New Biomarkers For Early Diagnosis Research Articles

Advances in new biomarkers for early diagnosis of pancreatic cancer

Advances in new biomarkers for early diagnosis of pancreatic cancer

A comprehensive analysis of the oncogenic and prognostic role of TBC1Ds in human hepatocellular carcinoma.

TBC1D family members (TBC1Ds) are a group of proteins that contain the Tre2-Bub2-Cdc16 (TBC) domain. Recent studies have shown that TBC1Ds are involved in tumor growth, but no analysis has been done of expression patterns and prognostic values of TBC1Ds in hepatocellular carcinoma (HCC). The expression levels of TBC1Ds were evaluated in HCC using the TIMER, UALCN and Protein Atlas databases. The correlation between the mRNA levels of TBC1Ds and the prognosis of patients with HCC in the GEPIA database was then analyzed. An enrichment analysis then revealed genes that potentially interact with TBC1Ds. The correlation between levels of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC were studied using the TIMER 2.0 database. Finally, a series of in vitro assays verified the role of TBC1Ds in HCC progression. This study revealed the upregulated expression of TBC1Ds in HCC and the strong positive correlation between the mRNA levels of TBC1Ds and poor prognosis of patients with HCC. The functions of TBC1Ds were mainly related to autophagy and the AMPK pathway. There was also a significant correlation between level of TBC1Ds and tumor-infiltrating immune cells (TIICs) in HCC. The promoting role of TBC1Ds in HCC progression was verified in vitro assays. The results of this analysis indicate that TBC1Ds may serve as new biomarkers for early diagnosis and treatment of HCC.

Comprehensive proteomics of CSF, plasma, and urine identify DDC and other biomarkers of early Parkinson’s disease

Parkinson’s disease (PD) starts at the molecular and cellular level long before motor symptoms appear, yet there are no early-stage molecular biomarkers for diagnosis, prognosis prediction, or monitoring therapeutic response. This lack of biomarkers greatly impedes patient care and translational research—l-DOPA remains the standard of care more than 50 years after its introduction. Here, we performed a large-scale, multi-tissue, and multi-platform proteomics study to identify new biomarkers for early diagnosis and disease monitoring in PD. We analyzed 4877 cerebrospinal fluid, blood plasma, and urine samples from participants across seven cohorts using three orthogonal proteomics methods: Olink proximity extension assay, SomaScan aptamer precipitation assay, and liquid chromatography–mass spectrometry proteomics. We discovered that hundreds of proteins were upregulated in the CSF, blood, or urine of PD patients, prodromal PD patients with DAT deficit and REM sleep behavior disorder or anosmia, and non-manifesting genetic carriers of LRRK2 and GBA mutations. We nominate multiple novel hits across our analyses as promising markers of early PD, including DOPA decarboxylase (DDC), also known as l-aromatic acid decarboxylase (AADC), sulfatase-modifying factor 1 (SUMF1), dipeptidyl peptidase 2/7 (DPP7), glutamyl aminopeptidase (ENPEP), WAP four-disulfide core domain 2 (WFDC2), and others. DDC, which catalyzes the final step in dopamine synthesis, particularly stands out as a novel hit with a compelling mechanistic link to PD pathogenesis. DDC is consistently upregulated in the CSF and urine of treatment-naïve PD, prodromal PD, and GBA or LRRK2 carrier participants by all three proteomics methods. We show that CSF DDC levels correlate with clinical symptom severity in treatment-naïve PD patients and can be used to accurately diagnose PD and prodromal PD. This suggests that urine and CSF DDC could be a promising diagnostic and prognostic marker with utility in both clinical care and translational research.

New Perspectives in Neuroprotection for Ischemic Stroke

The constant failure of new neuroprotective therapies for ischemic stroke has partially halted the search for new therapies in recent years, mainly because of the high investment risk required to develop a new treatment for a complex pathology, such as stroke, with a narrow intervention window and associated comorbidities. However, owing to recent progress in understanding the stroke pathophysiology, improvement in patient care in stroke units, development of new imaging techniques, search for new biomarkers for early diagnosis, and increasingly widespread use of mechanical recanalization therapies, new opportunities have opened for the study of neuroprotection. This review summarizes the main protective agents currently in use, some of which are already in the clinical evaluation phase. It also includes an analysis of how recanalization therapies, new imaging techniques, and biomarkers have improved their efficacy.

