Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma

Background

MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC.

Methodology/Principal Findings

62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dC_T of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%.

Conclusions/Significance

The serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.     

Serum microRNAs as biomarkers for hepatocellular carcinoma in Chinese patients with chronic hepatitis B virus infection

Background

MicroRNAs (miRNAs) have been shown to anticipate great cancer diagnostic potential. Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. The objective of this study was to investigate the potential of serum miRNAs as novel biomarkers for hepatocellular carcinoma (HCC).

Methodology/Principal Findings

This study was divided into four phases: (I) Ten candidate serum miRNAs were detected by using real-time RT-PCR, corresponding 10 HCC patients with chronic hepatitis B virus (HBV) infection and 10 age- and sex-matched healthy subjects. (II) Marker validation by real-time RT-PCR on HBV patients with (n = 48) or without HCC (n = 48), and healthy subjects (n = 24). (III) Marker detection by real-time RT-PCR in sera from another 14 HCC patients before and 1 month after surgical resection. (IV) We examined the correlation between the expressions of candidate serum miRNAs with clinical parameters of HCC patients. Although miR-222, miR-223 or miR-21 were significantly up- or down-regulated between HCC patients and healthy controls, no significant difference was observed in the levels of these miRNAs between HBV patients without and with HCC. MiR-122 in serum was significantly higher in HCC patients than healthy controls (p<0.001). More importantly, it was found that the levels of miR-122 were significantly reduced in the post-operative serum samples when compared to the pre-operative samples. Although serum miR-122 was also elevated in HBV patients with HCC comparing with those without HCC, the difference was at the border line (p = 0.043).

Conclusions/Significance

Our results suggest that serum miR-122 might serve as a novel and potential noninvasive biomarker for detection of HCC in healthy subjects, moreover, it might serve as a novel biomarker for liver injury but not specifically for detection of HCC in chronic HBV infection patients.     

Plasma MicroRNAs as Potential Noninvasive Biomarkers for In-Stent Restenosis

Objective

To investigate whether microRNAs (miRs) can serve as novel biomarkers for in-stent restenosis (ISR).

Methods

This retrospective, observational single-centre study was conducted at the cardiovascular department of a tertiary hospital centre in the north of China. Follow-up coronary angiography at 6 to 12 months was performed in 181 consecutive patients implanted with drug-eluting stents. Fifty-two healthy volunteers served as the control group. The plasma miRs levels were analyzed by quantitative real-time PCR. Receiver-operating characteristic curve (ROC) analysis was performed to investigate the characters of these miRs as potential biomarkers of ISR.

Results

MiR-21 levels in ISR patients were significantly higher than those in non-ISR patients and healthy controls (P<0.05), while miR-100 (P<0.05), miR-143 (P<0.001) and miR-145 (P<0.0001) levels were significantly decreased in ISR patients. Further analysis showed that miR-21 levels were remarkably increased (P = 0.045), while miR-100 (P = 0.041), miR-143 (P = 0.029) and miR-145 (P<0.01) levels were dramatically decreased in patients with diffuse ISR compared to those with focal ISR. ROC analysis demonstrated that the area under curve of miR-145, miR-143, miR-100 and miR-21 were 0.880 (95% confidence interval; CI = 0.791–0.987, P<0.001), 0.818 (95% confidence interval; CI = 0.755–0.963, P<0.001), 0.608 (95% confidence interval; CI = 0.372–0.757, P<0.05) and 0.568 (95% confidence interval; CI = 0.372–0.757, P<0.05), with specificity of 83.1%, 80.1%, 68.9% and 68.6%, and sensitivity of 88.7%, 82.1%, 60.2% and 50.1%, respectively.

Conclusions

Circulating miR-143 and miR-145 levels are associated with the occurrence of ISR and can serve as novel noninvasive biomarkers for ISR.     

