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Background/Objectives: The aim of this study was to evaluate brain metabolism using MR spectroscopy (MRS) after recovery from Coronavirus disease (COVID-19) and to test the impact of disease severity on brain metabolites. Methods: We performed MRS on 81 individuals (45 males, 36 females, aged 40–60), who had normal MRI findings and had recovered from COVID-19, classifying them into mild (17), moderate (36), and severe (28) groups based on disease severity during the acute phase. The study employed two-dimensional spectroscopic imaging above the corpus callosum, focusing on choline (Cho), creatine (Cr), and N-acetylaspartate (NAA). We analyzed Cho/Cr and NAA/Cr ratios as well as absolute concentrations using water as an internal reference. Results: Results indicated that the Cho/Cr ratio was higher with increasing disease severity, while absolute Cho and NAA/Cr ratios showed no significant differences across the groups. Notably, absolute Cr and NAA levels were significantly lower in patients with severe disease. Conclusions: These findings suggest that the severity of COVID-19 during the acute phase is associated with significant changes in brain metabolism, marked by an increase in Cho/Cr ratios and a reduction in Cr and NAA levels, reflecting substantial metabolic alterations post-recovery. [ABSTRACT FROM AUTHOR]

Background and Aim: Several agents are under investigation for nonalcoholic fatty liver disease (NAFLD). We assessed the comparative efficacy of pharmacologic interventions for patients with NAFLD focusing on magnetic resonance imaging (MRI) biomarkers. Methods: We searched Medline, Embase, and CENTRAL. We included randomized controlled trials of more than 12 weeks of intervention that recruited patients with biopsy‐confirmed or MRI‐confirmed NAFLD and assessed the efficacy of interventions on liver fat content (LFC) and fibrosis by means of MRI. We performed random‐effects frequentist network meta‐analyses and assessed confidence in our estimates using the CINeMA (Confidence in Network Meta‐Analysis) approach. Results: We included 47 trials (8583 patients). Versus placebo, thiazolidinediones were the most efficacious for the absolute change in LFC, followed by vitamin E, fibroblast growth factor (FGF) analogs, and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) with mean differences ranging from −7.46% (95% confidence interval [−11.0, −3.9]) to −4.36% (−7.2, −1.5). No differences between drug classes were evident. Patients receiving GLP‐1 RAs or glucose‐dependent insulinotropic polypeptide (GIP)/GLP‐1 RAs were more likely to achieve ≥30% relative reduction in LFC. Among agents, efruxifermin produced the largest reduction in LFC compared to placebo [−13.5% (−18.5, −8.5)], followed by pioglitazone, while being superior to most interventions. The effect of interventions on magnetic resonance elastography assessed fibrosis was small and insignificant. The confidence in our estimates was low to very low. Conclusions: Several drug classes may reduce LFC in patients with NAFLD without a significant effect on fibrosis; nevertheless, trial duration was small, and confidence in the effect estimates was low. [ABSTRACT FROM AUTHOR]

To investigate the potential clinical value of urinary exosomal (uE) miR-451a as a biomarker for IgAN, urinary exosomes were isolated from 40 patients with IgAN, 30 patients with primary renal diseases without IgA as disease controls (non-IgAN group) and 21 healthy controls (HCs). The expression of miR-451a within exosomes was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). uE miR-451a was significantly upregulated in patients with IgAN compared to non-IgAN and HCs. The uE miR-451a level was positively correlated with the change in eGFR and negatively correlated with serum creatinine, urinary macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). A dual-luciferase reporter assay confirmed that MIF was a direct target of miR-451a. Receiver operating characteristic (ROC) curve analysis revealed that the expression of uE miR-451a showed potential diagnostic value for IgAN. Additionally, the uE miR-451a level could distinguish patients with IgAN with mild tubular atrophy/interstitial fibrosis from those with severe tubular atrophy/interstitial fibrosis. After a mean follow-up of 14.2 months, the levels of eGFR loss (ml/min/1.73 m2/year) were negatively correlated with baseline miR-451a. The levels of baseline miR-451a in the complete remission group were significantly higher than those in the non-complete remission group. uE miR-451a expression was significantly elevated in patients with IgA nephropathy and may serve as a potential biomarker for the diagnosis of IgAN and evaluation of tubulointerstitial damage, while the baseline levels of uE miR-451a may be predictors of therapeutic efficacy and disease progression. [ABSTRACT FROM AUTHOR]

Although many biomarkers have been proposed, and several are in widespread clinical use, there is no single readout or combination of readouts that correlates tightly with gluten exposure, disease activity, or end-organ damage in treated patients with celiac disease. Challenges to developing and evaluating better biomarkers include significant interindividual variability-related to immune amplification of gluten exposure and how effects of immune activation are manifest. Furthermore, the current "gold standard" for assessment of end-organ damage, small intestinal biopsy, is itself highly imperfect, such that a marker that is a better reflection of the "ground truth" may indeed appear to perform poorly. The goal of this review was to analyze past and present efforts to establish robust noninvasive tools for monitoring treated patients with celiac disease and to highlight emerging tools that may prove to be useful in clinical practice. [ABSTRACT FROM AUTHOR]

To investigate the potential clinical value of urinary exosomal (uE) miR-451a as a biomarker for IgAN, urinary exosomes were isolated from 40 patients with IgAN, 30 patients with primary renal diseases without IgA as disease controls (non-IgAN group) and 21 healthy controls (HCs). The expression of miR-451a within exosomes was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). uE miR-451a was significantly upregulated in patients with IgAN compared to non-IgAN and HCs. The uE miR-451a level was positively correlated with the change in eGFR and negatively correlated with serum creatinine, urinary macrophage migration inhibitory factor (MIF), interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). A dual-luciferase reporter assay confirmed that MIF was a direct target of miR-451a. Receiver operating characteristic (ROC) curve analysis revealed that the expression of uE miR-451a showed potential diagnostic value for IgAN. Additionally, the uE miR-451a level could distinguish patients with IgAN with mild tubular atrophy/interstitial fibrosis from those with severe tubular atrophy/interstitial fibrosis. After a mean follow-up of 14.2 months, the levels of eGFR loss (ml/min/1.73 m2/year) were negatively correlated with baseline miR-451a. The levels of baseline miR-451a in the complete remission group were significantly higher than those in the non-complete remission group. uE miR-451a expression was significantly elevated in patients with IgA nephropathy and may serve as a potential biomarker for the diagnosis of IgAN and evaluation of tubulointerstitial damage, while the baseline levels of uE miR-451a may be predictors of therapeutic efficacy and disease progression.

Abstract Background The study aimed to investigate an association of increased liver fibrosis with acute myocardial infarction (AMI), and to investigate the mediating effect of serum follistatin-like protein 3 (FSTL3) on the association in patients with type 2 diabetes mellitus (T2DM). Method A total of 1424 participants were included in this study, and were firstly divided into two groups: 429 T2DM patients and 995 T2DM patients with NAFLD to assess the association of NAFLD and AMI. Then 995 T2DM co-existent NAFLD patients were categorized by NAFLD fibrosis risk to explore the association between NAFLD fibrosis risk and AMI. Immunohistochemistry staining and semi-quantitative analysis of liver FSTL3 were performed in 60 patients with NAFLD. There were 323 individuals (191 without AMI and 132 with AMI) in T2DM co-existent NAFLD patients who had serum samples, and serum FSTL3 was tested and mediation effect of FSTL3 in association of NAFLD fibrosis and AMI was performed. Results First, increased NAFLD fibrosis risk was an independent risk factor for AMI in patients with T2DM and co-existent NAFLD. In addition, analysis of Gene Expression Omnibus (GEO) database and immunohistochemical staining confirmed the increased expression of FSTL3 in the liver of NAFLD patients with fibrosis. Serum FSTL3 significantly increased in patients with high NAFLD fibrosis risk and AMI, and closely associated with NAFLD fibrosis and AMI severity in T2DM patients with co-existent NAFLD. Most importantly, analysis of the level of mediation revealed that increased serum FSTL3 partially mediated the association of increased NAFLD fibrosis risk with AMI in T2DM patients with co-existent NAFLD. Conclusions NAFLD fibrosis was closely associated with AMI in T2DM patients. FSTL3 expression was enriched in the liver of NAFLD patients with significant and advanced fibrosis, and serum FSTL3 partially mediated the association of increased liver fibrosis risk with AMI in T2DM patients.