MicroRNA biomarkers in leprosy: insights from the Northern Brazilian Amazon population and their implications in disease immune-physiopathology.

Leprosy, or Hansen's Disease, is a chronic infectious disease caused by Mycobacterium leprae that affects millions of people worldwide. Despite persistent efforts to combat it leprosy remains a significant public health concern particularly in developing countries. The underlying pathophysiology of the disease is not yet fully understood hindering the development of effective treatment strategies. However, recent studies have shed light on the potential role of microRNAs (miRNAs), small non-coding RNA molecules that can regulate gene expression, as promising biomarkers in various disease, including leprosy. This study aimed to validate a set of nine circulating miRNAs to propose new biomarkers for early diagnosis of the disease. Hsa-miR-16-5p, hsa-miR-106b-5p, hsa-miR-1291, hsa-miR-144-5p, and hsa-miR-20a-5p showed significant differential expression between non-leprosy group (non-LP) and leprosy group (LP), accurately discriminating between them (AUC > 0.75). In addition, our study revealed gender-based differences in miRNA expression in LP. Notably, hsa-miR-1291 showed higher expression in male LP, suggesting its potential as a male-specific biomarker. Similarly, hsa-miR-16-5p and hsa-miR-20a-5p displayed elevated expression in female LP, indicating their potential as female-specific biomarkers. Additionally, several studied miRNAs are involved in the dysregulation of apoptosis, autophagy, mitophagy, cell cycle, and immune system in leprosy. In conclusion, the validation of miRNA expression highlights several miRNAs as potential biomarkers for early diagnosis and provides new insights into the pathogenesis of the disease.

Exploration of aminopeptidase N as new biomarker for early diagnosis of thyroid cancer

False-positive diagnosis and overdiagnosis are ongoing issues in clinical diagnosis of thyroid cancer. Identifying new disease markers is crucial for early diagnosis and improved treatment. Aminopeptidase N (APN) is a promising biomarker for cancer diagnosis due to its critical roles in tumor invasion, metastasis, angiogenesis, and other processes. However, its potential as biomarker for thyroid cancer diagnosis needs further investigation. This study developed an ultra-sensitive near-infrared fluorescence probe, LAN-apn, to investigate the expression level of APN in thyroid cancer and evaluate its potential as biomarker of thyroid cancer. LAN-apn could accurately and sensitively determine APN through fluorescence method (DL = 0.069 ng/mL) and colorimetric method (DL = 4.5 ng/mL). In addition, LAN-apn allowed for successful fluorescence imaging of APN in thyroid cancer cells and thyroid cancer tumors both in vivo and in vitro, and confirmed that APN was significantly upregulated in thyroid cancer. Therefore, APN may become a new biomarker for thyroid cancer diagnosis, and LAN-apn could be used as a new imaging tool for the study of APN-thyroid cancer relationship and the early diagnosis of thyroid cancer.

The effects of extracellular vesicles and their cargo on metabolism and its adaptation to physical exercise in insulin resistance and type 2 diabetes.

Lifestyle modification represents the first-line strategy for the prevention and treatment of type 2 diabetes mellitus (T2DM), which is frequently associated with obesity and characterized by defective pancreatic insulin secretion and/or insulin resistance. Exercise training is an essential component of lifestyle modification and has been shown to ameliorate insulin resistance by reducing body fat mass and by enhancing skeletal muscle mitochondrial biogenesis and insulin-independent glucose uptake. Additionally, exercising stimulates the release of exerkines such as metabolites or cytokines, but also long non-coding RNA, microRNAs, cell-free DNA (cf-DNA), and extracellular vesicles (EVs), which contribute to inter-tissue communication. There is emerging evidence that EV number and content are altered in obesity and T2DM and may be involved in several metabolic processes, specifically either worsening or improving insulin resistance. This review summarizes the current knowledge on the metabolic effects of exercise training and on the potential role of humoral factors and EV as new biomarkers for early diagnosis and tailored treatment of T2DM.

The role of the microbiota-gut-brain axis and intestinal microbiome dysregulation in Parkinson's disease.

