Indians.