Background: The study aimed to investigate an association of increased liver fibrosis with acute myocardial infarction (AMI), and to investigate the mediating effect of serum follistatin-like protein 3 (FSTL3) on the association in patients with type 2 diabetes mellitus (T2DM). Method: A total of 1424 participants were included in this study, and were firstly divided into two groups: 429 T2DM patients and 995 T2DM patients with NAFLD to assess the association of NAFLD and AMI. Then 995 T2DM co-existent NAFLD patients were categorized by NAFLD fibrosis risk to explore the association between NAFLD fibrosis risk and AMI. Immunohistochemistry staining and semi-quantitative analysis of liver FSTL3 were performed in 60 patients with NAFLD. There were 323 individuals (191 without AMI and 132 with AMI) in T2DM co-existent NAFLD patients who had serum samples, and serum FSTL3 was tested and mediation effect of FSTL3 in association of NAFLD fibrosis and AMI was performed. Results: First, increased NAFLD fibrosis risk was an independent risk factor for AMI in patients with T2DM and co-existent NAFLD. In addition, analysis of Gene Expression Omnibus (GEO) database and immunohistochemical staining confirmed the increased expression of FSTL3 in the liver of NAFLD patients with fibrosis. Serum FSTL3 significantly increased in patients with high NAFLD fibrosis risk and AMI, and closely associated with NAFLD fibrosis and AMI severity in T2DM patients with co-existent NAFLD. Most importantly, analysis of the level of mediation revealed that increased serum FSTL3 partially mediated the association of increased NAFLD fibrosis risk with AMI in T2DM patients with co-existent NAFLD. Conclusions: NAFLD fibrosis was closely associated with AMI in T2DM patients. FSTL3 expression was enriched in the liver of NAFLD patients with significant and advanced fibrosis, and serum FSTL3 partially mediated the association of increased liver fibrosis risk with AMI in T2DM patients. [ABSTRACT FROM AUTHOR]

This study showed that, in patients with T2DM, significant fibrosis was present in 6% and severe fibrosis or cirrhosis in 9% of patients [[11]]. Performance of the Enhanced liver fibrosis test to estimate advanced fibrosis among patients with nonalcoholic fatty liver disease. Keywords: Nonalcoholic fatty liver disease; Type 2 diabetes; Noninvasive biomarkers; Hepatocellular carcinoma; Clinically significant liver fibrosis EN Nonalcoholic fatty liver disease Type 2 diabetes Noninvasive biomarkers Hepatocellular carcinoma Clinically significant liver fibrosis 355 359 5 10/03/23 20230901 NES 230901 Cancer is a leading cause of premature mortality in patients with type 2 diabetes mellitus (T2DM) [[1]] and T2DM is strongly associated with site-specific cancers including hepatocellular carcinoma (HCC) [[2]]. Since thresholds for each of the liver fibrosis stages have now been validated in a large series of patients who have undergone liver biopsy as the gold standard for staging liver fibrosis [[32]], there is a case to suggest that all people with T2DM should undergo liver fibrosis biomarker testing and VCTE. [Extracted from the article]

Background and Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bell’s staging is routinely used to guide diagnosis, but early diagnostic signs are nonspecific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed. We investigated fecal cytokine levels, coupled with gut microbiota profiles, as a noninvasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers. Methods: Premature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Mary’s or Queen Charlotte’s & Chelsea) between January 2011 and December 2012. During the NICU stay, expert neonatologists grouped individuals by modified Bell’s staging (healthy, NEC1, NEC2/3) and fecal samples from diapers were collected consecutively. Microbiota profiles were assessed by 16S rRNA gene amplicon sequencing and cytokine concentrations were measured by V-Plex multiplex assays. Results: Early evaluation of microbiota profiles revealed only minor differences. However, at later time points, significant changes in microbiota composition were observed for Bacillota (adj. P = .0396), with Enterococcus being the least abundant in Bell stage 2/3 NEC. Evaluation of fecal cytokine levels revealed significantly higher concentrations of IL-1α (P = .045), IL-5 (P = .0074), and IL-10 (P = .032) in Bell stage 1 NEC compared to healthy individuals. Conclusion: Differences in certain fecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles contribute to improving knowledge about NEC pathogenesis.

Introduction: The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort. Methods: A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort. Results: Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in bothcohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity). Conclusion: These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarkerguided clinical trials. [ABSTRACT FROM AUTHOR]

Identifying and treating tumors early is the key to secondary prevention in cancer control. At present, prevention of oral cancer is still challenging because the molecular drivers responsible for malignant transformation of the 11 clinically defined oral potentially malignant disorders are still unknown. In this review, we focused on studies that elucidate the epigenetic alterations demarcating malignant and nonmalignant epigenomes and prioritized findings from clinical samples. Head and neck included, the genomes of many cancer types are largely hypomethylated and accompanied by focal hypermethylation on certain specific regions. We revisited prior studies that demonstrated that sufficient uptake of folate, the primary dietary methyl donor, is associated with oral cancer reduction. As epigenetically driven phenotypic plasticity, a newly recognized hallmark of cancer, has been linked to tumor initiation, cell fate determination, and drug resistance, we discussed prior findings that might be associated with this hallmark, including gene clusters (11q13.3, 19q13.43, 20q11.2, 22q11-13) with great potential for oral cancer biomarkers, and successful examples in screening early-stage nasopharyngeal carcinoma. Although one-size-fits-all approaches have been shown to be ineffective in most cancer therapies, the rapid development of epigenome sequencing methods raises the possibility that this nonmutagenic approach may be an exception. Only time will tell. [ABSTRACT FROM AUTHOR]

Simple Summary: Exosomes are vesicles that vary between 40 and 150 nm in diameter and are secreted by cells. These carry miRNAs that have various roles in intercellular signaling. They have different biological functions and are unique to the secreting cell. This provides information about the state of the cell and its involvement in pathological processes such as cancer. Exosomes play an important role in cancer signaling since they have both pro- and antitumor functions. In addition, they can render cells sensitive or resistant to chemotherapeutic agents. Exosomal miRNAs play an important role in promoting tumor growth and metastasis by altering the signaling pathway and promoting angiogenesis. They increase the metastatic ability of cancer cells by increasing the secretion of matrix metalloproteinases, which degrade the extracellular matrix, thereby allowing cells to spread to different parts of the body. The level of miRNAs in exosomes can be used to identify the cancer stage and grade, which eliminates the need for invasive cancer biopsies. Since exosomes can cross the blood–brain barrier, they are an excellent choice for drug delivery. As exosomes are isolated from the cells or biological fluids of the patient, their use minimizes the risk of infection and inflammation. A better understanding of exosomes and their cargoes can be exploited in the development of cancer therapeutics. Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40–150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial–mesenchymal transition, angiogenesis, apoptosis, and immune evasion. Depending on the type of miRNA that it carries as its cargo, it can render cells chemo- or radiosensitive or resistant and can also act as a tumor suppressor. Since the composition of exosomes is affected by the cellular state, stress, and changes in the environment, they can be used as diagnostic or prognostic biomarkers. Their unique ability to cross biological barriers makes them an excellent choice as vehicles for drug delivery. Because of their easy availability and stability, they can be used to replace cancer biopsies, which are invasive and expensive. Exosomes can also be used to follow the progression of diseases and monitor treatment strategies. A better understanding of the roles and functions of exosomal miRNA can be used to develop noninvasive, innovative, and novel treatments for cancer. [ABSTRACT FROM AUTHOR]