Parkinson's disease (PD) is a complex progressive neurodegenerative disease associated with aging. Its main pathological feature is the degeneration and loss of dopaminergic neurons related to the misfolding and aggregation of α-synuclein. The pathogenesis of PD has not yet been fully elucidated, and its occurrence and development process are closely related to the microbiota-gut-brain axis. Dysregulation of intestinal microbiota may promote the damage of the intestinal epithelial barrier, intestinal inflammation, and the upward diffusion of phosphorylated α-synuclein from the enteric nervous system (ENS) to the brain in susceptible individuals and further lead to gastrointestinal dysfunction, neuroinflammation, and neurodegeneration of the central nervous system (CNS) through the disordered microbiota-gut-brain axis. The present review aimed to summarize recent advancements in studies focusing on the role of the microbiota-gut-brain axis in the pathogenesis of PD, especially the mechanism of intestinal microbiome dysregulation, intestinal inflammation, and gastrointestinal dysfunction in PD. Maintaining or restoring homeostasis in the gut microenvironment by targeting the gut microbiome may provide future direction for the development of new biomarkers for early diagnosis of PD and therapeutic strategies to slow disease progression.

Cellular Functions of Deubiquitinating Enzymes in Ovarian Adenocarcinoma.

In ovarian cancer patients, the 5-year survival rate is 90% for stages I and II, but only 30% for stages III and IV. Unfortunately, as 75% of the patients are diagnosed at stages III and IV, many experience a recurrence. To ameliorate this, it is necessary to develop new biomarkers for early diagnosis and treatment. The ubiquitin-proteasome system is a post-translational modification that plays an important role in regulating protein stability through ubiquitination. In particular, deubiquitinating enzymes (DUBs) regulate protein stability through deubiquitinating substrate proteins. In this review, DUBs and substrates regulated by these enzymes are summarized based on their functions in ovarian cancer cells. This would be useful for the discovery of biomarkers for ovarian cancer and developing new therapeutic candidates.

Wide-Field Three-Dimensional Depth-Invariant Cellular-Resolution Imaging of the Human Retina.

Three-dimensional (3D) cellular-resolution imaging of the living human retina over a large field of view will bring a great impact in clinical ophthalmology, potentially finding new biomarkers for early diagnosis and improving the pathophysiological understanding of ocular diseases. While hardware-based and computational adaptive optics (AO) optical coherence tomography (OCT) have been developed to achieve cellular-resolution retinal imaging, these approaches support limited 3D imaging fields, and their high cost and intrinsic hardware complexity limit their practical utility. Here, this work demonstrates 3D depth-invariant cellular-resolution imaging of the living human retina over a 3 × 3 mm field of view using the first intrinsically phase-stable multi-MHz retinal swept-source OCT and novel computational defocus and aberration correction methods. Single-acquisition imaging of photoreceptor cells, retinal nerve fiber layer, and retinal capillaries is presented across unprecedented imaging fields. By providing wide-field 3D cellular-resolution imaging in the human retina using a standard point-scan architecture routinely used in the clinic, this platform proposes a strategy for expanded utilization of high-resolution retinal imaging in both research and clinical settings.

Expression Analysis of TREM2 and TC2N Genes in Human Breast Cancer Tissues

Background: Since breast cancer is the most common type of cancer in women around the world, finding new biomarkers for early diagnosis of breast cancer is invaluable. Objectives: This research assessed the mRNA expression of triggering receptors expressed on myeloid cell 2 (TREM2) and tandem C2 domains nuclear protein (TC2N) genes among Iranian patients with breast cancer. Methods: We acquired 50 samples of cancerous breast tumors and corresponding adjacent non-cancerous tissues from Iranian women. The gene expression of TREM2 and TC2N was measured by quantitative real-time polymerase chain reaction (q-RT-PCR). In addition, the association between TREM2 and TC2N levels with various clinicopathologic characteristics was also investigated. Results: The increased levels of TREM2 and TC2N mRNAs were shown in breast cancerous tissues in comparison with adjacent non-cancerous tissues (P < 0.05). Among the clinicopathological characteristics evaluated, tumor size, necrosis, and lymphatic tissue invasion were significantly associated with high TREM2 expression. A significant relationship was also seen between increased TC2N expression and tumor grade. Sensitivity and specificity were shown at 84% and 94%, respectively, for TREM2 and 72% and 100% for TC2N. Conclusions: The data suggest that TREM2 expression, but not TC2N, could be a suitable biomarker for breast cancer diagnosis.

