The cyclin-dependent kinase inhibitor p21(WAF1/CIP1) is a critical regulator of cell cycle, and it is easily degraded by proteasome through ubiquitin-dependent and -independent pathway. The mechanism of the post-translational regulation of p21 stability remains to be further clarified. In the present study, we have identified nucleophosmin (NPM)/B23, a multifunctional protein that bound p21 and contributed to its stability. The direct interaction between p21 and NPM was confirmed by reciprocal co-immunoprecipitation and GST pull-down assay. Confocal microscopy showed that NPM partially co-localized with p21 in nucleoplasm and their co-localization increased treated with Act D which induces the nucleoplasmic translocation of NPM. We observed the half life of p21 was prolonged with overexpression of NPM or Act D treatment. Knockdown of NPM by siRNA resulted in downregulation of p21 and impaired upregulation of p21 treated with Act D. Further, we examined the effect of NPM expression on the ubiquitination of p21. Overexpression of NPM inhibited the ubiquitination of p21, and depletion of NPM remarkably improved the ubiquitination of p21. Altogether, we provide evidence for a direct binding between NPM and p21, and assign NPM as a positive post-translational regulator of p21.

Early detection of esophageal squamous cell carcinoma (ESCC) is urgently needed to reduce the high morbidity and mortality of disease. Circulating microRNAs (miRNAs) are promising molecular biomarkers for ESCC prediction. We performed a comprehensive meta-analysis to systematically evaluate the diagnostic accuracy of circulating miRNAs in diagnosis of ESCC patients. Eligible studies were identified and assessed for quality employing multiple search strategies. Summary estimates for sensitivity, specificity, and other measures of accuracy of miRNAs in the diagnosis of ESCC were pooled using the bivariate random effects model. A total of 27 studies from 11 published articles were included in the meta-analysis. The overall sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of circulating miRNAs for the diagnosis of ESCC were 79.9% (95% confidence intervals [CI]: 76.2%-83.1%), 81.3% (95% CI: 75.7-85.9), 4.27 (95%CI: 3.27-5.58), 0.25 (95% CI: 0.21-0.29), and 17.29 (95% CI: 12.01-24.86), respectively. The area under the summary receiver operating characteristic curve was 0.87 (95% CI: 0.84-0.90). The subgroup analyses based on research country (China vs. Japan), specimen type (plasma vs. serum), miRNAs profiling (single vs. multiple), and test method (screening vs. candidate; Taqman vs. SYBR) indicated no significant difference in the diagnostic accuracy of each subgroup. Collectively, our findings indicate that circulating miRNAs have significant potential to be used as noninvasive biomarkers for early detection of ESCC. Moreover, the subgroup analyses demonstrated the feasibility of using blood miRNAs as an ESCC diagnostic biomarker in Japanese and Chinese populations. Further, both plasma and serum are recommended as clinical specimens for miRNA detection. Further studies will be needed to validate these findings using larger numbers of patients.

Introduction: Circulating microRNAs (miRNAs) are promising molecular biomarkers for the early detection of esophageal squamous cell carcinoma (ESCC). We investigated the serum miRNA expression profiles from microarray-based technologies and evaluated the diagnostic value of serum miRNAs as potential biomarkers for ESCC by using feature selection algorithms.Methods: Serum miRNA expression profiles were obtained from 52 ESCC patients and 52 age- and sex-matched controls via performing a high-throughput microarray assay. Five representative feature selection algorithms including the false discovery rate procedure, family-wise error rate procedure, Lasso logistic regression, hybrid huberized support vector machine (SVM), and SVM using the squared-error loss with the elastic-net penalty were jointly carried out to select the significantly differentially expressed miRNAs based on the miRNA profiles.Results: Three miRNAs including miR-16-5p, miR-451a, and miR-574-5p were identified as the powerful biomarkers for the diagnosis of ESCC. The diagnostic accuracy of the combination of these three miRNAs was evaluated by using logistic regression and the SVM. The averages of the area under the receiver operating curve and classification accuracies based on different classifiers were more than 0.80 and 0.79, respectively. The cross-validation results suggested that the three-miRNA-based classifiers could clearly distinguish ESCC patients from healthy controls. Moreover, the classifying performance of the miRNA panel persisted in discriminating the healthy group from patients with ESCC stage I-II (AUC > 0.76) and patients with ESCC stage III-IV (AUC > 0.80).Conclusions: These results in this study have moved forward the identification of novel biomarkers for the diagnosis of ESCC.