The requirement of blood-circulating sensitive biomarkers for monitoring liver transplant (LT) is currently a necessary step aiming at the reduction of standard invasive protocols, such as liver biopsy. In this respect, the main objective of this study is to assess circulating microRNA (c-miR) changes in recipients' blood before and after LT and to correlate their blood levels with gold standard biomarkers and with outcomes such as rejection or complications after graft. An miR profile was initially performed; then, the most deregulated miRs were validated by RT-qPCR in 14 recipients pre- and post-LT and compared to a control group of 24 nontransplanted healthy subjects. MiR-122-5p, miR-92a-3p, miR-18a-5p, and miR-30c-5p, identified in the validation phase, were also analyzed considering an additional 19 serum samples collected from LT recipients and focusing on different follow-up (FU) times. The results showed significant, FU-related changes in c-miRs. In particular, miR-122-5p, miR-92a-3p, and miR-18a-5p revealed the same trend after transplantation and an increase in their level was found in patients with complications, independently from FU times. Conversely, the variations in the standard haemato-biochemical parameters for liver function assessment were not significant in the same FU period, confirming the importance of c-miRs as potential noninvasive biomarkers for monitoring patients' outcomes. [ABSTRACT FROM AUTHOR]

IntroductionThe use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort.MethodsA prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort.ResultsTwenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity).ConclusionThese results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.

IntroductionGiven the important roles of immune tolerance and inflammation in both preterm and term labor, some inflammation-related genes could be related to the initiation of labor, even preterm labor. Inspection of cell-free RNA (cfRNA) engaged in inflammation in maternal blood may represent the varied gestational age and may have significant implications for the development of noninvasive diagnostics for preterm birth.MethodsTo identify potential biomarkers of preterm birth, we investigated the cfRNA and exosomal miRNA in the peripheral blood of pregnant women at different gestational ages that undergo term labor or preterm labor. 17 inflammatory initiation-related cfRNAs were screened by overlapping with the targets of decreasing miRNAs during gestation and highly expressed cfRNAs at late gestation in maternal blood. To reveal the origins and mechanisms of these screened cfRNAs, the datasets of single-cell RNA sequencing from peripheral blood mononuclear cells of pregnant women, the fetal lung, and the placenta across different gestational ages were analyzed.ResultsDuring late gestation, TNFSF4 expression increased exclusively in pro-inflammatory macrophages of maternal blood, whereas its receptor, TNFRSF4, increased expression in T cells from the decidua, which suggested the potential cell-cell communication of maternally-originated pro-inflammatory macrophages with the decidual T cells and contributed to the initiation of labor. Additionally, the cfRNA of TNFSF4 was also increased in preterm labor compared to term labor in the validation cohorts. The EIF2AK2 and TLR4 transcripts were increased in pro-inflammatory macrophages from both fetal lung and placenta but not in those from maternal mononuclear cells at late gestation, suggesting these cfRNAs are possibly derived from fetal tissues exclusively. Moreover, EIF2AK2 and TLR4 transcripts were found highly expressed in the pro-inflammatory macrophages from decidua as well, which suggested these specific fetal-origin macrophages may function at the maternal-fetal interface to stimulate uterine contractions, which have been implicated as the trigger of parturition and preterm labor.DiscussionTaken together, our findings not only revealed the potential of peripheral TNFSF4 as a novel cfRNA biomarker for noninvasive testing of preterm labor but further illustrated how maternal and fetal signals coordinately modulate the inflammatory process at the maternal-fetal interface, causing the initiation of term or preterm labor.

Abstract Background Breast cancer (BC) is one of the most prevalent cancers in developing and developed countries among women worldwide. Mammography is one of the superior methods for BC detection, but it carries up to 20% false-negative results, especially in early cases. Histological examination of tissue biopsies and fine-needle aspiration cytology are invasive techniques. Hence, minimally invasive markers are needed for the improved detection of BC. microRNAs, small, noncoding, single-stranded RNAs functioning as tumor suppressor genes or oncogenes, are attractive biomarkers for early detection. This study aimed to examine the serum levels of miR21 and miR10b in patients with BC especially in the early stages compared to healthy controls to evaluate their potential use as BC biomarkers. Methods This study included 90 females who were divided into two groups. Group I included 70 patients with BC and was subdivided into group Ia with 40 nonmetastatic BC patients and group Ib with 30 metastatic BC patients. Group II included 20 apparently healthy females as a control group. Serum miR21 and miR10b as biomarkers and miR16 as a housekeeping gene were evaluated using real-time polymerase chain reaction. Results The median levels of miR10b and miR21 were statistically significantly upregulated in the sera of patients with BC compared to healthy controls (P = 0.001). Receiver operating characteristic curve analyses demonstrated that serum levels of miR10b and miR21 were useful biomarkers for distinguishing between patients with BC and the control group, with an area under the curve (AUC) of 0.991 with 97.1% sensitivity and 100% specificity at a cutoff of 3.1 for miR10b and an AUC of 0.965 with 95.7% sensitivity and 85% specificity at a cutoff of 1.7 for miR21. Regarding the early stages of BC, the median levels of the fold change of serum miR21 and miR10b were statistically significantly higher in patients with BC (stages I and IIa) than in the control group (P < 0.001). Conclusions Both miR21 and miR10b have valuable diagnostic roles in detecting the early stages of BC.

Alcohol use disorder (AUD) is a common mental illness with high morbidity and disability. The discovery of laboratory biomarkers has progressed slowly, resulting in suboptimal diagnosis and treatment of AUD. This study aimed to identify promising biomarkers, as well as the potential miRNA-mRNA networks associated with AUD pathogenesis. RNA sequencing was performed on plasma-derived small extracellular vesicles (sEVs) from AUD patients and healthy controls (HCs) to harvest miRNAs expression profiles. Machine learning (ML) models were built to screen characteristic miRNAs, whose target mRNAs were analyzed using TargetScan, miRanda and miRDB databases. Gene Expression Omnibus (GEO) datasets (GSE181804 and GSE180722) providing postmortem hippocampal gene expression profiles of AUD subjects were mined. A total of 247 differentially expressed (DE) plasma-derived sEVs miRNAs and 122 DE hippocampal mRNAs were obtained. Then, 22 overlapping sEVs miRNAs with high importance scores were gained by intersecting 5 ML models. As a result, we established a putative sEVs miRNA-hippocampal mRNA network that can effectively distinguish AUD patients from HCs. In conclusion, we proposed 5 AUD-representative sEVs miRNAs (hsa-miR-144-5p, hsa-miR-182-5p, hsa-miR-142-5p, hsa-miR-7-5p, and hsa-miR-15b-5p) that may participate in the pathogenesis of AUD by modulating downstream target hippocampal genes. These findings may provide novel insights into the diagnosis and treatment of AUD. [ABSTRACT FROM AUTHOR]

