MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome.

Children with Down syndrome (DS) are at increased risk for acute myeloid leukemias (ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The chromosome 21 microRNA (miR)-125b cluster has been previously shown to cooperate with GATA1s in transformation of fetal hematopoietic progenitors. In this study, we report that the expression of miR-486-5p is increased in ML-DS compared with non-DS acute megakaryocytic leukemias (AMKLs). miR-486-5p is regulated by GATA1 and GATA1s that bind to the promoter of its host gene ANK1. miR-486-5p is highly expressed in mouse erythroid precursors and knockdown (KD) in ML-DS cells reduced their erythroid phenotype. Ectopic expression and KD of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gata1s to enhance their self renewal. Consistent with its activation of AKT, overexpression and KD experiments showed its importance for growth and survival of human leukemic cells. Thus, miR-486-5p cooperates with GATA1s in supporting the growth and survival, and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS.

Predicting progression of bladder urothelial carcinoma using microRNA expression.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Recurrence and progression prediction in urothelial cancer is currently based on clinical and pathological factors: tumour grade, tumour stage, number of lesions, tumour size, previous recurrence rate, and presence of concomitant carcinoma in situ. These factors are not specific enough to predict progression and ∼50% of patients diagnosed as high risk in fact do not progress within 3 years. Patient follow-up is both expensive and unpleasant (frequent invasive cystoscopies). Molecular biomarkers, including microRNAs have been studied to provide additional prognostic information for these patients, but to date no molecular biomarker has become the 'gold standard' for patient diagnosis and follow-up. We used Rosetta Genomics' highly specific microRNA expression profiling platforms to study the prognostic role of microRNAs in bladder cancer. Using microdissection we chose specific tumour microRNAs to study in order to avoid background contamination. Tumour progression was associated with altered levels of microRNAs. In particular, high expression levels of miR-29c* were associated with a good prognosis. The study found that the use of microRNAs for determining progression and invasiveness for patients with urothelial cancer could potentially have a substantial impact on the treatment and follow-up individual patients. OBJECTIVE: To identify microRNAs that could be useful as prognostic markers for non-muscle-invasive (NMI) bladder carcinoma. PATIENTS AND METHODS: Formalin-fixed, paraffin-embedded samples of 108 NMI bladder carcinomas, and 29 carcinomas invading bladder muscle were collected, and microRNA expression levels were measured using microarrays. For 19 samples, microdissection was performed to compare microRNA expression between the tumour and surrounding tissue. MicroRNAs that were found to be unrelated to the tumour itself were excluded as potential prognostic markers. RESULTS: Expression profiles identified microRNAs that were differentially expressed in NMI tumours from patients who later progressed to carcinoma invading bladder muscle compared with NMI tumours from patients that did not progress. The microRNA profile of tumours invading the bladder muscle was more similar to that of NMI tumours from patients who later progressed, than to that of the same-stage NMI tumours from patients who did not later progress. The expression level of one microRNA, miR-29c*, was significantly under-expressed in tumours that progressed and could be used to stratify patients with T1 disease into risk groups. CONCLUSIONS: MicroRNAs can be useful biomarkers for prognosis in patients with urothelial carcinoma. In our study, expression levels of several microRNAs, including miR-29c* identified high- and low-risk groups. These biomarkers show promise for the stratification of patients with bladder cancer.

Comorbid personality disorders in manic bipolar I disorder patients is associated with increased use of long-acting injectable antipsychotic treatment and higher rates of rehospitalization.

Personality disorder comorbidity is considered a poor prognostic factor among bipolar disorder patients. However, an evidence-based pharmacological treatment for this sub-population is lacking, and only few studies investigated the impact of personality disorder on bipolar disorder-I course. Here, we studied the effect of comorbid personality disorder on the administrated psychopharmacotherapy and rehospitalization risk among manic bipolar disorder-I patients. A sample of 340 patients with bipolar disorder-I, who were hospitalized with acute manic episode between 2005 and 2013, were retrospectively followed for a mean duration of 1129 days. Drug treatment at discharge and rehospitalization rates during follow-up time were compared between bipolar disorder-I patients with (n = 55) or without (n = 285) personality disorder comorbidity. Multivariate survival analyses adjusted for covariates were conducted. During the study period, 39.4% of bipolar disorder-I patients were rehospitalized due to a mood episode. Comorbid personality disorder was significantly associated with higher rates of long-acting injectable antipsychotics administration at discharge from hospitalization (adjusted odds ratio 2.66, 95% confidence interval: 1.19-5.94, P = 0.017). Comorbid personality disorder significantly increased the adjusted risk of rehospitalization due to a mood episode (hazard ratio = 2.04, 95% confidence interval: 1.29-3.23, P = 0.002). In conclusion, comorbid personality disorder in manic bipolar disorder-I patients is associated with increased use of long-acting injectable antipsychotics and higher rates of rehospitalization.