Gene Polymorphisms of Micrornas in Helicobacter pylori-Induced High Risk Atrophic Gastritis and Gastric Cancer

Background and aims

MicroRNAs (miRNAs) are known for their function as translational regulators of tumor suppressor or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs related genes have been shown to affect the regulatory capacity of miRNAs and were linked with gastric cancer (GC) and premalignant gastric conditions. The purpose of this study was to evaluate potential associations between miRNA-related gene polymorphisms (miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608) and the presence of GC or high risk atrophic gastritis (HRAG) in European population.

Methods

Gene polymorphisms were analyzed in 995 subjects (controls: n = 351; GC: n = 363; HRAG: n = 281) of European descent. MiR-27a T>C (rs895819), miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913), miR-492 G>C (rs2289030) and miR-608 C>G (rs4919510) SNPs were genotyped by RT-PCR.

Results

Overall, SNPs of miRNAs were not associated with the presence of GC or HRAG. We observed a tendency for miR-196a-2 CT genotype to be associated with higher risk of GC when compared to CC genotype, however, the difference did not reach the adjusted P-value (odds ratio (OR) - 1.46, 95% confidence interval (CI) 1.03-2.07, P = 0.032). MiR-608 GG genotype was more frequent in GC when compared to controls (OR −2.34, 95% CI 1.08–5.04), but significance remained marginal (P = 0.029). A similar tendency was observed in a recessive model for miR-608, where CC + CG vs GG genotype comparison showed a tendency for increased risk of GC with OR of 2.44 (95% CI 1.14–5.22, P = 0.021). The genotypes and alleles of miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 SNPs had similar distribution between histological subtypes of GC and were not linked with the presence of diffuse or intestinal-type GC.

Conclusions

Gene polymorphisms of miR-27a, miR-146a, miR-196a-2, miR-492, miR-492a and miR-608 were not associated with the presence of HRAG, GC or different histological subtypes of GC in European subjects.     

Overexpression of microRNAs from the miR-17-92 paralog clusters in AIDS-related non-Hodgkin's lymphomas

Background

Individuals infected by HIV are at an increased risk for developing non-Hodgkin''s lymphomas (AIDS-NHL). In the highly active antiretroviral therapy (HAART) era, there has been a significant decline in the incidence of AIDS-associated primary central nervous system lymphoma (PCNSL). However, only a modest decrease in incidence has been reported for other AIDS-NHL subtypes. Thus, AIDS-NHLs remain a significant cause of morbidity and mortality in HIV infected individuals. Recently, much attention has been directed toward the role of miRNAs in cancer, including NHL. Several miRNAs, including those encoded by the miR-17-92 polycistron, have been shown to play significant roles in B cell tumorigenesis. However, the role of miRNAs in NHL in the setting of HIV infection has not been defined.

Methodology/Principal Findings

We used quantitative realtime PCR to assess the expression of miRNAs from three different paralog clusters, miR-17-92, miR-106a-363, and miR-106b-25 in 24 cases of AIDS-NHLs representing four tumor types, Burkitt''s lymphoma (BL, n = 6), diffuse large B-cell lymphoma (DLBCL, n = 8), primary central nervous system lymphoma (PCNSL, n = 5), and primary effusion lymphoma (PEL, n = 5). We also used microarray analysis to identify a differentiation specific miRNA signature of naïve, germinal center, and memory B cell subsets from tonsils (n = 4). miRNAs from the miR-17-92 paralog clusters were upregulated by B cells, specifically during the GC differentiation stage. We also found overexpression of these miRNA clusters in all four AIDS-NHL subtypes. Finally, we also show that select miRNAs from these clusters (miR-17, miR-106a, and miR-106b) inhibited p21 in AIDS-BL and DLBCL cases, thus providing a mechanistic role for these miRNAs in AIDS-NHL pathogenesis.