Context: Nonalcoholic fatty liver disease (NAFLD) is a multisystem disease, associated with fibrosis and an increased risk of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Objective: This work aimed to investigate the association of NAFLD fibrosis with the development of CKD in aged patients with T2DM. Methods: This cross-sectional study enrolled 13 915 participants. A further 1734 individuals who had been followed annually for 5 years comprised the retrospective cohort study. Noninvasive markers, NAFLD fibrosis score (NFS), and fibrosis index based on 4 factors (FIB-4) were applied to determine NAFLD fibrosis risk. Results: In the cross-sectional study, there was an additive interaction for NAFLD with increased risk of fibrosis and T2DM on CKD incidence. Logistic regression demonstrated that as NAFLD fibrosis risk progressed from low to intermediate and high, there was a stepwise increase in CKD in patients with NAFLD, T2DM, and those with coexistent NAFLD and T2DM when stratified by diabetes and fibrosis stage. FIB-4 had a much higher odds ratio (OR) value than NFS for prediction of CKD incidence. In the cohort study, individuals were grouped according to FIB-4 and NFS. Cox regression analysis showed that FIB-4 intermediate risk (hazard ratio [HR] 1.268; 95% CI, 1.056-1.521) and high risk (HR 2.516; 95% CI, 1.970-3.214) were significant predictors of CKD progression. When NFS was applied, only high risk was a significant predictor. Conclusion: NAFLD with an increased risk of fibrosis and presence of T2DM had an additive interaction on CKD incidence. Increased risk of NAFLD fibrosis was closely associated with CKD incidence and progression in aged T2DM patients. FIB-4 outperformed NFS as a noninvasive means to predict CKD development. [ABSTRACT FROM AUTHOR]

Objective Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist and can act synergistically to drive adverse outcomes of one another. This study aimed to unravel the metabolomic changes in patients with NAFLD and T2DM, to identify potential noninvasive biomarkers, and to provide insights for understanding the link between NAFLD and T2DM. Methods Three hundred participants aged 35 to 70 years who were diagnosed with NAFLD (n = 100), T2DM (n = 100), or a comorbidity of NAFLD and T2DM (n = 100) were included in this study. Anthropometrics and routine blood chemistry were assessed after overnight fast. The global serum metabolomic analysis was performed by ultra-performance liquid chromatography-Orbitrap mass spectrometry. Multivariate data analysis methods were utilized to identify the potential biomarkers. Results A set of serum biomarkers that could effectively separate NAFLD from NAFLD + T2DM and T2DM from NAFLD + T2DM were identified. We found that patients with coexisting NAFLD and T2DM had significantly higher levels of total protein (TP), triglycerides (TG), glucose in urine, and gamma-hydroxybutyric acid than those with NAFLD and had significant increased levels of TP, albumin, alanine aminotransferase, aspartate aminotransferase, total cholesterol, cholinesterase, TG, low-density lipoprotein, and apolipoprotein A when compared to patients with T2DM. Conclusion The metabolomics results provide evidence that the comorbidity of NAFLD and T2DM considerably altered patients' metabolomics patterns compared to those of patients with only NAFLD or T2DM. [ABSTRACT FROM AUTHOR]

Noninvasive sample sources of exosomes, such as exhaled breath and sputum, which are in close proximity to the tumor microenvironment and may contain biomarkers indicative of lung cancer, are far more permissive than invasive sample sources for biomarker screening. Standardized exosome extraction and characterization approaches for low-volume noninvasive samples are critically needed. We isolated and characterized exhaled breath condensate (EBC) and sputum exosomes from healthy nonsmokers ( n = 30), tobacco smokers ( n = 30), and lung cancer patients ( n = 40) and correlated the findings with invasive sample sources. EBC samples were collected by using commercially available R-Tubes. To collect sputum samples the participants were directed to take deep breaths, hold their breath, and cough in a collection container. Dynamic light scattering, nanoparticle tracking analysis, and transmission electron microscopy were used to evaluate the exosome morphology. Protein isolation, western blotting, exosome quantification via EXOCET, and Fourier transform infrared spectroscopy were performed for molecular characterization. Exosomes were successfully isolated from EBC and sputum samples, and their yields were adequate and sufficiently pure for subsequent downstream processing and characterization. The exosomes were confirmed based on their size, shape, and surface marker expression. Remarkably, cancer exosomes were the largest in size not only in the plasma subgroups, but also in the EBC ( p  < 0.05) and sputum ( p = 0.0036) subgroups, according to our findings. A significant difference in exosome concentrations were observed between the control sub-groups ( p  < 0.05). Our research confirmed that exosomes can be extracted from noninvasive sources, such as EBC and sputum, to investigate lung cancer diagnostic biomarkers for research, clinical, and early detection in smokers., (© 2024 IOP Publishing Ltd.)

PurposeTo noninvasively assess spectroscopic and metabolic profiles of healthy tongue tissue and in an exploratory objective in nontreated and treated patients with tongue squamous cell carcinoma (SCC).MethodsFourteen healthy subjects (HSs), one patient with nontreated tongue SCC (NT-SCC), and two patients with treated tongue SCC (T-SCC) underwent MRI and single-voxel proton magnetic resonance spectroscopy (1H-MRS) evaluations (3 and 1.5T). Multi-echo-times 1H-MRS was performed at the medial superior part (MSP) and the anterior inferior part (AIP) of the tongue in HS, while 1H-MRS voxel was placed at the most aggressive part of the tumor for patients with tongue SCC. 1H-MRS data analysis yielded spectroscopic metabolite ratios quantified to total creatine.ResultsIn HS, compared to MSP and AIP, 1H-MRS spectra revealed higher levels of creatine, a more prominent and well-identified trimethylamine-choline (TMA-Cho) peak. However, larger prominent lipid peaks were better differentiated in the tongue MSP. Compared to HS, patients with NT-SCC exhibited very high levels of lipids and relatively higher values of TMA-Cho peak. Interestingly, patients with T-SCC showed almost nonproliferation activity. However, high lipids levels were measured, although they were relatively lower than lipids levels measured in patients with NT-SCC.ConclusionThe present study demonstrated the potential use of in-vivo1H-MRS to noninvasively assess spectroscopic and metabolic profiles of the healthy tongue tissue in a spatial location-dependent manner. Preliminary results revealed differences between HS and patients with tongue NT-SCC as well as tongue T-SCC, which should be confirmed with more patients. 1H-MRS could be included, in the future, in the arsenal of tools for treatment response evaluation and noninvasive monitoring of patients with tongue SCC.

Exosomes are extracellular vesicles that originate from endosomes and are released by all cells irrespective of their origin or type. They play an important role in cell communication and can act in an autocrine, endocrine, or paracrine fashion. They are 40–150 nm in diameter and have a similar composition to the cell of origin. An exosome released by a particular cell is unique since it carries information about the state of the cell in pathological conditions such as cancer. miRNAs carried by cancer-derived exosomes play a multifaceted role by taking part in cell proliferation, invasion, metastasis, epithelial–mesenchymal transition, angiogenesis, apoptosis, and immune evasion. Depending on the type of miRNA that it carries as its cargo, it can render cells chemo- or radiosensitive or resistant and can also act as a tumor suppressor. Since the composition of exosomes is affected by the cellular state, stress, and changes in the environment, they can be used as diagnostic or prognostic biomarkers. Their unique ability to cross biological barriers makes them an excellent choice as vehicles for drug delivery. Because of their easy availability and stability, they can be used to replace cancer biopsies, which are invasive and expensive. Exosomes can also be used to follow the progression of diseases and monitor treatment strategies. A better understanding of the roles and functions of exosomal miRNA can be used to develop noninvasive, innovative, and novel treatments for cancer.