Reducing Stigma Toward Psychiatry Among Medical Students: A Multicenter Controlled Trial.

OBJECTIVE: To examine the effect of a novel antistigma intervention curriculum (ASIC) in reducing stigma toward psychiatry among medical students. METHODS: Medical students from 8 hospitals in central Israel were divided into intervention (n = 57) and control (n = 163) arms. The students completed the 30-item Attitudes Toward Psychiatry (ATP-30) and the Attitudes Toward Mental Illness (AMI) scales at psychiatry rotation onset and conclusion. The ASIC was designed to target prejudices and stigma through direct informal encounters with people with serious mental illness (SMI) during periods of remission and recovery. Supervised small-group discussions followed those encounters to facilitate processing of thoughts and emotions that ensued and to discuss salient topics in psychiatry. The study was conducted between November 2017 and July 2018. RESULTS: Significant between-group differences were found at endpoint for attitudes toward psychiatry and psychiatric patients (P < .001). Although changing attitudes toward psychiatry as a career choice was not part of the ASIC, a significant between-group difference emerged by endpoint (P < .001). CONCLUSIONS: Implementation of an ASIC that includes contact with individuals with lived SMI experience followed by supervised small-group discussions is effective in reducing stigma in medical students' perceptions of people with mental illness and psychiatry. Further evaluation is warranted with regard to the long-term destigmatizing effects of an ASIC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03907696.

Multicentre validation of a microRNA-based assay for diagnosing indeterminate thyroid nodules utilising fine needle aspirate smears.

AIMS: The distinction between benign and malignant thyroid nodules has important therapeutic implications. Our objective was to develop an assay that could classify indeterminate thyroid nodules as benign or suspicious, using routinely prepared fine needle aspirate (FNA) cytology smears. METHODS: A training set of 375 FNA smears was used to develop the microRNA-based assay, which was validated using a blinded, multicentre, retrospective cohort of 201 smears. Final diagnosis of the validation samples was determined based on corresponding surgical specimens, reviewed by the contributing institute pathologist and two independent pathologists. Validation samples were from adult patients (≥18 years) with nodule size >0.5 cm, and a final diagnosis confirmed by at least one of the two blinded, independent pathologists. The developed assay, RosettaGX Reveal, differentiates benign from malignant thyroid nodules, using quantitative RT-PCR. RESULTS: Test performance on the 189 samples that passed quality control: negative predictive value: 91% (95% CI 84% to 96%); sensitivity: 85% (CI 74% to 93%); specificity: 72% (CI 63% to 79%). Performance for cases in which all three reviewing pathologists were in agreement regarding the final diagnosis (n=150): negative predictive value: 99% (CI 94% to 100%); sensitivity: 98% (CI 87% to 100%); specificity: 78% (CI 69% to 85%). CONCLUSIONS: A novel assay utilising microRNA expression in cytology smears was developed. The assay distinguishes benign from malignant thyroid nodules using a single FNA stained smear, and does not require fresh tissue or special collection and shipment conditions. This assay offers a valuable tool for the preoperative classification of thyroid samples with indeterminate cytology.

Comparison of body mass index and body surface area as outcome predictors in patients with systolic heart failure.

BACKGROUND: We investigated whether the 'obesity paradox' in heart failure (HF) is influenced by common confounders, and assessed if body surface area (BSA) may correlate more closely than body mass index (BMI) with prognosis. METHODS: We studied 630 systolic HF patients at their initial visit to the HF clinic. Body size was measured by BMI and BSA. The association between body indices and mortality was assessed by Cox proportional-hazard analyses. RESULTS: There were 248 deaths during mean follow-up of 39 months. A progressive inverse association of BMI and BSA tertiles (T1-T3) with mortality risk was observed (for BSA: T3, reference, T2, hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.01-1.95, p = 0.04 and T1, HR = 1.78, 95% CI 1.29-2.45, p < 0.001; for BMI: T3, reference, T2, HR = 1.29, 95% CI 0.92-1.79, p = 0.13 and T1, HR = 1.66, 95% CI 1.21-2.27, p = 0.002). The obesity paradox was attenuated after multivariate adjustment, and did not persist after adjustment for age alone (for BMI: T3, reference, T2, HR = 1.13, 95% CI 0.81-1.58, p = 0.47; T1, HR = 1.30, 95% CI 0.94-1.80, p = 0.12; for BSA: T3, reference, T2, HR = 0.96, 95% CI 0.68-1.35, p = 0.82; T1, HR = 1.15, 95% CI 0.82-1.63, p = 0.42). CONCLUSIONS: BSA provides prognostic information similar to BMI in systolic HF. However, the obesity paradox of both BMI and BSA in HF may be confounded by the younger age of the obese patients.