Conclusion

Dysregulation of miR-17-92 paralog clusters is a common feature of AIDS-associated NHLs.     

miR-16 and miR-21 expression in the placenta is associated with fetal growth

Background

Novel research has suggested that altered miRNA expression in the placenta is associated with adverse pregnancy outcomes and with potentially harmful xenobiotic exposures. We hypothesized that aberrant expression of miRNA in the placenta is associated with fetal growth, a measurable phenotype resulting from a number of intrauterine factors, and one which is significantly predictive of later life outcomes.

Methodology/Principal Findings

We analyzed 107 primary, term, human placentas for expression of 6 miRNA reported to be expressed in the placenta and to regulate cell growth and development pathways: miR-16, miR-21, miR-93, miR-135b, miR-146a, and miR-182. The expression of miR-16 and miR-21 was markedly reduced in infants with the lowest birthweights (p<0.05). Logistic regression models suggested that low expression of miR-16 in the placenta predicts an over 4-fold increased odds of small for gestational age (SGA) status (p = 0.009, 95% CI = 1.42, 12.05). Moreover, having both low miR-16 and low miR-21 expression in the placenta predicts a greater increase in odds for SGA than having just low miR-16 or miR-21 expression (p<0.02), suggesting an additive effect of both of these miRNA.

Conclusions/Significance

Our study is one of the first to investigate placental miRNA expression profiles associated with birthweight and SGA status. Future research on miRNA whose expression is associated with in utero exposures and markers of fetal growth is essential for better understanding the epigenetic mechanisms underlying the developmental origins of health and disease.     

Five microRNAs in plasma as novel biomarkers for screening of early-stage non-small cell lung cancer

Background

In order to find novel noninvasive biomarkers with high accuracy for the screening of early-stage non-small cell lung cancer (NSCLC), we investigate the predictive power of 5 microRNAs (miR-20a, miR-145, miR-21, miR223 and miR-221) as potential biomarkers in early-stage NSCLC.

Methods

In training set, 25 early-stage NSCLC patients and 25 matched healthy controls are included to assess the miRNA expression profile between early-stage NSCLC patients and healthy controls by real-time RT-PCR. We found that five of these miRNAs (miR-20a, miR-223, miR-21, miR-221 and miR-145) levels in NSCLC patients were significantly dysregulated compared with the healthy groups and thus were selected to validation set. Therefore, a validation experiment was further performed to investigate the potential predictive power of these five miRNAs based on 126 early-stage NSCLC patients, 42 NCPD patients and 60 healthy controls. The receiver operating characteristic (ROC) curves were generated for the five miRNAs.

Results

ROC curve analyses suggested that these five plasma miRNAs could be promising biomarkers for NSCLC, with relatively high AUC values as follows: miR-20a, 0.89 with 95% CI of [0.85-0.93]; miR-223, 0.94 with 95% CI of [0.91-0.96]; miR-21, 0.77 with 95% CI of [0.71-0.83]; miR-155, 0.92 with 95% CI of [0.89-0.96]; miR-145, 0.77 with 95% CI of [0.71-0.83]. Stratified analyses indicated that plasma miR-20a, miR-223, miR-21 and miR-145 showed better predictive value in smokers than in non-smokers, while miR-155 might be more suitable for non-smokers. In addition, all of these five miRNAs could differentiate NSCLC from controls with a higher accuracy in advanced stage and squamous carcinoma subgroups.

Conclusions

In conclusion, our study suggested that five plasma miRNAs (miR-20a, miR-145, miR-21, miR-223 and miR-221) can be used as promising biomarkers in early screening of NSCLC. Nevertheless, further validation and optimizing improvement should be performed on larger sample to confirm our results.     

Technical Factors Involved in the Measurement of Circulating MicroRNA Biomarkers for the Detection of Colorectal Neoplasia

Background

Circulating miRNAs are emerging as promising blood-based biomarkers for colorectal and other human cancers; however, technical factors that confound the development of these assays remain poorly understood and present a clinical challenge. The aim of this study was to systematically evaluate the effects of factors that may interfere with the accurate measurement of circulating miRNAs for clinical purposes.

