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The differential diagnosis of erosive osteoarthritis of the hand (EHOA) and psoriatic arthritis (PsA) is challenging, especially considering the absence of specific diagnostic biomarkers. The aim of the present study was to evaluate whether a pattern of microRNAs (miRNAs) (miR-21, miR-140, miR-146a, miR-155, miR-181a, miR-223), pro-inflammatory cytokines [interleukin (IL)-1β, IL-6, IL-17a, IL-23a, and tumor necrosis factor (TNF)-α], and adipokines (adiponectin, chemerin, leptin, resistin, and visfatin) could help to differentiate EHOA from PsA. Fifty patients with EHOA, fifty patients with PsA, and fifty healthy subjects (HS) were studied. The gene expression of miRNAs and cytokines were evaluated by real-time PCR from peripheral blood mononuclear cells and serum levels of cytokines and adipokines were quantified by ELISA in PsA and EHOA patients and HS. Gene expression showed the significant up-regulation of the analyzed miRNAs in EHOA and PsA patients as compared to HS and higher miR-155 in EHOA vs. PsA patients. The expression levels of IL-1β and IL-6 did not show any significant differences between EHOA and PsA, while IL-17a and IL-23a were significantly up-regulated in PsA compared to EHOA. Circulating TNF-α levels were higher in EHOA compared to PsA, while PsA patients exhibited significantly elevated levels of IL-23a. The combination of miR-155 with C-reactive protein enhanced the ability to differentiate EHOA from PsA, further supporting the potential of miR-155 as a diagnostic biomarker.

Genomic studies have yielded important insights into the pathogenesis of obesity. Circulating microRNAs (miRNAs) are valuable biomarkers of systemic diseases and potential therapeutic targets. We sought to define the circulating pattern of miRNAs in obesity and examine changes after weight loss. We assessed the genomewide circulating miRNA profile cross-sectionally in 32 men and after surgery-induced weight loss in 6 morbidly obese patients. The most relevant miRNAs were cross-sectionally validated in 80 men and longitudinally in 22 patients (after surgery-induced weight loss). We evaluated the effects of diet-induced weight loss in 9 obese patients. Thirty-six circulating miRNAs were associated with anthropometric variables in the initial sample. In the validation study, morbidly obese patients showed a marked increase of miR-140-5p, miR-142-3p (both P < 0.0001), and miR-222 (P = 0.0002) and decreased levels of miR-532-5p, miR-125b, miR-130b, miR-221, miR-15a, miR-423-5p, and miR-520c-3p (P < 0.0001 for all). Interestingly, in silico targets leukemia inhibitory factor receptor (LIFR) and transforming growth factor receptor (TGFR) of miR-140-5p, miR-142-3p, miR-15a, and miR-520c-3p circulated in association with their corresponding miRNAs. Moreover, a discriminant function of 3 miRNAs (miR-15a, miR-520c-3p, and miR-423-5p) was specific for morbid obesity, with an accuracy of 93.5%. Surgery-induced (but not diet-induced) weight loss led to a marked decrease of miR-140-5p, miR-122, miR-193a-5p, and miR-16-1 and upregulation of miR-221 and miR-199a-3p (P < 0.0001 for all). Circulating miRNAs are deregulated in severe obesity. Weight loss-induced changes in this profile and the study of in silico targets support this observation and suggest a potential mechanistic relevance.

Traumatic brain injury (TBI) is a prevalent and debilitating condition, which often leads to the development of post-traumatic epilepsy (PTE), a condition that yet lacks preventive strategies. Biperiden, an anticholinergic drug, is a promising candidate that has shown efficacy in murine models of PTE. MicroRNAs (miRNAs), small regulatory RNAs, can help in understanding the biological basis of PTE and act as TBI- and PTE-relevant biomarkers that can be detected peripherally, as they are present in extracellular vesicles (EVs) that cross the blood–brain barrier. This study aimed to investigate miRNAs in serum EVs from patients with TBI, and their association with biperiden treatment and PTE. Blood samples of 37 TBI patients were collected 10 days after trauma and treatment initiation in a double-blind clinical trial. A total of 18 patients received biperiden, with three subjects developing PTE, and 19 received placebo, with two developing PTE. Serum EVs were characterized by size distribution and protein profiling, followed by high-throughput sequencing of the EV miRNome. Differential expression analysis revealed no significant differences in miRNA expression between TBI patients with and without PTE. Interestingly, miR-9-5p displayed decreased expression in biperiden-treated patients compared to the placebo group. This miRNA regulates genes enriched in stress response pathways, including axonogenesis and neuronal death, relevant to both PTE and TBI. These findings indicate that biperiden may alter miR-9-5p expression in serum EVs, which may play a role in TBI resolution.