Background: Circulating miRNAs have been identified as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC), but their efficacy in discovering early-stage ESCC is still unsatisfying. Esophageal squamous dysplasia (ESD) is the precursor lesion of ESCC. Notably, little is known about the role(s) of circulating miRNAs in identifying ESD. In this study, we, therefore, aimed to identify serum miRNAs as novel diagnostic markers for detecting ESD and ESCC. Methods: The genome-wide miRNA expression was profiled in 104 (52 ESCC and 52 controls) serum samples using microarray. Seven candidate miRNAs from the microarray assay were evaluated for their diagnostic performance in another cohort of 266 participants (96 ESCC, 92 ESD, and 78 healthy controls). Results: The serum levels of miR-16-5p, miR-197-5p, miR-451a, and miR-92a-3p were associated with ESCC; the biomarker based on the panel of these four miRNAs could efficiently distinguish patients with ESCC from the controls [AUC ¼ 0.856; 95% confidence interval (CI), 0.794-0.905; P < 0.001]. The serum levels of miR-16-5p, miR-320c, miR-638, and miR-92a-3p were significantly higher in patients with ESD than in controls, and this four-miRNA signature could efficiently differentiate patients with ESD from the controls (AUC ¼ 0.842; 95% CI, 0.778-0.893; P < 0.001). In addition, compared with serum carcinoembryonic antigen and carbohydrate antigen 199, miRNA-based panels had a better diagnostic performance in distinguishing patients with ESCC and ESD from healthy controls. Conclusions: Our study identified two novel panels of circulating miRNAs with high efficiency in detecting ESCC and ESD, suggesting that circulating miRNAs, in particular the combination of them, might serve as noninvasive biomarkers for the early detection of ESCC. Impact: This study suggests the feasibility of using circular miRNA-based blood tests to aid in the detection of ESD and ESCC.

BackgroundAccumulating evidence has demonstrated that microRNAs (miRNAs) could serve as promising molecular biomarkers for cancer detection. This study aims to systematically assess the diagnostic performance of salivary miRNAs in detection of cancer through a comprehensive meta-analysis.MethodsEligible studies were identified using PubMed and other computerized databases up to October 31, 2015, supplemented by a manual search of references from retrieved articles. The pooled sensitivity, specificity, and other measurements of accuracy of salivary miRNAs in the diagnosis of cancer were analyzed using the bivariate binomial mixed model.ResultsSeventeen studies from 8 articles with 694 subjects were included in this meta-analysis. All studies have a relatively high score of quality assessment. The overall sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of salivary miRNAs in detection of cancer were 0.77 (95% confidence intervals [CI]: 0.69–0.84), 0.77 (95%CI: 0.65–0.88), 3.37 (95%CI: 2.26–5.02), 0.29 (95%CI: 0.23–0.38), and 11.41 (95%CI: 7.35–17.73), respectively. The AUC was 0.84 (95%CI: 0.80–0.87). Moreover, both whole saliva and saliva supernatant could be used as sources of clinical specimens for miRNAs detection.ConclusionsOur meta-analysis demonstrated that salivary miRNAs may serve as potential noninvasive biomarkers for cancer detection. The findings need to be confirmed with further research before it can be applied in the clinic.

Background: Pangenotypic direct-acting antiviral agents (DAAs) glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL) are effective against all hepatitis C virus (HCV) genotype infections. However, data on pangenotypic DAA treatment for mixed genotype HCV infection are sparse. Methods: This is a retrospective, single site cohort study analyzing all patients with mixed HCV genotype infections treated with GLE/PIB or SOF/VEL from August 2018 to August 2020 in Chiayi Chang Gung Memorial Hospital, Taiwan. The primary study endpoint was sustained virologic response (SVR) 12 weeks after treatment cessation. We also reported adverse events (AEs). Results: A total of 108 patients with mixed infections of any two or three genotypes of 1a, 1b, 2, 3, and 6 received pangenotypic DAAs during the study period. A total of 67 patients received GLE/PIB and 41 received SOF/VEL. The evaluable population analysis revealed SVR rates of 94% (63/67) and 95.1% (39/41) for GLE/PIB and SOF/VEL therapy, respectively, and the per-protocol analysis revealed an SVR of 100% for both regimens. Four patients in the GLE/PIB group and two patients in the SOF/VEL were lost to follow-up. The most common AEs for GLE/PIB versus SOF/VEL therapy included pruritus (14.9% vs 2.4%), fatigue (6.0% vs 7.3%), abdominal discomfort (4.5% vs 7.3%), and acid reflux (3.0% vs 4.9%). DAA-related significant laboratory abnormalities occurred in three patients with > 1.5 × elevated bilirubin level in the GLE/PIB group. None of the above AEs resulted in DAA discontinuation. Conclusions: Pangenotypic DAAs are well tolerated by and yield high SVR rates in patients with mixed genotype HCV infection.

The Jumonji domain-containing protein-3 (JMJD3) is a histone demethylase that regulates the trimethylation of histone H3 on lysine 27 (H3K27me3). H3K27me3 is an important epigenetic event associated with transcriptional silencing. JMJD3 has been studied extensively in immune diseases, cancer, and tumor development. There is a comprehensive epigenetic transformation during the transition of embryonic stem cells (ESCs) into specialized cells or the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Recent studies have illustrated that JMJD3 plays a major role in cell fate determination of pluripotent and multipotent stem cells (MSCs). JMJD3 has been found to enhance self-renewal ability and reduce the differentiation capacity of ESCs and MSCs. In this review, we will focus on the recent advances of JMJD3 function in stem cell fate.

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