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A miRNA signature predicts benefit from addition of hypoxia-modifying therapy to radiation treatment in invasive bladder cancer.
Khan, MT, Irlam-Jones, JJ, Pereira, RR, Lane, B, Valentine, HR, Aragaki, K, Dyrskjøt, L, McConkey, DJ, Hoskin, PJ, Choudhury, A, et al
British journal of cancer. 2021;(1):85-93
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Abstract
BACKGROUND miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer. METHODS Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation. RESULTS A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen-nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094-0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24-0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08-0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033). CONCLUSION A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.
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Alcoholic and Non-Alcoholic Beer Modulate Plasma and Macrophage microRNAs Differently in a Pilot Intervention in Humans with Cardiovascular Risk.
Daimiel, L, Micó, V, Díez-Ricote, L, Ruiz-Valderrey, P, Istas, G, Rodríguez-Mateos, A, Ordovás, JM
Nutrients. 2020;(1)
Abstract
Beer is a popular beverage and some beneficial effects have been attributed to its moderate consumption. We carried out a pilot study to test if beer and non-alcoholic beer consumption modify the levels of a panel of 53 cardiometabolic microRNAs in plasma and macrophages. Seven non-smoker men aged 30-65 with high cardiovascular risk were recruited for a non-randomised cross-over intervention consisting of the ingestion of 500 mL/day of beer or non-alcoholic beer for 14 days with a 7-day washout period between interventions. Plasma and urine isoxanthohumol were measured to assess compliance with interventions. Monocytes were isolated and differentiated into macrophages, and plasma and macrophage microRNAs were analysed by quantitative real-time PCR. Anthropometric, biochemistry and dietary parameters were also measured. We found an increase in plasma miR-155-5p, miR-328-3p, and miR-92a-3p after beer and a decrease after non-alcoholic beer consumption. Plasma miR-320a-3p levels decreased with both beers. Circulating miR-320a-3p levels correlated with LDL-cholesterol. We found that miR-17-5p, miR-20a-5p, miR-145-5p, miR-26b-5p, and miR-223-3p macrophage levels increased after beer and decreased after non-alcoholic beer consumption. Functional analyses suggested that modulated microRNAs were involved in catabolism, nutrient sensing, Toll-like receptors signalling and inflammation. We concluded that beer and non-alcoholic beer intake modulated differentially plasma and macrophage microRNAs. Specifically, microRNAs related to inflammation increased after beer consumption and decreased after non-alcoholic beer consumption.
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Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients.
Fujita, K, Mimura, S, Iwama, H, Nakahara, M, Oura, K, Tadokoro, T, Nomura, T, Tani, J, Yoneyama, H, Morishita, A, et al
International journal of molecular sciences. 2018;(7)
Abstract
The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg-IFNα-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication.
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Ursodeoxycholic acid improves liver function via phenylalanine/tyrosine pathway and microbiome remodelling in patients with liver dysfunction.
Kim, DJ, Yoon, S, Ji, SC, Yang, J, Kim, YK, Lee, S, Yu, KS, Jang, IJ, Chung, JY, Cho, JY
Scientific reports. 2018;(1):11874
Abstract
Ursodeoxycholic acid (UDCA) is a metabolic by-product of intestinal bacteria, showing hepatoprotective effects. However, its underlying molecular mechanisms remain unclear. The purpose of this study was to elucidate the action mechanisms underlying the protective effects of UDCA and vitamin E against liver dysfunction using metabolomics and metagenomic analysis. In this study, we analysed blood and urine samples from patients with obesity and liver dysfunction. Nine patients were randomly assigned to receive UDCA (300 mg twice daily), and 10 subjects received vitamin E (400 IU twice daily) for 8 weeks. UDCA significantly improved the liver function scores after 4 weeks of treatment and effectively reduced hepatic deoxycholic acid and serum microRNA-122 levels. To better understand its protective mechanism, a global metabolomics study was conducted, and we found that UDCA regulated uremic toxins (hippuric acid, p-cresol sulphate, and indole-derived metabolites), antioxidants (ascorbate sulphate and N-acetyl-L-cysteine), and the phenylalanine/tyrosine pathway. Furthermore, microbiome involvement, particularly of Lactobacillus and Bifidobacterium, was demonstrated through metagenomic analysis of bacteria-derived extracellular vesicles. Meanwhile, vitamin E treatment did not result in such alterations, except that it reduced uremic toxins and liver dysfunction. Our findings suggested that both treatments were effective in improving liver function, albeit via different mechanisms.