The role of microRNA profiling in prognosticating progression in Ta and T1 urinary bladder cancer.

OBJECTIVE: To analyze microRNA profile in Ta and T1 urinary bladder cancers in combination and separately and to relate this to the risk of later developing higher-stage disease. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded samples of 44 Ta and 42 T1 bladder cancers representing cases with and without stage progression during follow-up were collected and microRNA expression levels were measured by microarray analysis. RESULTS: In a comparison between the progressors and controls, in the Ta/T1 group, miR-10a-5p and miR-31-5p were differentially expressed. miR-10a-5p was also correlated to time to progression (P = 0.00012). In the subgroup analysis, 3 microRNAs, miR-10a-5p, miR-31-5p, and miR-130a-3p, were differentially expressed among Ta tumors and had a fold change of more than 1.5 (P<0.038). The comparison concerning microRNA expression between the progressors and controls in category T1 cancers revealed no significant differences. CONCLUSIONS: Profiling revealed that certain microRNAs predicted the risk of developing higher-stage disease among patients with Ta cancers. Lower miR-10a-5p expression in Ta progressing tumors indicates that this microRNA could be important for later malignant potential among this group of patients.

Relation of reduced expression of MiR-150 in platelets to atrial fibrillation in patients with chronic systolic heart failure.

Atrial fibrillation (AF) is associated with poor prognosis in patients with heart failure (HF). Although platelets play an important role in rendering a prothrombotic state in AF, the exact mechanism by which the effect is mediated is still debated. MicroRNAs (miRNAs), which have been shown to be involved in a variety of cardiovascular conditions, are abundant in platelets and in a cell-free form in the circulation. In the present study, we performed a genome-wide screen for miRNA expression in platelets of patients with systolic HF and in controls without cardiac disease, in pursuit of specific miRNAs that are associated with the presence of AF. MiRNA expression was measured in platelets from 50 patients with systolic HF and 50 controls, of which, samples from 41 patients with HF and 35 controls were used in the final analysis because of a quality control process. MiR-150 expression was 3.2-fold lower (p = 0.0003) in platelets of patients with HF with AF relative to those without AF. A similar effect was seen in serum samples from the same patients, in which miR-150 levels were 1.5-fold lower (p = 0.004) in patients with HF with AF. Furthermore, the serum levels of miR-150 were correlated to platelet levels in patients with AF (r = 0.65, p = 0.0087). In conclusion, miR-150 expression levels in platelets of patients with systolic HF with AF are significantly reduced and correlated to the cell-free circulating levels of this miRNA.

Serum levels of microRNAs in patients with heart failure.

AIMS: Diagnosis and risk stratification of patients with heart failure remain a challenge. The small non-coding RNAs known as microRNAs regulate gene expression and seem to play an important role in the pathogenesis of heart failure. In the current study, we aim to characterize the levels of microRNAs in the sera of chronic systolic heart failure patients vs. controls and assess the possible correlation between elevation in the levels of specific microRNAs and clinical prognostic parameters in heart failure patients. METHODS AND RESULTS: The levels of 186 microRNAs were measured in the sera of 30 stable chronic systolic heart failure patients and 30 controls using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The differences in microRNA levels between the two groups were characterized, and a score, based on the levels of four specific microRNAs with the most significant increase in the heart failure group (miR-423-5p, miR-320a, miR-22, and miR-92b), was defined. The score was used to discriminate heart failure patients from controls with a sensitivity and specificity of 90%. Moreover, in the heart failure group, there was a significant association between the score and important clinical prognostic parameters such as elevated serum natriuretic peptide levels, a wide QRS, and dilatation of the left ventricle and left atrium (r = 0.63, P = 3e-4; P = 0.009; P = 0.03; and P = 0.01, respectively). CONCLUSIONS: Elevated serum levels of specific microRNAs: miR-423-5p, miR-320a, miR-22, and miR-92b, identify systolic heart failure patients and correlate with important clinical prognostic parameters.

Risk score model for predicting mortality in advanced heart failure patients followed in a heart failure clinic.