Methods

Blood samples from 53 subjects, including routinely drawn serum samples, matched plasma from 30 subjects, and matched serum samples drawn before and after bowel preparation for colonoscopy from 29 subjects were collected. Additionally, 38 serum specimens stored in the clinical laboratory for seven days were used to test the stability of miRNAs. Hemolysis controls with serial dilutions of hemoglobin were prepared. RNA was extracted from serum, plasma or hemolyzed controls with spiked-in cel-miR-39, and levels of miR-21, miR-29a, miR-125b and miR-16 were examined by real-time RT-PCR. Hemolysis was measured by spectrophotometry.

Results

The expression levels of miR-16 and the degree of hemolysis were significantly higher in plasma than in serum (P<0.0001). Measured miR-21, miR-29a, miR-125b and miR-16 expression increased with hemoglobin levels in hemolyzed controls. The degree of hemolysis in serum samples correlated significantly with the levels of miR-21 (P<0.0001), miR-29a (P = 0.0002), miR-125b (P<0.0001) and miR-16 (P<0.0001). All four miRNAs showed significantly lower levels in sera that had been stored at 4°C for seven days (P<0.0001). Levels of miR-21 (P<0.0001), miR-29a (P<0.0001) and miR-16 (P = 0.0003), and the degree of hemolysis (P = 0.0002) were significantly higher in sera drawn after vs. before bowel preparation.

Conclusions

The measured levels of miRNAs in serum and plasma from same patients varied in the presence of hemolysis, and since hemolysis and other factors affected miRNA expression, it is important to consider these confounders while developing miRNA-based diagnostic assays.     

Feasibility of Fecal MicroRNAs as Novel Biomarkers for Pancreatic Cancer

Introduction

Pancreatic cancer (PCA) is an aggressive tumor that associates with high mortality rates. Majority of PCA patients are diagnosed usually at late tumor stages when the therapeutic options are limited. MicroRNAs (miRNA) are involved in tumor development and are commonly dysregulated in PCA. As a proof-of-principle study, we aimed to evaluate the potential of fecal miRNAs as biomarkers for pancreatic cancer.

Materials and Methods

Total RNA was extracted from feces using Qiagen''s miRNA Mini Kit. For miRNA expression analyses we selected a subset of 7 miRNAs that are frequently dysregulated in PCA (miR-21, -143, -155, -196a, -210, -216a, -375). Subsequently, expression levels of these miRNAs were determined in fecal samples from controls (n = 15), chronic pancreatitis (n = 15) and PCA patients (n = 15) using quantitative TaqMan-PCR assays.

Results

All selected miRNAs were detectable in fecal samples with high reproducibility. Four of seven miRNAs (miR-216a, -196a, -143 und -155) were detected at lower concentrations in feces of PCA patients when compared to controls (p<0.05). Analysis of fecal miRNA expression in controls and patients with chronic pancreatitis and PCA revealed that the expression of miR-216a, -196a, -143 und -155 were highest in controls and lowest in PCA. The expression of the remaining three miRNAs (miR-21, -210 and -375) remained unchanged among controls and the patients with either chronic pancreatitis or PCA.

Conclusion

Our data provide novel evidence for the differential expression of miRNAs in feces of patients with PCA. If successfully validated in large-scale prospective studies, the fecal miRNA biomarkers may offer novel tools for PCA screening research.     

Identification and Validation of Oncologic miRNA Biomarkers for Luminal A-like Breast Cancer

Introduction

Breast cancer is a common disease with distinct tumor subtypes phenotypically characterized by ER and HER2/neu receptor status. MiRNAs play regulatory roles in tumor initiation and progression, and altered miRNA expression has been demonstrated in a variety of cancer states presenting the potential for exploitation as cancer biomarkers. Blood provides an excellent medium for biomarker discovery. This study investigated systemic miRNAs differentially expressed in Luminal A-like (ER+PR+HER2/neu-) breast cancer and their effectiveness as oncologic biomarkers in the clinical setting.

