A systematic review and meta-analysis of miRNAs for the detection of cervical cancer.

Aim: This study aimed to critically appraise the evidence of the diagnostic effectiveness of miRNAs for the detection of cervical cancer. Methods & materials: A systematic review and meta-analysis was performed, searching PubMed, EMBASE and Web of Science. An umbrella meta-analysis of meta-analyses of individual biomarkers was performed. A Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment of evidence was also performed. Results: A total of 52 miRNAs were included. Umbrella meta-analysis revealed significant heterogeneity in terms of sensitivity, specificity, receiver operating characteristic (ROC), positive predictive value and/or negative predictive value. Umbrella effects were 0.76 (95% CI: 0.73-0.78), 0.78 (95% CI: 0.75-0.81), 0.77 (95% CI: 0.75-0.80), 0.75 (95% CI: 0.71-0.79) and 0.76 (95% CI: 0.74-0.79), respectively. Conclusion: Moderate quality evidence suggested miR199a-5p, miR21-5p and miR-141a had excellent diagnostic performance.

miRNAs are small chemical messengers that play a role in the regulation of protein produced inside the cytoplasm of cells, including cancer cells. In cervical cancer cells, miRNAs become dysregulated ­ that is, their levels become increased or decreased ­ and therefore detecting their relative abundance or absence in test samples may enable identification of cervical cancer. This study aimed to systematically collect and appraise the evidence for the diagnostic ability of miRNAs for detection of cervical cancer. A systematic appraisal of the evidence was conducted by searching three research databases (PubMed, EMBASE and Web of Science) to collect evidence published up to 13 November 2022. Results for diagnostic performance of 52 miRNAs were extracted from 20 relevant studies. An assessment of risk of bias for each study was performed using a standardized checklist, which identified one high-quality study, 18 moderate-quality studies and one low-quality study. Results for each individual biomarker were assessed by meta-analytic methods, which generated weighted averages for 38 of 52 miRNAs. All 52 miRNAs were then compared using an umbrella meta-analysis (a weighted average of all miRNA biomarkers), which identified significant differences in diagnostic ability between miRNAs. Sensitivity analyses suggested that these differences were partly explained by differences in grades of cervical cancer and differences in types of sample used for testing. A GRADE assessment of the overall evidence quality suggested that moderate-quality evidence supported further investigation of three miRNA biomarkers (miR-199a-5p, miR-21-5p and miR-141a), which performed excellently (i.e., better than the umbrella weighted average) across five performance parameters, including sensitivity, specificity, receiver operator characteristic, positive predictive value and negative predictive value. In summary, this study suggested miR-199a-5p, miR-21-5p and miR-141a had excellent diagnostic performance for detection of cervical cancer and recommends further investigation of these miRNAs in randomized controlled trials.

A systematic review and meta-analysis of the diagnostic effectiveness of human papillomavirus methylation biomarkers for detection of cervical cancer.

Background: The aim of this systematic review and meta-analysis was to assess the evidence for the diagnostic effectiveness of human papillomavirus (HPV) methylation biomarkers for detection of cervical cancer. Methods: PubMed, Embase and Web of Science were searched. Nine articles focusing on HPV methylation for detection of precancerous and cancerous cervical lesions were included. The QUADAS-2 tool was used for quality assessment. The receiver operating characteristic (ROC) was the main diagnostic performance parameter extracted. Results: Of the nine articles included in this study, seven were of moderate quality and two were of high quality. A meta-analysis of the ROC for 27 HPV methylation biomarkers revealed an overall pooled ROC of 0.770 (95% CI: 0.720-0.819; I2: 98.4%; Q: 1537.4; p < 0.01). Four methylation biomarkers had strong diagnostic ability (ROC > 0.900), 17 were moderate (ROC: 0.7000-0.8999) and six were poor (ROC < 0.700). Conclusion: HPV methylation biomarkers hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

This study reviewed the literature to assess the available evidence for the ability of biomarkers based on human papillomavirus (HPV) methylation (i.e., the detection of methyl groups in HPV DNA in cervical specimens) to screen for cervical precancerous and cancerous lesions. Scientific databases were searched, and abstracts screened for relevance. The quality of the included articles was assessed using a quality assessment tool called QUADAS-2. The main diagnostic performance parameter extracted from the included articles was the receiver operating characteristic (ROC), a measure of the ability of a biomarker to detect all true cases (true positives) while excluding all true non-cases (true negatives). After screening, nine articles were included, of which seven were of moderate quality and two were of high quality. ROC data were extracted for 27 biomarkers, of which four methylation biomarkers had high diagnostic ability (i.e., ROC > 0.900), 17 had moderate diagnostic ability (ROC: 0.7000­0.8999) and six had low diagnostic ability (ROC < 0.700). An umbrella meta-analysis (i.e., a weighted-average ROC for all HPV methylation biomarkers) revealed an ROC consistent with moderate diagnostic ability (0.770). The main conclusion from this study was that HPV methylation biomarkers, especially ones with high diagnostic ability, hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

Impact of PD1 and PDL1 immunotherapy on non-small cell lung cancer outcomes: a systematic review.