Modularized Enzymatic Tandem Reaction for tsRNA Detection.

tRNA-derived small RNA (tsRNA) has emerged as a new biomarker for early diagnosis and prognosis prediction of breast cancer. Like the detection of other small non-coding RNAs, the traditional DNA circuit could be used for the tsRNA detection. However, the highly coupling DNA strands in the circuit increase the difficulty of design and could raise a false-positive signal. Here, we demonstrated a versatile modularized enzymatic tandem reaction, namely, reverse-transcribed nicking exponential truncation (RT-NExT). This enzymatic reaction was constructed by cohesive modules, which can work independently or in assembly. Each module could amplify and initiate the downstream module. The RT-NExT reaction could detect 10-18 M ts-66 or ts-86 within 10 min and exhibited excellent consistency to the qRT-PCR when measuring the tsRNA expression level of breast cancer or healthy patients. RT-NExT provides an appealing detection strategy for further research on the clinical diagnosis with tsRNAs.

Presepsin – (sCD14-ST): an early marker of sepsis

Sepsis remains the leading cause of death in intensive care units in all age groups around the world. Early diagnosis is key to achieving better results. Therefore, new biomarkers are certainly needed that could better inform clinicians treating such patients. Biomarkers can play an important role in this process because they can indicate the presence, absence, or severity of sepsis and can play a key role in providing supporting information to guide clinicians to prompt diagnosis and extend treatment beyond standard therapy. Presepsin is the N-terminal fragment of soluble CD14 subtype (sCD14-ST). Presepsin is a promising new marker for diagnosing and monitoring sepsis. It shows high specificity, confirmed by experimental and clinical studies. Presepsin appears to be the most promising new biomarker for early diagnosis of sepsis and at the same time an important prognostic biomarker. Presepsin is also a valuable tool for identifying patients at high risk of complications and in monitoring the progression of the disease.

Bioinformatics Analysis Identifies Key Genes in Recurrent Implantation Failure Based on Immune Infiltration.

Recurrent implantation failure (RIF) is a thorny problem often encountered in the field of assisted reproduction. Existing evidences suggest that immune dysregulation may be involved in the pathogenesis of RIF. The purpose of this study is to explore immune-related genes contributing to RIF through data mining. The endometrial expression profiles of 24 RIF and 24 controls were obtained from the GEO database. The immune infiltration in bulk tissue was estimated by single sample gene set enrichment analysis (ssGSEA) method based on marker gene sets for immune cells generated from endometrial single-cell RNA sequencing data. The results showed that the infiltration levels of B cells and regulatory T cells (Tregs) were significantly reduced in the RIF group. Four hub genes (GJA1, PRKAG2, CPT1A, and ICA1) were identified by integrated analysis of weighted gene co-expression network analysis (WGCNA), random forest and LASSO regression. Moreover, these hub genes were significantly correlated with certain immune-related factors, especially CXCL12, CEACAM1, and XCR1. Single-gene GSEA indicated that the pathways associated with hub genes included the regulation of cell cycle, the process of epithelial-mesenchymal transition and transplant rejection, etc. A predictive model for RIF was constructed based on hub genes and performed well in the training dataset and the other two external datasets. Thus, this study identified immune-related key genes in RIF and provided new biomarkers for early diagnosis.