Methods

Blood samples were prospectively collected from patients with Luminal A-like breast cancer (n = 54) and controls (n = 56). RNA was extracted, reverse transcribed and subjected to microarray analysis (n = 10 Luminal A-like; n = 10 Control). Differentially expressed miRNAs were identified by artificial neural network (ANN) data-mining algorithms. Expression of specific miRNAs was validated by RQ-PCR (n = 44 Luminal A; n = 46 Control) and potential relationships between circulating miRNA levels and clinicopathological features of breast cancer were investigated.

Results

Microarray analysis identified 76 differentially expressed miRNAs. ANN revealed 10 miRNAs for further analysis (miR-19b, miR-29a, miR-93, miR-181a, miR-182, miR-223, miR-301a, miR-423-5p, miR-486-5 and miR-652). The biomarker potential of 4 miRNAs (miR-29a, miR-181a, miR-223 and miR-652) was confirmed by RQ-PCR, with significantly reduced expression in blood of women with Luminal A-like breast tumors compared to healthy controls (p = 0.001, 0.004, 0.009 and 0.004 respectively). Binary logistic regression confirmed that combination of 3 of these miRNAs (miR-29a, miR-181a and miR-652) could reliably differentiate between cancers and controls with an AUC of 0.80.

Conclusion

This study provides insight into the underlying molecular portrait of Luminal A-like breast cancer subtype. From an initial 76 miRNAs, 4 were validated with altered expression in the blood of women with Luminal A-like breast cancer. The expression profiles of these 3 miRNAs, in combination with mammography, has potential to facilitate accurate subtype-specific breast tumor detection.     

Up-regulated Dicer expression in patients with cutaneous melanoma

Background

MicroRNAs (miRNAs) are small non-coding RNAs (18–24 nucleotides) that have recently been shown to regulate gene expression during cancer progression. Dicer, a central enzyme in the multi-component miRNA biogenesis pathway, is involved in cutting precursor miRNAs to functionally mature forms. Emerging evidence shows that Dicer expression is deregulated in some human malignancies and it correlates with tumor progression, yet this role has not yet been investigated in skin cancers.

Methods and Findings

Using an anti-human monoclonal antibody against Dicer and immunohistochemistry, we compared the expression of Dicer protein among 404 clinically annotated controls and skin tumors consisting of melanocytic nevi (n = 71), a variety of melanomas (n = 223), carcinomas (n = 73) and sarcomas (n = 12). Results showed a cell-specific up-regulated Dicer in 81% of cutaneous, 80% of acrolentiginous and 96% of metastatic melanoma specimens compared to carcinoma or sarcoma specimens (P<0.0001). The expression of Dicer was significantly higher in melanomas compared to benign melanocytic nevi (P<0.0001). In patients with cutaneous melanomas, Dicer up-regulation was found to be significantly associated with an increased tumor mitotic index (P = 0.04), Breslow''s depth of invasion (P = 0.03), nodal metastasis (P = 0.04) and a higher American Joint Committee on Caner (AJCC) clinical stage (P = 0.009). Using western blot analysis, we confirmed the cell-specific up-regulation of Dicer protein in vitro. A pooled-analysis on mRNA profiling in cutaneous tumors showed up-regulation of Dicer at the RNA level in cutaneous melanoma, also showing deregulation of other enzymes that participate in the biogenesis and maturation of canonical miRNAs.

Conclusions

Increased Dicer expression may be a clinically useful biomarker for patients with cutaneous melanoma. Understanding deregulation of Dicer and its influence on miRNA maturation is needed to predict the susceptibility of melanoma patients to miRNA-based therapy in the future.     