The prevalence of heart failure (HF) in the population is increasing, concomitant with high incidence of rehospitalizations and mortality. The aim of this study was to characterize a prognostic risk score model for patients with chronic HF. A total of 500 patients followed at the HF clinic were evaluated by clinical, functional, laboratory, imaging, and therapeutic variables that were correlated to mortality during a follow-up period of 25 months. Risk stratification was carried out by applying a risk score model based on multivariate analysis. Predictors correlated with mortality during follow-up were systolic blood pressure <110 mm Hg, male sex, age older than 70 years, 6-minute walk distance <300 m, lack of ß-blocker therapy, hyperuricemia (>7.5 mg/dL), hyponatremia, and prolonged QTc interval (>450 ms). Based on these variables, a risk score model (score 0-55) was established and included low risk, score <21 (9% mortality during 2-year follow-up); moderate risk, 21 to 29 (22%); high risk, 30 to 35 (35%), and very high risk: ≥36 points (62% 2-year mortality). The risk model had good discrimination ability (concordance index 0.75), which was better than the performance of the Seattle Heart Failure Model on our cohort (0.69). Simple noninvasive characteristics examined during the initial admission to the HF clinic can serve as prognostic markers for mortality and may help in the process of therapeutic decision-making in patients with HF.

A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma.

The definitive identification of malignant pleural mesothelioma (MPM) has significant clinical implications, yet other malignancies often involve the lung pleura, confounding the diagnosis of MPM. In the absence of accurate markers, MPM can be difficult to distinguish from peripheral lung adenocarcinoma and metastatic epithelial cancers. MicroRNA expression is tissue-specific and highly informative for identifying tumor origin. We identified microRNA biomarkers for the differential diagnosis of MPM and developed a standardized microRNA-based assay. Formalin-fixed, paraffin-embedded samples of 33 MPM and 210 carcinomas were used for assay development. Using microarrays, we identified microRNAs differentially expressed between MPM and various carcinomas. Hsa-miR-193-3p was overexpressed in MPM, while hsa-miR-200c and hsa-miR-192 were overexpressed in peripheral lung adenocarcinoma and carcinomas that frequently metastasize to lung pleura. We developed a standardized diagnostic assay based on the expression of these microRNAs. The assay reached a sensitivity of 100% and a specificity of 94% in a blinded validation set of 68 samples from the lung and pleura. This diagnostic assay can provide a useful tool in the differential diagnosis of MPM from other malignancies in the pleura.

Serum microRNAs are promising novel biomarkers.

BACKGROUND: Circulating nucleic acids (CNAs) offer unique opportunities for early diagnosis of clinical conditions. Here we show that microRNAs, a family of small non-coding regulatory RNAs involved in human development and pathology, are present in bodily fluids and represent new effective biomarkers. METHODS AND RESULTS: After developing protocols for extracting and quantifying microRNAs in serum and other body fluids, the serum microRNA profiles of several healthy individuals were determined and found to be similar, validating the robustness of our methods. To address the possibility that the abundance of specific microRNAs might change during physiological or pathological conditions, serum microRNA levels in pregnant and non pregnant women were compared. In sera from pregnant women, microRNAs associated with human placenta were significantly elevated and their levels correlated with pregnancy stage. CONCLUSIONS AND SIGNIFICANCE: Considering the central role of microRNAs in development and disease, our results highlight the medically relevant potential of determining microRNA levels in serum and other body fluids. Thus, microRNAs are a new class of CNAs that promise to serve as useful clinical biomarkers.

MicroRNAs accurately identify cancer tissue origin.

MicroRNAs (miRNAs) belong to a class of noncoding, regulatory RNAs that is involved in oncogenesis and shows remarkable tissue specificity. Their potential for tumor classification suggests they may be used in identifying the tissue in which cancers of unknown primary origin arose, a major clinical problem. We measured miRNA expression levels in 400 paraffin-embedded and fresh-frozen samples from 22 different tumor tissues and metastases. We used miRNA microarray data of 253 samples to construct a transparent classifier based on 48 miRNAs. Two-thirds of samples were classified with high confidence, with accuracy >90%. In an independent blinded test-set of 83 samples, overall high-confidence accuracy reached 89%. Classification accuracy reached 100% for most tissue classes, including 131 metastatic samples. We further validated the utility of the miRNA biomarkers by quantitative RT-PCR using 65 additional blinded test samples. Our findings demonstrate the effectiveness of miRNAs as biomarkers for tracing the tissue of origin of cancers of unknown primary origin.