A nested case control study of a longitudinal cohort comparing pregnant women enrolled at 10 to 13 gestational weeks was carried out to evaluate risk assessment for preeclampsia and IUGR based on circulating placental specific C19MC microRNAs in early pregnancy. The expression of placental specific C19MC microRNAs (miR-516b-5p, miR-517-5p, miR-518b, miR-520a-5p, miR-520h, and miR-525-5p) was determined in plasma samples from pregnancies that subsequently developed preeclampsia (n = 21), IUGR (n = 18), and 58 normal pregnancies using real-time PCR and comparative Ct method relative to synthetic Caenorhabditis elegans microRNA (cel-miR-39). Circulating C19MC microRNAs were up-regulated (miR-517-5p, p = 0.005; miR-518b, p = 0.013; miR-520h, p = 0.021) or showed a trend toward up-regulation in patients destined to develop preeclampsia (miR-520a-5p, p = 0.067; miR-525-5p, p = 0.073). MiR-517-5p had the best predictive performance for preeclampsia with a sensitivity of 42.9%, a specificity of 86.2%, a PPV of 52.9% and a NPV of 80.6%. The combination of all examined circulating C19MC microRNAs had no advantage over using only the miR-517-5p biomarker to predict the occurrence of preeclampsia (a sensitivity of 20.6%, a specificity of 90.8%, a PPV of 44.8%, and a NPV of 76.0%). Up-regulation of miR-517-5p, miR-518b and miR-520h was associated with a risk of later development of preeclampsia. First trimester screening of extracellular miR-517-5p identified a proportion of women with subsequent preeclampsia. No circulating C19MC microRNA biomarkers were identified that could predict later occurrence of IUGR.

We aimed to explore whether changes in circulating levels of miRNAs according to type 2 diabetes mellitus (T2DM) or prediabetes status could be used as biomarkers to evaluate the risk of developing the disease. The study included 462 patients without T2DM at baseline from the CORDIOPREV trial. After a median follow-up of 60 months, 107 of the subjects developed T2DM, 30 developed prediabetes, 223 maintained prediabetes and 78 remained disease-free. Plasma levels of four miRNAs related to insulin signaling and beta-cell function were measured by RT-PCR. We analyzed the relationship between miRNAs levels and insulin signaling and release indexes at baseline and after the follow-up period. The risk of developing disease based on tertiles (T1-T2-T3) of baseline miRNAs levels was evaluated by COX analysis. Thus, we observed higher miR-150 and miR-30a-5p and lower miR-15a and miR-375 baseline levels in subjects with T2DM than in disease-free subjects. Patients with high miR-150 and miR-30a-5p baseline levels had lower disposition index ( p  = 0.047 and p  = 0.007, respectively). The higher risk of disease was associated with high levels (T3) of miR-150 and miR-30a-5p ( HR T3-T1  = 4.218 and HR T3-T1  = 2.527, respectively) and low levels (T1) of miR-15a and miR-375 ( HR T1-T3  = 3.269 and HR T1-T3  = 1.604, respectively). In conclusion, our study showed that deregulated plasma levels of miR-150 , miR-30a-5p , miR-15a , and miR-375 were observed years before the onset of T2DM and pre-DM and could be used to evaluate the risk of developing the disease, which may improve prediction and prevention among individuals at high risk for T2DM. Metabolic disease: a red flag for diabetes risk Tiny RNA molecules circulating in the blood could give early warning of type 2 diabetes risk. MicroRNAs help regulate the expression of other genes, and recent research has linked irregularities in these molecules to many different diseases. Researchers led by José López Miranda of the University of Córdoba in Spain monitored a cohort of 462 patients for several years to assess how plasma levels of certain microRNAs are deregulated before the onset and progression of diabetes. They observed a striking ‘signature’ of altered expression in four microRNAs for patients who developed diabetes over the course of the study. Intriguingly, patients with markedly elevated blood sugar—state known as prediabetes—exhibited a similar signature, but with more modest alteration in the gene expression levels, indicating that these microRNAs could help clinicians track and prevent disease onset.

Acute rejection (AR) is critical for long-term graft survival in kidney transplant recipients (KTRs). This study aimed to evaluate the efficacy of the integrated risk score of omics-based biomarkers in predicting AR in KTRs. This prospective, randomized, controlled, multicenter, pilot study enrolled 40 patients who recently underwent high-immunologic-risk kidney transplantation (KT). Five omics biomarkers were measured, namely, blood mRNA (three-gene signature), urinary exosomal miRNA (three-gene signature), urinary mRNA (six-gene signature), and two urinary exosomal proteins (hemopexin and tetraspanin-1) at 2 weeks and every 4 weeks after KT for 1 year. An integrated risk score was generated by summing each biomarker up. The biomarker group was informed about the integrated risk scores and used to adjust immunosuppression, but not the control group. The outcomes were graft function and frequency of graft biopsy. Sixteen patients in the biomarker group and nineteen in the control group completed the study. The mean estimated glomerular filtration rate after KT did not differ between the groups. Graft biopsy was performed in two patients (12.5%) and nine (47.4%) in the biomarker and control groups, respectively, with the proportion being significantly lower in the biomarker group (p = 0.027). One patient (6.3%) in the biomarker group and two (10.5%) in the control group were diagnosed with AR, and the AR incidence did not differ between the groups. The tacrolimus trough level was significantly lower in the biomarker group than in the control group at 1 year after KT (p = 0.006). Integrated omics biomarker monitoring may help prevent unnecessary or high-complication-risk biopsy and enables tailored immunosuppression by predicting the risk of AR in KTRs.