Background: Breast cancer (BC) is one of the most prevalent cancers in developing and developed countries among women worldwide. Mammography is one of the superior methods for BC detection, but it carries up to 20% false-negative results, especially in early cases. Histological examination of tissue biopsies and fine-needle aspiration cytology are invasive techniques. Hence, minimally invasive markers are needed for the improved detection of BC. microRNAs, small, noncoding, single-stranded RNAs functioning as tumor suppressor genes or oncogenes, are attractive biomarkers for early detection. This study aimed to examine the serum levels of miR21 and miR10b in patients with BC especially in the early stages compared to healthy controls to evaluate their potential use as BC biomarkers. Methods: This study included 90 females who were divided into two groups. Group I included 70 patients with BC and was subdivided into group Ia with 40 nonmetastatic BC patients and group Ib with 30 metastatic BC patients. Group II included 20 apparently healthy females as a control group. Serum miR21 and miR10b as biomarkers and miR16 as a housekeeping gene were evaluated using real-time polymerase chain reaction. Results: The median levels of miR10b and miR21 were statistically significantly upregulated in the sera of patients with BC compared to healthy controls (P = 0.001). Receiver operating characteristic curve analyses demonstrated that serum levels of miR10b and miR21 were useful biomarkers for distinguishing between patients with BC and the control group, with an area under the curve (AUC) of 0.991 with 97.1% sensitivity and 100% specificity at a cutoff of 3.1 for miR10b and an AUC of 0.965 with 95.7% sensitivity and 85% specificity at a cutoff of 1.7 for miR21. Regarding the early stages of BC, the median levels of the fold change of serum miR21 and miR10b were statistically significantly higher in patients with BC (stages I and IIa) than in the control group (P < 0.001). Conclusions: Both miR21 and miR10b have valuable diagnostic roles in detecting the early stages of BC. [ABSTRACT FROM AUTHOR]

Background: Extrachromosomal circular deoxyribonucleic acid (eccDNA) is evolving as a valuable biomarker, while little is known about its presence in urine. Methods: Here, we report the discovery and analysis of urinary cell‐free eccDNAs (ucf‐eccDNAs) in healthy controls and patients with advanced chronic kidney disease (CKD) by Circle‐Seq. Results: Millions of unique ucf‐eccDNAs were identified and comprehensively characterised. The ucf‐eccDNAs are GC‐rich. Most ucf‐eccDNAs are less than 1000 bp and are enriched in four pronounced peaks at 207, 358, 553 and 732 bp. Analysis of the genomic distribution of ucf‐eccDNAs shows that eccDNAs are found on all chromosomes but enriched on chromosomes 17, 19 and 20 with a high density of protein‐coding genes, CpG islands, short interspersed transposable elements (SINEs) and simple repeat elements. Analysis of eccDNA junction sequences further suggests that microhomology and palindromic repeats might be involved in eccDNA formation. The ucf‐eccDNAs in CKD patients are significantly higher than those in healthy controls. Moreover, eccDNA with miRNA genes is highly enriched in CKD ucf‐eccDNA. Conclusions: This work discovers and provides the first deep characterisation of ucf‐eccDNAs and suggests ucf‐eccDNA as a valuable noninnvasive biomarker for urogenital disorder diagnosis and monitoring. [ABSTRACT FROM AUTHOR]

Immunotherapy (IO) has increasingly been demonstrated to provide therapeutic benefit to patients with metastatic colorectal cancer (mCRC). However, only a subset of mCRC tumors respond to IO. Monitoring response with tumor biomarkers like carcinoembryonic antigen (CEA) has been challenging in patients with microsatellite stable (MSS) mCRC due to low expression of CEA (CEA/lo). Noninvasive blood-based biomarkers such as circulating tumor DNA (ctDNA) can inform early treatment response and augment radiographic monitoring. We describe a case study of a patient with chemotherapy-refractory CEA/lo MSS mCRC, with metastatic disease present in a cardiophrenic lymph node. The patient was given 2 cycles of combination IO (ipilimumab/nivolumab). Response was monitored by ctDNA using a multiplex PCR next-generation sequencing assay, CEA, and CT scan. After IO administration, ctDNA levels rapidly declined, becoming undetectable. This was concurrent with radiographic resolution of the lymph node metastasis. Serial monitoring of CEA during this same period was uninformative, with no significant changes observed. Significant decline in ctDNA identified metastatic response to IO in a patient with CEA/lo, MSS mCRC and was concurrently validated by CT scan. This case study provides evidence that ctDNA can be used as a prospective surrogate for radiographic tumor response.

The requirement of blood-circulating sensitive biomarkers for monitoring liver transplant (LT) is currently a necessary step aiming at the reduction of standard invasive protocols, such as liver biopsy. In this respect, the main objective of this study is to assess circulating microRNA (c-miR) changes in recipients’ blood before and after LT and to correlate their blood levels with gold standard biomarkers and with outcomes such as rejection or complications after graft. An miR profile was initially performed; then, the most deregulated miRs were validated by RT-qPCR in 14 recipients pre- and post-LT and compared to a control group of 24 nontransplanted healthy subjects. MiR-122-5p, miR-92a-3p, miR-18a-5p, and miR-30c-5p, identified in the validation phase, were also analyzed considering an additional 19 serum samples collected from LT recipients and focusing on different follow-up (FU) times. The results showed significant, FU-related changes in c-miRs. In particular, miR-122-5p, miR-92a-3p, and miR-18a-5p revealed the same trend after transplantation and an increase in their level was found in patients with complications, independently from FU times. Conversely, the variations in the standard haemato-biochemical parameters for liver function assessment were not significant in the same FU period, confirming the importance of c-miRs as potential noninvasive biomarkers for monitoring patients’ outcomes.

The human urinary proteome provides an assessment of kidney injury with specific biomarkers for different kidney injury phenotypes. In an effort to fully map and decipher changes in the urine proteome and peptidome after kidney transplantation, renal allograft biopsy matched urine samples were collected from 396 kidney transplant recipients. Centralized and blinded histology data from paired graft biopsies was used to classify urine samples into diagnostic categories of acute rejection, chronic allograft nephropathy, BK virus nephritis, and stable graft. A total of 245 urine samples were analyzed by liquid chromatography-mass spectrometry using isobaric Tags for Relative and Absolute Quantitation (iTRAQ) reagents. From a group of over 900 proteins identified in transplant injury, a set of 131 peptides were assessed by selected reaction monitoring for their significance in accurately segregating organ injury causation and pathology in an independent cohort of 151 urine samples. Ultimately, a minimal set of 35 proteins were identified for their ability to segregate the 3 major transplant injury clinical groups, comprising the final panel of 11 urinary peptides for acute rejection (93% area under the curve [AUC]), 12 urinary peptides for chronic allograft nephropathy (99% AUC), and 12 urinary peptides for BK virus nephritis (83% AUC). Thus, urinary proteome discovery and targeted validation can identify urine protein panels for rapid and noninvasive differentiation of different causes of kidney transplant injury, without the requirement of an invasive biopsy.