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Physical Activity Modulates the Overexpression of the Inflammatory miR-146a-5p in Obese Patients.
Russo, A, Bartolini, D, Mensà, E, Torquato, P, Albertini, MC, Olivieri, F, Testa, R, Rossi, S, Piroddi, M, Cruciani, G, et al
IUBMB life. 2018;(10):1012-1022
Abstract
Specific microRNAs (miRs), including the "angio-miR-126" and the "inflamma-miR-146a-5p," have been proposed as biomarkers and even therapeutic targets of obesity-associated metabolic diseases. Physical activity, a key measure of prevention for obesity and its complications, is reported to influence the expression of these miRs. In this study, we investigate whether a physical activity program proven to improve metabolic parameters in obese patients can correct the circulating levels of these miRs. Plasma miR-126 and miR-146a-5p were measured in a cohort of obese patients (n = 31, 16F + 15M) before and after the 3-month physical activity program of the CURIAMO trial (registration number for clinical trials: ACTRN12611000255987) and in 37 lean controls (24F + 13M). miR-146a-5p, but not miR-126, was significantly increased in obese patients as compared with lean controls and decreased in approximately two-thirds of the participants post-intervention with a response that positively correlated with pre-intervention levels of this miR. Waist circumference, the inflammatory cytokine IL-8 and lipid parameters, principally total cholesterol, showed the strongest correlation with both the baseline levels and post-intervention correction of miR-146a-5p. Post-hoc analysis of experimental data supports the use of miR-146a-5p as a biomarker and predictor of the clinical response to physical activity in obese patients. Furthermore, miR-146a-5p expression was confirmed to increase together with that of the inflammatory genes TLR4, NF-κB, IL-6, and TNF-α in LPS-stimulated human mononuclear leukocytes. In conclusion, the inflamma-miR-146a-5p can serve as a personalized predictor of clinical outcome in obese patients entering physical activity weight-reduction programs. © 2018 IUBMB Life, 70(10):1012-1022, 2018.
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A pilot study on the effects of probiotic supplementation on neuropsychological performance and microRNA-29a-c levels in antiretroviral-treated HIV-1-infected patients.
Ceccarelli, G, Fratino, M, Selvaggi, C, Giustini, N, Serafino, S, Schietroma, I, Corano Scheri, G, Pavone, P, Passavanti, G, Alunni Fegatelli, D, et al
Brain and behavior. 2017;(8):e00756
Abstract
INTRODUCTION The gut microbiota is involved in the regulation of cognition, mood, anxiety, and pain, and can impact cognitive functions by producing neuroactive substances or releasing bacterial by-products and metabolites. No information is available on the effects of a probiotic supplementation on brain function of HIV+ subjects. In light of the above considerations, we performed a pilot study in cART-treated HIV-1-positive patients with long-term virologic suppression. The aims were to analyze the effect of high-concentration multistrain probiotic supplementation (Vivomixx®; Visbiome®) on several neurocognitive abilities and to evaluate the safety of this supplementation. METHODS To address those issues, neurocognitive performances were explored by administering neuropsychological tests; moreover, miRNA-29a-c levels were measured in cerebrospinal fluid (CSF) to confirm the persistent undetectable levels of HIV-RNA in the central nervous system after probiotic supplementation. RESULTS Our results show that the Rey auditory verbal learning test (RAVLT) (immediate and delayed recall), Rey-Osterrieth complex figure test (ROCF) (copy immediate and delayed recall), phonological verbal fluency (PVF) test, Toronto alexithymia scale-20 (Tas-20), State-trait anxiety inventory Y-2 (STAY Y-2), and time and weight estimation test (STEP) scores improved significantly during the study. Moreover, we found unchanged levels, associated to high degree of individual variability, in miRNA-29 levels in CSF collected before and after probiotic supplementation. CONCLUSIONS In conclusion, we observed that HIV patients treated with 6 months of this probiotic supplementation appear to have an improvement in some neurocognitive functions; moreover, this approach is safe and did not modify significantly the levels of miRNA in CSF. Further studies are needed to better understand the contribution of the probiotics in modulating gut-brain-axis in HIV patients.