Determination of 14 Circulating microRNAs in Swedes and Iraqis with and without Diabetes Mellitus Type 2

Background

Recent reports suggest that immigrants from Middle Eastern countries are a high-risk group for type 2 diabetes (T2D) compared with Swedes, and that the pathogenesis of T2D may be ethnicity-specific. Deregulation of microRNA (miRNA) expression has been demonstrated to be associated with T2D but ethnic differences in miRNA have not been investigated. The aim of this study was to explore the ethnic specific expression (Swedish and Iraqi) of a panel of 14 previously identified miRNAs in patients without T2D (including those with prediabetes) and T2D.

Methods

A total of 152 individuals were included in the study (84 Iraqis and 68 Swedes). Nineteen Iraqis and 14 Swedes were diagnosed with T2D. Expression of the 14 selected miRNAs (miR-15a, miR-20, miR-21, miR-24, miR-29b, miR-126, miR-144, miR-150, miR-197, miR-223, miR-191, miR-320a, miR-486-5p, and miR-28-3p) in plasma samples was measured by real-time PCR.

Results

In the whole study population, the expression of miR-24 and miR-29b was significantly different between T2D patients and controls after adjustment for age, sex, waist circumference, family history of T2D, and a sedentary lifestyle. Interestingly, when stratifying the study population according to country of birth, we found that higher expression of miR-144 was significantly associated with T2D in Swedes (OR = 2.43, p = 0.035), but not in Iraqis (OR = 0.54, p = 0.169). The interaction test was significant (p = 0.017).

Conclusion

This study suggests that the association between plasma miR-144 expression and T2D differs between Swedes and Iraqis.     

Prognostic significance of miR-205 in endometrial cancer

Purpose

microRNAs have emerged as key regulators of gene expression, and their altered expression has been associated with tumorigenesis and tumor progression. Thus, microRNAs have potential as both cancer biomarkers and/or potential novel therapeutic targets. Although accumulating evidence suggests the role of aberrant microRNA expression in endometrial carcinogenesis, there are still limited data available about the prognostic significance of microRNAs in endometrial cancer. The goal of this study is to investigate the prognostic value of selected key microRNAs in endometrial cancer by the analysis of archival formalin-fixed paraffin-embedded tissues.

Experimental Design

Total RNAs were extracted from 48 paired normal and endometrial tumor specimens using Trizol based approach. The expression of miR-26a, let-7g, miR-21, miR-181b, miR-200c, miR-192, miR-215, miR-200c, and miR-205 were quantified by real time qRT-PCR expression analysis. Targets of the differentially expressed miRNAs were quantified using immunohistochemistry. Statistical analysis was performed by GraphPad Prism 5.0.

Results

The expression levels of miR-200c (P<0.0001) and miR-205 (P<0.0001) were significantly increased in endometrial tumors compared to normal tissues. Kaplan-Meier survival analysis revealed that high levels of miR-205 expression were associated with poor patient overall survival (hazard ratio, 0.377; Logrank test, P = 0.028). Furthermore, decreased expression of a miR-205 target PTEN was detected in endometrial cancer tissues compared to normal tissues.

Conclusion

miR-205 holds a unique potential as a prognostic biomarker in endometrial cancer.     

Comparative brain stem lesions on MRI of acute disseminated encephalomyelitis, neuromyelitis optica, and multiple sclerosis

Background

Brain stem lesions are common in patients with acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), and multiple sclerosis (MS).

Objectives

To investigate comparative brain stem lesions on magnetic resonance imaging (MRI) among adult patients with ADEM, NMO, and MS.

Methods

Sixty-five adult patients with ADEM (n = 17), NMO (n = 23), and MS (n = 25) who had brain stem lesions on MRI were enrolled. Morphological features of brain stem lesions among these diseases were assessed.