DISCOVERY OF NOVEL EPIGENETIC BIOMARKERS IN ORAL MALIGNANT LESIONS BY EPIGENOMICS AND TRANSCRIPTOMICS APPROACHES

Objectives: DNA methylation, which is the most frequently observed epigenetic change, is very important because it is seen in the early stages of cancer. Abnormal methylation of promoter regions and silencing of tumor suppressor genes play a key role in the development of oral squamous cell carcinoma (OSCC). In our study*, it was aimed to identify and validate new biomarker candidates via epigenomics/transcriptomics approaches, to understand the molecular mechanisms of OSCC and to discover new biomarkers for early diagnosis. Materials and Methods: After DNA/RNA isolation of tumor/matched-normal tissue samples from 6 OSCC patients, BC-DNA/cDNA synthesis was performed, respectively. The methylation and expression profiles were analyzed by the R(v3.5.1) environment methods using IlluminaHumanMethylation450chips and IlluminaiScan, respectively. A candidate gene showing methylation-dependent expression loss after bioinformatic analysis was validated by QRT-PCR AND QMSP methods in tissues and body fluids of 20 OSCC and 20 oral premalignant lesions (OPML) patients, respectively. Results: To identify epigenetic biomarker candidate, we selected gene which show either hypermethylation and lower expression patterns. This candidate gene (unpublished data), which is belong subfamily of the protein-tyrosine kinase, was found to be methylated in 65% of tumors, 20% of matched-normal tissues of OSCC. The methylation rates of the candidate gene in tumor, matched-normal tissues and saliva of OPML patients were found to be 55%, 40% and 10%, respectively. The decreased expression levels of candidate gene were observed in 55% OSCC and 35% OPML tumors, respectively. Conclusions: Our candidate gene could be a biomarker for early detection of OSCC. 

Epigenetic Modulation in Viral Hepatitis C Infected Patients after Successful Therapy

Nowadays, hepatitis C-virus (HCV) represents a challenging liver condition for infected patients and health care systems worldwide. Thus, identifying new biomarkers for early diagnosis and therapy response prediction should be prioritized. Our study aims to identify new epigenetic markers in patients with HCV infection before and after successful direct-acting agents therapy (DAA) and correlate them with standard diagnostic tools. We analyzed blood samples from 12 healthy volunteers and 22 HCV infected patients, before and 3 months after DAA, by assessing: liver transaminases, alpha-fetoprotein, cryoglobulinemia, miR-7-1-3p, miR-21-3p, miR122-5p, miR-885-5p, miR-16-5p, and liver fibrosis (FibroScan®). The study groups were Ctrl (Control group), HCV (HCV infected patients before therapy), and SVR (sustained viral response group). miR-7-1-3p was up-regulated in SVR compared to HCV. No difference was observed between Ctrl and HCV. MiR-21-3p was up-regulated in SVR compared to Ctrl. MiR-122-5p was up-regulated in both, HCV and SVR groups, while miR-885-5p was up-regulated in HCV and down-regulated in SVR group. Moreover, miR-122-5p and miR-885-5p were correlated with liver cytolysis. Our results revealed an innovative panel of epigenetic biomarkers in the early stage of HCV infection and its variation after successful DAA therapy.

Biomechanics of human trabecular meshwork in healthy and glaucoma eyes via dynamic Schlemm's canal pressurization

Background and objectiveThe trabecular meshwork (TM) consists of extracellular matrix (ECM) with embedded collagen and elastin fibers providing its mechanical support. TM stiffness is considerably higher in glaucoma eyes. Emerging data indicates that the TM moves dynamically with transient intraocular pressure (IOP) fluctuations, implying the viscoelastic mechanical behavior of the TM. However, little is known about TM viscoelastic behavior. We calculated the viscoelastic mechanical properties of the TM in n = 2 healthy and n = 2 glaucoma eyes. MethodsA quadrant of the anterior segment was submerged in a saline bath, and a cannula connected to an adjustable saline reservoir was inserted into Schlemm's canal (SC). A spectral domain-OCT (SD-OCT) provided continuous cross-sectional B-scans of the TM/JCT/SC complex during pressure oscillation from 0 to 30 mmHg at two locations. The TM/JCT/SC complex boundaries were delineated to construct a 20-µm-thick volume finite element (FE) mesh. Pre-tensioned collagen and elastin fibrils were embedded in the model using a mesh-free penalty-based cable-in-solid algorithm. SC pressure was represented by a position- and time-dependent pressure boundary; floating boundary conditions were applied to the other cut edges of the model. An FE-optimization algorithm was used to adjust the ECM/fiber mechanical properties such that the TM/JCT/SC model and SD-OCT imaging data best matched over time. ResultsSignificantly larger short- and long-time ECM shear moduli (p = 0.0032), and collagen (1.82x) and elastin (2.72x) fibril elastic moduli (p = 0.0001), were found in the TM of glaucoma eyes compared to healthy controls. ConclusionsThese findings provide additional clarity on the mechanical property differences in healthy and glaucomatous outflow pathway under dynamic loading. Understanding the viscoelastic properties of the TM may serve as a new biomarker in early diagnosis of glaucoma.