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microRNAs and DICER1 are regulated by 1,25-dihydroxyvitamin D in prostate stroma.
Dambal, S, Giangreco, AA, Acosta, AM, Fairchild, A, Richards, Z, Deaton, R, Wagner, D, Vieth, R, Gann, PH, Kajdacsy-Balla, A, et al
The Journal of steroid biochemistry and molecular biology. 2017;:192-202
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Abstract
Vitamin D deficiency increases the risk of lethal prostate adenocarcinomas (PCa) and the majority of older men are deficient. Although PCa arises from the epithelium, the surrounding stroma has hormonal regulatory control over the epithelium and contributes to carcinogenesis. Herein, we describe regulation of microRNAs (miRs) by the active hormone dihydroxyvitamin D (1,25(OH)2D) in human prostate stroma. 1,25(OH)2D binds the vitamin D receptor (VDR) transcription factor to regulate gene expression, including miRs, which have emerged as potent regulators of protein expression. 1,25(OH)2D-regulated miRs were identified by profiling in primary human prostatic stromal cells (PrS) and three miRs, miR-126-3p, miR 154-5p and miR-21-5p were subsequently validated in laser-capture micro-dissected prostate stromal tissue from a vitamin D3 clinical trial (N=45). Regulation of these miRs by 1,25(OH)2D was VDR-dependent. Network analysis of known and putative mRNA targets of these miRs was enriched with cancer and inflammation pathways, consistent with known roles of stroma and of vitamin D in carcinogenesis. Expression of the miR processing ribonuclease, DICER1, positively correlated with vitamin D metabolite levels in the clinical trial specimens. High epithelial/stromal ratios of DICER1 were significantly associated biochemical recurrence (OR 3.1, p=0.03) in a tissue microarray of 170 matched PCa patients. In summary, these results underscore the role of the prostate stroma in regulating responses to the hormone 1,25(OH)2D and identified miRs and DICER1 as being regulated in human prostate stroma. Regulation of stromal DICER1 by 1,25(OH)2D may also have clinical relevance in protection against aggressive PCa.
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Circulating miR-30d Predicts Survival in Patients with Acute Heart Failure.
Xiao, J, Gao, R, Bei, Y, Zhou, Q, Zhou, Y, Zhang, H, Jin, M, Wei, S, Wang, K, Xu, X, et al
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2017;(3):865-874
Abstract
BACKGROUND/AIMS: Identification of novel biomarkers to identify acute heart failure (AHF) patients at high risk of mortality is an area of unmet clinical need. Recently, we reported that the baseline level of circulating miR-30d was associated with left ventricular remodeling in response to cardiac resynchronization therapy in advanced chronic heart failure patients. However, the role of circulating miR-30d as a prognostic marker of survival in patients with AHF has not been explored. METHODS Patients clinically diagnosed with AHF were enrolled and followed up for 1 year. Quantitative reverse transcription polymerase chain reactions were used to determine serum miR-30d levels. The univariate logistic regression analysis and multivariate logistic regression analysis were used to determine the predictors for all-cause mortality in AHF patients. Kaplan-Meier survival analysis was used to analyze the role of miR-30d in prediction of survival. RESULTS A total of 96 AHF patients were enrolled and followed up for 1 year. Serum miR-30d was significantly lower in AHF patients who expired in the one year follow-up period compared to those who survived. Univariate logistic regression analysis yielded 18 variables that were associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 4 variables including heart rate, hemoglobin, serum sodium, and serum miR-30d level associated with mortality. ROC curve analysis showed that hemoglobin, heart rate and serum sodium displayed poor prognostic value for AHF (AUCs not higher than 0.700) compared to miR-30d level (AUC = 0.806). Kaplan-Meier survival analysis confirmed that patients with higher serum miR-30d levels had significantly lower mortality (P=0.001). CONCLUSION In conclusion, this study shows evidence for the predictive value of circulating miR-30d as 1-year all-cause mortality in AHF patients. Large multicentre studies are further needed to validate our findings and accelerate the transition to clinical utilization.