INTRODUCTION: Despite comprising many cancer diagnoses, few treatments are suitable for patients with advanced non-small cell lung cancer (aNSCLC). Trials suggest blockade of programmed death 1 (PD1) or its ligand (PDL1) may be effective for these patients. However, this therapy's impact on outcomes other than survival, and outcomes of patients not in trials, remains largely unknown. Therefore, we compared the effectiveness of PD1 and PDL1 immunotherapy to chemotherapy and placebo across multiple clinical outcomes. METHODS: Six databases were searched on 12-13 October 2019 for randomised controlled trials (RCTs) and observational studies investigating nivolumab, pembrolizumab, atezolizumab or durvalumab. Study selection was performed independently by two reviewers. Data for overall survival, progression-free survival, adverse effects (AEs) and quality of life (QoL) were descriptively and meta-analysed. Factors impacting treatment outcomes, including PDL1 expression, were explored. The similarity between RCT and observational data was assessed. RESULTS: From 5423 search results, 139 full texts and abstracts were included. Immunotherapy was associated with a lower risk of death than both comparators. In RCTs, the incidence of treatment-related AEs was approximately 20% lower among patients using immunotherapy compared with chemotherapy. However, no other consistent benefits were observed. Progression-free survival results were inconsistent. Improvements to QoL varied according to the instrument used; however, QoL was not recorded widely. Survival results were similar between study designs; however, AEs incidence was lower in observational studies. DISCUSSION: Among patients with aNSCLC, immunotherapy improved overall survival and incidence of treatment-related AEs compared with chemotherapy. Benefits to progression-free survival and QoL were less consistent. PROSPERO REGISTRATION NUMBER: CRD42019153345.

Complex cross-talk between EZH2 and miRNAs confers hallmark characteristics and shapes the tumor microenvironment.

Cancer epigenetic mechanisms support the acquisition of hallmark characteristics during oncogenesis. EZH2 - an important histone methyltransferase that writes histone H3 lysine 27 trimethylation marks - is known to be dysregulated in cancer cells. However, the interactions between EZH2 and miRNAs that form a complex network of cross-talk and reciprocal regulation that enable cancer cells to acquire hallmark characteristics have been relatively poorly appreciated. The specific functions of EZH2 appear to be regulated by a vast array of miRNAs, which direct EZH2 toward regulation over the development of specific hallmark characteristics. This review discusses recent advances in the understanding of EZH2, focusing on its collaboration with miRNAs to orchestrate oncogenesis. These epigenetic processes promote the evasion of apoptosis/cell cycle arrest, cellular dedifferentiation and the establishment of a tumor microenvironment that facilitates local cancer cell invasion, anti-cancer drug resistance and evasion of the immune response.

Cancer epigenetics involves cellular processes that ensure that gene expression changes that enable cancer cells to outcompete their neighboring normal tissues are passed on from one cancer cell to the next. One key epigenetic player is called EZH2, which is an enzyme that transfers methyl (CH₃) groups from donor molecules to the histone proteins around which DNA is coiled. The transfer of methyl groups to histones ­ a process called histone methylation ­ silences the production of proteins from the genes coded in DNA. To achieve this goal, EZH2 is directed to affect specific genes through interactions with other molecules consisting of short sequences of RNA (a molecule similar in structure to DNA). The specific RNA molecules in question are called miRNAs or non-coding RNAs. These EZH2/miRNA interactions form a complex web of circuits that enables cancer cells to gain characteristics that give them a competitive advantage over their normal tissue neighbors. This review discusses recent advances in the understanding of the role of EZH2 in cancer formation, focusing on the interactions it has with miRNAs (and other non-coding RNAs) to organize many different processes linked with cancer formation. These processes include the avoidance of cell death or cell growth arrest, the development of stem cell properties and the formation of an environment around tumor cells that allows them to invade adjacent normal tissue (i.e., metastasize) and avoid being killed by anti-cancer drugs and the immune system.

Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration.

Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1-Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.