Results

Patients with ADEM had a higher frequency of midbrain lesions than did patients with NMO (94.1% vs. 17.4%, P<0.001) and MS (94.1% vs. 40.0%, P<0.001); patients with NMO had a lower frequency of pons lesions than did patients with MS (34.8% vs. 84.0%, P<0.001) and ADEM (34.8% vs. 70.6%, P = 0.025); and patients with NMO had a higher frequency of medulla oblongata lesions than did patients with ADEM (91.3% vs. 35.3%, P<0.001) and MS (91.3% vs. 36.0%, P<0.001). On the axial section of the brain stem, the majority (82.4%) of patients with ADEM showed lesions on the ventral part; the brain stem lesions in patients with NMO were typically located in the dorsal part (91.3%); and lesions in patients with MS were found in both the ventral (44.0%) and dorsal (56.0%) parts. The lesions in patients with ADEM (100%) and NMO (91.3%) had poorly defined margins, while lesions of patients with MS (76.0%) had well defined margins. Brain stem lesions in patients with ADEM were usually bilateral and symmetrical (82.4%), while lesions in patients with NMO (87.0%) and MS (92.0%) were asymmetrical or unilateral.

Conclusions

Brain stem lesions showed various morphological features among adult patients with ADEM, NMO, and MS. The different lesion locations may be helpful in distinguishing these diseases.     

Plasma miR-601 and miR-760 Are Novel Biomarkers for the Early Detection of Colorectal Cancer

Background

Colorectal cancer (CRC) is a major cause of death worldwide. Sensitive, non-invasive diagnostic screen methods are urgently needed to improve its survival rates. Stable circulating microRNA offers unique opportunities for the early diagnosis of several diseases, including cancers. Our aim has been to find new plasma miRNAs that can be used as biomarkers for the detection of CRC.

Methodology/Principal Findings

According to the results of miRNA profiling performed on pooling plasma samples form 10 CRC patients or 10 healthy controls, a panel of miRNAs (hsa-miR-10a, -19a, -22*, -24, -92a, 125a-5p, -141, -150, -188-3p, -192, -210, -221, -224*, -376a, -425*, -495, -572, -601, -720, -760 and hsa-let-7a, -7e) were deregulated in CRC plasma with fold changes >5. After large scale validation by qRT-PCR performed on another 191 independent individuals (90 CRC, 43 advanced adenoma and 58 healthy participants), we found that the levels of plasma miR-601 and miR-760 were significantly decreased in colorectal neoplasia (carcinomas and advanced adenomas) compared with healthy controls. ROC curve analysis showed that plasma miR-601 and miR-760 were of significant diagnostic value for advanced neoplasia. These two miRNAs together yield an AUC of 0.792 with 83.3% sensitivity and 69.1% specificity for separating CRC from normal controls, and yield an AUC of 0.683 with 72.1% sensitivity and 62.1% specificity in discriminating advanced adenomas from normal controls.

Conclusions/Significance

Plasma miR-601 and miR-760 can potentially serve as promising non-invasive biomarkers for the early detection of CRC.     

Clinical impact of down-regulated plasma miR-92a levels in non-Hodgkin's lymphoma

Background

We undertook a study to evaluate the clinical relevance of miR-92a in plasma obtained from non-Hodgkin''s lymphoma (NHL) patients, because the miR-17-92 polycistronic miRNA cluster plays a crucial role in lymphomagenesis and affects neo-angiogenesis.

Methodology/Principal Findings

Plasma miR-92a values in NHL were extremely low (<5%), compared with healthy subjects (P<.0001), irrespective of lymphoma sub-type. The very low plasma level of miR-92a increased in the complete response (CR) phase but did not reach the normal range, and the plasma level was lower again in the relapse phase. Patients in CR or CR unconfirmed with a plasma miR-92a level of less than the cut-off level showed a significantly high relapse rate compared with patients with normalized plasma miR-92a level.

Conclusions/Significance

The current results therefore indicate that the plasma miR-92a value could be a novel biomarker not only for diagnosis but also for monitoring lymphoma patients after chemotherapy.