Respiratory tract microbiome is closely related to respiratory tract infections, while characterization of oropharyngeal microbiome in recovered coronavirus disease 2019 (COVID‐19) patients is not studied. Herein, oropharyngeal swabs are collected from confirmed cases (CCs) with COVID‐19 (73 subjects), suspected cases (SCs) (36), confirmed cases who recovered (21), suspected cases who recovered (36), and healthy controls (Hs) (140) and then completed MiSeq sequencing. Oropharyngeal microbial α‐diversity is markedly reduced in CCs versus Hs. Opportunistic pathogens are increased, while butyrate‐producing genera are decreased in CCs versus Hs. The classifier based on eight optimal microbial markers is constructed through a random forest model and reached great diagnostic efficacy in both discovery and validation cohorts. Notably, the classifier successfully diagnosed SCs with positive IgG antibody as CCs and is demonstrated from the perspective of the microbiome. Importantly, several genera with significant differences gradually increase and decrease along with recovery from COVID‐19. Forty‐four oropharyngeal operational taxonomy units (OTUs) are closely correlated with 11 clinical indicators of SARS‐CoV‐2 infection and Hs based on Spearman correlation analysis. Together, this research is the first to characterize oropharyngeal microbiota in recovered COVID‐19 cases and suspected cases, to successfully construct and validate the diagnostic model for COVID‐19 and to depict the correlations between microbial OTUs and clinical indicators. [ABSTRACT FROM AUTHOR]

Abstract Respiratory tract microbiome is closely related to respiratory tract infections, while characterization of oropharyngeal microbiome in recovered coronavirus disease 2019 (COVID‐19) patients is not studied. Herein, oropharyngeal swabs are collected from confirmed cases (CCs) with COVID‐19 (73 subjects), suspected cases (SCs) (36), confirmed cases who recovered (21), suspected cases who recovered (36), and healthy controls (Hs) (140) and then completed MiSeq sequencing. Oropharyngeal microbial α‐diversity is markedly reduced in CCs versus Hs. Opportunistic pathogens are increased, while butyrate‐producing genera are decreased in CCs versus Hs. The classifier based on eight optimal microbial markers is constructed through a random forest model and reached great diagnostic efficacy in both discovery and validation cohorts. Notably, the classifier successfully diagnosed SCs with positive IgG antibody as CCs and is demonstrated from the perspective of the microbiome. Importantly, several genera with significant differences gradually increase and decrease along with recovery from COVID‐19. Forty‐four oropharyngeal operational taxonomy units (OTUs) are closely correlated with 11 clinical indicators of SARS‐CoV‐2 infection and Hs based on Spearman correlation analysis. Together, this research is the first to characterize oropharyngeal microbiota in recovered COVID‐19 cases and suspected cases, to successfully construct and validate the diagnostic model for COVID‐19 and to depict the correlations between microbial OTUs and clinical indicators.

Objectives: To provide an in-depth analysis of noninvasive methods for the early diagnosis of oral premalignant lesions, focusing on novel biomarkers and optical technologies, and to discuss their potential in improving the prognosis of patients with oral oncological diseases. Methods: This state-of-the-art review examines various noninvasive diagnostic techniques, including the utilization of salivary microRNAs and optical technologies such as Raman spectroscopy, elastic scattering spectroscopy, diffuse reflectance spectroscopy, narrow-band imaging, autofluorescence imaging, toluidine blue staining, and microendoscopy. Results: Several noninvasive techniques have shown varying degrees of effectiveness in detecting oral cancer. Autofluorescence imaging exhibited sensitivities up to 100% but had variable specificity. toluidine blue staining reported sensitivity between 77% and 100% for high-risk lesions or cancer, with specificity around 45% to 67%. Spectroscopy techniques achieved 72% to 100% sensitivities and specificities of 75% to 98%. Microendoscopy presented a sensitivity of 84% to 95% and a specificity of 91% to 95%. Conclusion: The review highlights the strengths and limitations of each noninvasive diagnostic method and their recent advancements. Although promising results have been demonstrated, there is a need for further development of reliable strategies for early detection and intervention in oral oncology., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Bariatric surgery is among the therapeutic options for non-alcoholic fatty liver disease (NAFLD), affecting 90% of patients with obesity. The aim of this study was to evaluate the evolution of NAFLD lesions 1 year after surgery using noninvasive markers. Methods: From November 2011 to November 2012, 253 patients with obesity undergoing bariatric surgery in three French University Hospitals were included. Histological data regarding intraoperative liver biopsy were collected at baseline, clinical, and biological data, including FibroTest®, SteatoTest®, and NASHTest®, before and after surgery. Results: Fibrosis' prevalence was 74.2% with a positive predictive value (PPV) for FibroTest® of 78.6% and 43.4% for significant fibrosis (Kleiner ≥ F2) with a negative predictive value (NPV) of 56.1%. NAFLD's prevalence was 84% with a PPV for SteatoTest® of 85.9% and 7.7% for NASH with an NPV for NASHTest® of 93.8%. One year after bariatric surgery, mean BMI had significantly decreased from 46.5 to 31.7 kg/m2 (p < 0.001). Fibrosis assessed by the FibroTest® showed that 82.5% of patients were F0 after surgery compared to 90.9% before. Using SteatoTest®, the percent of patient without steatosis (S0) increased from 1.6 to 49.6% after surgery, and rate of severe steatosis (S3) improved from 43.3 to 3.9%. NASHTest® revealed that the percent of patients without NASH increased from 12.8 to 73.6% and rates of NASH improved from 12 to 0.8%. Conclusions: Validated noninvasive biomarkers SteatoTest® and NASHTest® suggested NAFLD and steatohepatitis improvement after bariatric surgery and might be useful tools for patient follow-up. Regarding fibrosis, FibroTest® was not accurate in patients with extreme obesity. [ABSTRACT FROM AUTHOR]

Background: Around 10% of gastric carcinomas (GC) contain Epstein–Barr virus (EBV) DNA. We characterized the GC-specific antibody response to this common infection, which may provide a noninvasive method to detect EBV-positive GC and elucidate its contribution to carcinogenesis. Methods: Plasma samples from EBV-positive (n = 28) and EBV-negative (n = 34) Latvian GC patients were immune-profiled against 85 EBV proteins on a multi-microbial Nucleic Acid Programmable Protein Array (EBV-NAPPA). Antibody responses were normalized for each sample as ratios to the median signal intensity (MNI) across all antigens, with seropositivity defined as MNI ≥ 2. Antibodies with ≥ 20% sensitivity at 95% specificity for tumor EBV status were verified by enzyme-linked immunosorbent assay (ELISA) and validated in independent samples from Korea and Poland (n = 24 EBV-positive, n = 65 EBV-negative). Results: Forty anti-EBV IgG and eight IgA antibodies were detected by EBV-NAPPA in ≥ 10% of EBV-positive or EBV-negative GC patients, of which nine IgG antibodies were discriminative for tumor EBV status. Eight of these nine were verified and seven were validated by ELISA: anti-LF2 (odds ratio = 110.0), anti-BORF2 (54.2), anti-BALF2 (44.1), anti-BaRF1 (26.7), anti-BXLF1 (12.8), anti-BRLF1 (8.3), and anti-BLLF3 (5.4). The top three had areas under receiver operating characteristics curves of 0.81–0.85 for distinguishing tumor EBV status. Conclusions: The EBV-associated GC-specific humoral response was exclusively directed against lytic cycle immediate-early and early antigens, unlike other EBV-associated malignancies such as nasopharyngeal carcinoma and lymphoma where humoral response is primarily directed against late lytic antigens. Specific anti-EBV antibodies could have utility for clinical diagnosis, epidemiologic studies, and immune-based precision treatment of EBV-positive GC. [ABSTRACT FROM AUTHOR]