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Validation of plasma microRNAs as biomarkers for myotonic dystrophy type 1.
Perfetti, A, Greco, S, Cardani, R, Fossati, B, Cuomo, G, Valaperta, R, Ambrogi, F, Cortese, A, Botta, A, Mignarri, A, et al
Scientific reports. 2016;:38174
Abstract
Non-invasive and simple to measure biomarkers are still an unmet need for myotonic dystrophy type 1 (DM1). Indeed, muscle biopsies can be extremely informative, but their invasive nature limits their application. Extracellular microRNAs are emerging humoral biomarkers and preliminary studies identified a group of miRNAs that are deregulated in the plasma or serum of small groups of DM1 patients. Here we adopted very stringent selection and normalization criteria to validate or disprove these miRNAs in 103 DM1 patients and 111 matched controls. We confirmed that 8 miRNAs out of 12 were significantly deregulated in DM1 patients: miR-1, miR-27b, miR-133a, miR-133b, miR-206, miR-140-3p, miR-454 and miR-574. The levels of these miRNAs, alone or in combination, discriminated DM1 from controls significantly, and correlated with both skeletal muscle strength and creatine kinase values. Interestingly, miR-133b levels were significantly higher in DM1 female patients. Finally, the identified miRNAs were also deregulated in the plasma of a small group (n = 30) of DM2 patients. In conclusion, this study proposes that miRNAs might be useful as DM1 humoral biomarkers.
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Expression of inflammation-related miRNAs in white blood cells from subjects with metabolic syndrome after 8 wk of following a Mediterranean diet-based weight loss program.
Marques-Rocha, JL, Milagro, FI, Mansego, ML, Zulet, MA, Bressan, J, Martínez, JA
Nutrition (Burbank, Los Angeles County, Calif.). 2016;(1):48-55
Abstract
OBJECTIVES The aim of this study was to evaluate the influence of a dietary strategy for weight loss (the RESMENA [reduction of metabolic syndrome in Navarra, Spain] diet) on the expression of inflammation-related microRNAS (miRNAs) and genes in white blood cells (WBC) from individuals with metabolic syndrome (MetS). METHODS The clinical, anthropometric, and biochemical characteristics of 40 individuals with MetS (20 men and 20 women; age: 48.84 ± 10.02 y; body mass index: 35.41 ± 4.42 kg/m(2)) were evaluated before and after an 8-wk hypocaloric diet based on the Mediterranean dietary pattern. Nutrient intake was assessed with a food frequency questionnaire and 48-h weighed food records. Total RNA was isolated from WBC and the expression of some inflammation-related miRNAs and mRNAs (IL-6, TNF-α, ICAM-1, IL-18, SERPINE1, VCAM-1, GAPDH) was assessed by quantitative polymerase chain reaction. RESULTS The RESMENA nutritional intervention improved most anthropometric and biochemical features. The expression of miR-155-3p was decreased in WBC, whereas Let-7b was strongly upregulated as a consequence of the dietary treatment. However, they were not correlated with the expression of the proinflammatory genes in the same cells. The changes in the expression of let-7b, miR-125b, miR-130a, miR-132-3p, and miR-422b were significantly associated with changes in diet quality when assessed by the Healthy Eating Index. Moreover, low consumption of lipids and saturated fat (g/d) were associated with higher expression of let-7b after the nutritional intervention. CONCLUSIONS The Mediterranean-based nutritional intervention was able to induce changes in the expression of let-7b and miR-155-3p in WBC from patients with MetS after 8 wk. Moreover, the quality of the diet has an important effect on the miRNAs expression changes. These results should be highlighted because these miRNAs have been associated with inflammatory gene regulation and important human diseases.