Objective. We aimed to establish a method to determine whether microRNA-193b (miR-193b) levels in ABCA1-labeled serum exosomes might serve as a marker for the diagnosis of Alzheimer’s disease. Methods. We used immunocapture methods to determine the levels of ABCA1-labeled exosomal miR-193b in cultures of white blood cells (WBCs), red blood cells (RBCs), mouse hippocampal neuron HT-22 cells, and primary mouse neuronal cells. ABCA1-labeled exosomal miR-193b levels were also evaluated in the cerebrospinal fluid (CSF) and serum of APP/PS1 double-transgenic mice, as well as control subjects (n=60) and study participants with subjective cognitive decline (SCD, n=89), stage and mild cognitive impairment (MCI, n=92), and dementia of the Alzheimer type (DAT, n=92). Results. ABCA1 levels of exosomes harvested from the medium of HT-22 cells and neurons were significantly higher than those of RBCs and WBCs (P<0.05). Exosomal ABCA1 from the CSF of APP/PS1 mice were transmitted to the serum of wild-type mice after injection, and high miR-193b levels were observed in both the serum and CSF after injection. The ABCA1-labeled exosomal miR-193b levels were higher in the CSF of MCI and DAT patients compared with the CSF of the control group (P<0.05). The ABCA1-labeled exosomal miR-193b were also slightly higher (P>0.05) in the serum of SCD patients and significantly higher in the serum of MCI and DAT patients compared with the serum of the control group (P<0.05). Conclusion. This study provides a method to capture specific exosomes. Detection of serum exosomes labeled with ABCA1 may facilitate the early diagnosis of AD.

Background Neoadjuvant chemotherapy (NAC) is a standard approach for treating locally advanced gastric cancer (GC), but resistance in some patients can result in treatment toxicity and surgical delays without therapeutic benefit. Identifying biomarkers predictive of NAC response is crucial for personalized treatment strategies. This study evaluated circulating microRNAs (miRNAs) as potential biomarkers for NAC response. Materials and methods Plasma samples from 39 GC patients undergoing NAC followed by gastrectomy (NCT04223401) were collected before treatment. Four miRNAs (miR-19a, miR-21, miR-27a, miR-200c) were analyzed via quantitative real-time polymerase chain reaction. NAC response was assessed in histological specimens using the Becker tumor regression grade (TRG), which classifies patients as Responders (TRG 1–2) or Non-responders (TRG 3). Results Among 39 patients, 20 (51%) were Responders, and 19 (49%) were Non-responders. miR-19a, miR-21, and miR-200c were significantly upregulated in Non-responders (p < 0.05). ROC analysis revealed miR-19a (AUC: 0.693), miR-21 (AUC: 0.700), and miR-200c (AUC: 0.772) as predictive of resistance. Univariate analysis revealed a correlation between higher levels of miR-19a, miR-21, and miR-200c and a low neutrophil count, with increased resistance risk. Multivariate analysis confirmed miR-200c as an independent predictor of resistance (OR: 20.90; 95% CI: 1.54-283.73). Conclusions This pilot study identifies circulating miR-19a, miR-21, and miR-200c as novel biomarkers for poor NAC response in GC, providing a foundation for personalized treatment strategies.

Transforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib. This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored. The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036). Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results.

Abstract Context Polycystic ovary syndrome (PCOS) is a prevalent disorder in adolescent girls, purportedly driven by hepato-visceral fat excess, and often followed by subfertility and type 2 diabetes. Objective We studied the baseline microRNA (miRNA) profile of girls with PCOS, and the effects of a randomized treatment with an oral contraceptive (OC) or with spironolactone–pioglitazone–metformin (SPIOMET, aiming at loss of hepato-visceral fat excess) for 1 year. Design & Patients The miRNA profile was assessed by RNA sequencing in girls with PCOS who had participated in a randomized, open-label, single-center, pilot study (n = 31; age 15.7 years, body mass index (BMI) 23.1 kg/m2). Healthy age- and BMI-matched girls (n = 13) served as controls. Differentially expressed miRNAs were validated by RT-qPCR in the entire study population. Post-treatment ovulation rates were assessed by salivary progesterone in PCOS girls. Setting Endocrinology Department, University Hospital. Results Girls with PCOS, compared with controls, had markedly reduced concentrations of circulating miR-451a, miR-652-3p, miR-106b-5p, and miR-206; pathway enrichment analysis showed that these miRNAs target genes involved in energy homeostasis and cell cycle control. In the present study, miR-451a could diagnose PCOS with 100% sensitivity and 100% specificity. SPIOMET (but not OC) was accompanied by on-treatment normalization of the miRNA profile in girls with PCOS; miR-451a concentrations after 1 year on OC or SPIOMET treatment associated closely (r = 0.66; P < .0001) with post-treatment ovulation rates. Conclusion SPIOMET treatment for 1 year normalizes the miRNA profile of girls with PCOS. Circulating miR-451a may become a biomarker to guide the diagnosis and treatment of PCOS in adolescence.