Immunotherapy (IO) has increasingly been demonstrated to provide therapeutic benefit to patients with metastatic colorectal cancer (mCRC). However, only a subset of mCRC tumors respond to IO. Monitoring response with tumor biomarkers like carcinoembryonic antigen (CEA) has been challenging in patients with microsatellite stable (MSS) mCRC due to low expression of CEA (CEA/lo). Noninvasive blood-based biomarkers such as circulating tumor DNA (ctDNA) can inform early treatment response and augment radiographic monitoring. We describe a case study of a patient with chemotherapy-refractory CEA/lo MSS mCRC, with metastatic disease present in a cardiophrenic lymph node. The patient was given 2 cycles of combination IO (ipilimumab/nivolumab). Response was monitored by ctDNA using a multiplex PCR next-generation sequencing assay, CEA, and CT scan. After IO administration, ctDNA levels rapidly declined, becoming undetectable. This was concurrent with radiographic resolution of the lymph node metastasis. Serial monitoring of CEA during this same period was uninformative, with no significant changes observed. Significant decline in ctDNA identified metastatic response to IO in a patient with CEA/lo, MSS mCRC and was concurrently validated by CT scan. This case study provides evidence that ctDNA can be used as a prospective surrogate for radiographic tumor response. [ABSTRACT FROM AUTHOR]

Carcinoma of the stomach is one of the major prevalent and principal causes of cancer-related deaths worldwide. Current advancement in technology has improved the understanding of the pathogenesis and pathology of gastric cancers (GC). But, high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate novel early diagnostic/prognostic markers and therapeutic targets for GC, which are sufficiently sensitive to GC. Current biomedical investigations have explored several budding GC biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray, and RNA/DNA-Seq. Recently, small non-coding microRNAs (miRNAs) are becoming vital regulators in oncogenesis pathways and can act as handy clinical biomarkers. The newly introduced class of biomarkers is rising as new molecules for cancer diagnosis and prognosis. For better understanding of the gastric carcinogenesis, miRNAs may help to elucidate the mechanisms of tumor growth and can help to discover novel untimely potent markers for early detection of GC. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic/prognostic tools and therapeutic targets. Thus, here we introduce potential future treatment strategies for gastrointestinal (GI) cancers, which indicate the practicality and clinical applications of miRNAs in GC.

Breast cancer causes severe mental stress on the affected woman during investigation, diagnosis and treatment as breast is regarded as a symbol of beauty, sexuality and motherhood. Over and above the primary function of feeding infant, breast symbolizes womanhood and serves as sexual object. Current biomedical research investigations have explored several potential breast cancer (BC) biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray and RNA/DNASeq. Recently smallest noncoding microRNAs are becoming the essential regulators in the oncogenesis pathways and they can act as handy noninvasive clinical diagnostic biomarkers. This newly introduced class of noninvasive biomarkers is rising as a new molecule for the cancer diagnosis and prognosis. A better understanding is the involvement of miRNAs in breast carcinogenesis can make available insights into the mechanisms of tumor development and could help to discover novel early potent noninvasive markers for early detection of breast Cancer. In recent clinical research the discovery of miRNAs in body fluids, such as serum and plasma opens the possibility of using them as noninvasive biomarkers of disease including breast cancer. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic and prognostic tool. Thus, here we bring in potential future early stage detection strategies for breast cancer, which indicate the practicality and clinical applications of miRNAs in breast cancer.

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of disease that can range from isolated macrovesicular hepatocellular steatosis to nonalcoholic steatohepatitis (NASH) with or without fibrosis to cirrhosis. The prevalence of NAFLD has increased over several decades, mirroring the global obesity pandemic. NAFLD currently represents the most common etiology of chronic liver disease in children and adolescents worldwide. Disease presentation in childhood strongly suggests that these children may have unique susceptibilities and more severe long-term consequences. Emerging data demonstrate that the pathogenesis of early-onset NAFLD is secondary to a complex interplay involving genetic, metabolic, environmental, and microbiological factors. Such influences may begin in utero. Dietary and lifestyle modifications remain the primary effective therapeutic interventions, although long-term efficacy is limited by poor adoption or adherence. Advances in the development and validation of non-invasive biomarkers and imaging modalities will facilitate diagnosis for affected children and adolescents and facilitate long-term natural history studies and the development of therapeutic interventions.

Abstract Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronically elevated liver enzymes. Diagnosis and risk stratification of NAFLD remains clinically challenge as patients with NAFLD are either asymptomatic or have nonspecific presenting complaints and may have normal liver enzymes. Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, is also difficult to differentiate noninvasively, and a liver biopsy is required to definitively diagnose NASH. Thus, the definitive diagnosis and risk stratification of NAFLD is embedded in histological assessment of the liver. Several clinical aides been investigated in an attempt to risk stratify and identify patients noninvasively as doing a liver biopsy in all patients with NAFLD are not feasible. Since these biomarkers are unable to differentiate NASH from non‐NASH, they have leveraged biochemical changes within the liver as patients progress to varying degree of hepatic fibrosis to identify patients with moderate fibrosis (fibrosis stage 2 or greater) and advanced fibrosis (fibrosis stage 3 or greater) to help guide the need for additional and more definitive workup. These clinical aides span from by‐products of apoptosis to statistical modelling of clinically available data to identify ‘at‐risk’ patients with NAFLD. The current review will focus the diagnostic performance of these noninvasive serum‐based biomarkers in NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronically elevated liver enzymes. Diagnosis and risk stratification of NAFLD remains clinically challenge as patients with NAFLD are either asymptomatic or have nonspecific presenting complaints and may have normal liver enzymes. Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, is also difficult to differentiate noninvasively, and a liver biopsy is required to definitively diagnose NASH. Thus, the definitive diagnosis and risk stratification of NAFLD is embedded in histological assessment of the liver. Several clinical aides been investigated in an attempt to risk stratify and identify patients noninvasively as doing a liver biopsy in all patients with NAFLD are not feasible. Since these biomarkers are unable to differentiate NASH from non‐NASH, they have leveraged biochemical changes within the liver as patients progress to varying degree of hepatic fibrosis to identify patients with moderate fibrosis (fibrosis stage 2 or greater) and advanced fibrosis (fibrosis stage 3 or greater) to help guide the need for additional and more definitive workup. These clinical aides span from by‐products of apoptosis to statistical modelling of clinically available data to identify 'at‐risk' patients with NAFLD. The current review will focus the diagnostic performance of these noninvasive serum‐based biomarkers in NAFLD. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are non-coding RNAs with a length of 18–22 nucleotides that regulate about a third of the human genome at the post-transcriptional level. MiRNAs are involved in almost all biological processes, including cell proliferation, apoptosis, and cell differentiation, but also play a key role in the pathogenesis of many diseases. Most miRNAs are expressed within the cells themselves. Due to various forms of transport from cells like exosomes, circulating miRNAs are stable and can be found in human body fluids, such as blood, saliva, cerebrospinal fluid, and urine. Circulating miRNAs are of great interest as potential noninvasive biomarkers for tumors, lipid disorders, diabetes mellitus, and cardiovascular diseases. However, the possibility of their use in the clinic is limited, and this is associated with a number of problems since currently there are significant differences between the procedures for processing samples, methods of analysis, and especially strategies for standardizing results. Moreover, miRNAs can represent not only potential biomarkers but also become new therapeutic agents and be used in modern clinical practice, which again confirms the need for their study. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%–25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte–macrophage–hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate whether acute pain associated with castration and tail docking of male piglets may modulate the expression of salivary microRNAs (miRNAs) and to explore their potential use as biomarkers. Thirtysix healthy 4-d-old piglets (Hermitage × Duroc) were randomly assigned to three groups: the first group (12 piglets) has been pretreated with anesthetic and anti-inflammatory drugs (ANA) and then castrated and tail docked; the second one (12 piglets) has been castrated and tail docked without any drugs (CONV); the third one (12 piglets) has been only handled (SHAM). Saliva was collected 10 min before (control group) and 30 to 45 min after the procedures. Salivary cortisol has been quantified. The expression concentrations of seven miRNAs, namely miR-19b, miR-27b-3p, miR-215, miR-22-3p, miR155-5p, hsa-miR-365-5p, and hsa-miR-204, were measured and assessed as potential biomarkers of pain by quantitative Polimerase Chain Reaction using TaqMan probes. The area under the receiver operating curve (AUC) was used to evaluate the diagnostic performance of miRNAs. The concentration of salivary cortisol increased after treatment in CONV and ANA, while no significant variation was observed in the SHAM group. The comparative analysis demonstrated that the concentrations of salivary miR-19b (P = 0.001), miR-27b (P = 0.042), and miR-365 (P < 0.0001) were significantly greater in CONV as compared with pretreatment. The AUC of pretreatment vs. CONV and CONV vs. ANA were excellent for miR19b and miR-365 and fair for miR-27b. Combining two miRNAs, namely miR-19b and miR-365, in a panel increased the efficiency of distinguishing between pre- and post-treatment groups. No differences have been identified between SHAM and ANA groups. mRNA potential targets of differentially expressed-miRNA were investigated, and genes related to pain and inflammation were identified: miR-19b potentially modulates TGF-beta and focal adhesion pathways, miR-365 regulates cytokines expression (i.e., IL-1, Tumor Necross Factor-alpha, and IL-8 cytokine), and miR-27b regulates macrophage inflammatory protein pathways (i.e., MIP1-beta). In conclusion, we demonstrated that the abundance of miR-19b, miR-27b, and miR-365 increases in the saliva of piglets castrated and tail docked without the administration of pain-relieving drugs. Further studies are needed to assess their potential during routine husbandry procedures and to extend their assessment in other stressful events, such as weaning or chronic pain. [ABSTRACT FROM AUTHOR]