Biomarkers of connective tissue disease-associated interstitial lung disease in bronchoalveolar lavage fluid: A label-free mass spectrometry-based relative quantification study.

BackgroundThe pathogenesis of connective tissue disease‐associated interstitial lung disease (CTD‐ILD) is unclear. This study aims to identify differentially expressed proteins (DEPs) in CTD‐ILD to determine the potential role of these DEPs that may play in the pathogenesis of CTD‐ILD and to offer potential therapeutic targets.MethodsBronchoalveolar lavage fluid (BALF) samples were collected from four patients with CTD‐ILD and four patients without CTD‐ILD. Label‐free mass spectrometry‐based relative quantification was used to identify the DEPs. Bioinformatics were used to determine the potential biological processes and signaling pathways associated with these DEPs.ResultsWe found 65 upregulated DEPs including SFTPD, CADM1, ACSL4, TSTD1, CD163, LUM, SIGLEC1, CPB2, TGFBI and HGD, and 67 downregulated DEPs including SGSH, WIPF1, SIL1, RAB20, OAS3, GMPR2, PLBD1, DNAJC3, RNASET2 and OAS2. The results of GO functional annotation for the DEPs showed that the DEPS were mainly enriched in the binding, cellular anatomical entity, cellular processes, and biological regulation GO terms. The results of KEGG analyses showed that the pathways most annotated with the DEPs were complement and coagulation cascades, metabolic pathways, pathways in cancer, and PPAR signaling pathway. COG analyses further informed the functions associated with these DEPs, with most focused on signal transduction mechanisms; posttranslational modification, protein turnover, chaperones; intracellular trafficking, secretion, and vesicular transport; amino acid transport and metabolism; and lipid transport and metabolism.ConclusionsDEPs identified between patients with vs. without CTD‐ILD may play important roles in the development of CTD‐ILD and are potential new biomarkers for early diagnosis of CTD‐ILD.

Underestimated Prediabetic Biomarkers: Are We Blind to Their Strategy?

Type 2 Diabetes (T2D) is currently one of the fastest growing health challenging, a non-communicable disease result of the XXI century lifestyle. Given its growing incidence and prevalence, it became increasingly imperative to develop new technologies and implement new biomarkers for early diagnosis in order to promote lifestyle changes and thus cause a setback of the disease. Promising biomarkers have been identified as predictive of T2D development; however, none of them have yet been implemented in clinical practice routine. Moreover, many prediabetic biomarkers can also represent potential therapeutical targets in disease management. Previous studies have identified the most popular biomarkers, which are being thoroughly investigated. However, there are some biomarkers with promising preliminary results with limited associated studies; hence there is still much to be understood about its mechanisms and associations in T2D pathophysiology. This work identifies and discusses the promising results of Galectin-3, Ophthalmate and Fetuin-A.

Assets of Circulating Extracellular Vesicles for Early Diagnosis and Prognosis of Gastric Cancer by Liquid Biopsy

Gastric cancer (GC) is an important human cancer, which needs new biomarkers for early diagnosis in order to improve the patients outcome. The aim of this review is to stress the huge interest of extracellular vesicles circulating into blood and other body fluids, as potential candidates for early diagnosis of gastric cancer. After briefly recalling the previous blood-based liquid biopsies as a non-invasive help to GC diagnosis and the main properties of extracellular vesicles, the review will be focused on the recent progressive emergence of exosomes as important partners in GC liquid biopsy. Faced with the always increasing number of exosomal biomarker candidates, the necessity of two independent searches is suggested. The biologists need to solve some pending biological problems about extracellular vesicles, and the eukaryotic microorganism Dictyostelium discoideum might be an appealing both "in vitro and in vivo" model for that purpose. On the other hand, the protocols for isolation and characterization of extracellular vesicles and their cargoes have to be strictly standardized for a further validation at a large scale, prerequisite for an efficient clinical translation of some promising biomarker (s) for gastric cancer diagnosis and prognosis.