Introduction: The identification of novel noninvasive biomarkers to ameliorate early-diagnosis, and disease prognosis, as well as to support personalized treatment and monitoring decisions is of first clinical priority for cancer patients' care. Exosomes are natural endosome-derived extracellular vesicles that have emerged as crucial mediators of intercellular communication and tumor progression. Considering that deregulated miRNA levels have been described in numerous human malignancies and that tumor-derived exosomes reflect miRNA expression of donor tumor cells, the evaluation of exosome-derived circulating miRNAs (exomiRs) may offer a new promising class of noninvasive molecular markers to improve patients' management and quality-of-life. Areas covered: In the current review we have summarized the existing knowledge on the clinical relevance of circulating exosomal miRNAs in improving cancer diagnosis and prognosis, and thus supporting personalized patients' management Expert commentary: Cancer research has highlighted the abundance of exomiRs in patients' plasma and serum samples, as well as their biomarker capabilities in the vast majority of human malignancies studied so far. Their analytical stability constitutes exomiRs ideal molecular markers to overcome numerous limitations of cancer clinical management, while future large-scale studies should unveil exomiRs translational utility in modern cancer molecular diagnostics. [ABSTRACT FROM AUTHOR]

Abstract Introduction The Alzheimer's disease (AD) process is likely initiated many years before clinical onset. Biomarkers of preclinical disease are critical for the development of disease‐modifying or even preventative therapies. Current biomarkers for early disease, including cerebrospinal fluid tau and amyloid β (Aβ) levels, structural and functional magnetic resonance imaging, and the use of brain amyloid imaging, are limited because they are very invasive or expensive. Noninvasive biomarkers may be a more accessible alternative, but none can currently detect preclinical AD with the required sensitivity and specificity. Methods Here, we show a novel, straight‐forward, and noninvasive approach for assessment of early stages of cognitive decline. Salivary samples from cases of amnestic mild cognitive impairment (aMCI) and AD, and neurology controls were analyzed. Results We have discovered and validated a new single saliva biomarker, lactoferrin, which in our cross‐sectional investigation perfectly discriminates clinically diagnosed aMCI and AD patients from a cognitively healthy control group. The accuracy for AD diagnosis shown by salivary lactoferrin was greater than that obtained from core cerebrospinal fluid (CSF) biomarkers, including total tau and CSF Aβ42. Furthermore, salivary lactoferrin can be used for population screening and for identifying those underdiagnosed subjects with very early stages of mild cognitive impairment and AD. Conclusion This biomarker may offer new insights in the early diagnostics for AD.

Purpose: We aimed to assess the diagnostic reliability of two indirect biomarkers, APRI and FIB-4, for the staging of liver fibrosis using transient elastography (TE) as reference standard, among HIV/HCV co-infected and HCV mono-infected patients. Methods: This is an observational, retrospective study on subjects who had access to the RESIST HCV from October 2013 to December 2016, a regional network encompassing 22 hospitals and academic centers throughout Sicily. Sensitivity, specificity and diagnostic accuracy of indirect biomarkers for liver stiffness measurement (LSM) < 9.5 kPa (significant fibrosis) and LSM ≥ 12.5 kPa (cirrhosis) were determined by receiver operator characteristics (ROC) curves. Results: 238 HIV/HCV co-infected and 1937 HCV mono-infected patients were included. Performances of FIB-4 and APRI for the detection of significant fibrosis and cirrhosis proved to be unsatisfactory, with very high false negative and false positive rates among both cohorts. No significant differences were found after stratification of HIV/HCV co-infected patients for BMI < or ≥ 25, ALT < or ≥ 40 IU/L, ALT < or ≥ 80 IU/L, and presence/absence of a bright liver echo pattern on ultrasonography. Conclusions: Differently from other studies, we detected the unreliability of APRI and FIB-4 for the assessment of liver fibrosis in both HCV mono-infected and HIV/HCV co-infected patients. [ABSTRACT FROM AUTHOR]

Carcinoma of the stomach is one of the major prevalent and principal causes of cancer-related deaths worldwide. Current advancement in technology has improved the understanding of the pathogenesis and pathology of gastric cancers (GC). But, high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate novel early diagnostic/prognostic markers and therapeutic targets for GC, which are sufficiently sensitive to GC. Current biomedical investigations have explored several budding GC biomarker by utilizing serum proteins, natural oncogenic genes during improvement in molecular technologies as microarray, and RNA/DNA-Seq. Recently, small non-coding microRNAs (miRNAs) are becoming vital regulators in oncogenesis pathways and can act as handy clinical biomarkers. The newly introduced class of biomarkers is rising as new molecules for cancer diagnosis and prognosis. For better understanding of the gastric carcinogenesis, miRNAs may help to elucidate the mechanisms of tumor growth and can help to discover novel untimely potent markers for early detection of GC. Here in this review, we summarize the recent research studies supporting the utility of miRNAs as novel early diagnostic/prognostic tools and therapeutic targets. Thus, here we introduce potential future treatment strategies for gastrointestinal (GI) cancers, which indicate the practicality and clinical applications of miRNAs in GC. [ABSTRACT FROM AUTHOR]