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Clinical Epigenetics Aug 2023Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.
METHODS
Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.
RESULTS
Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63-0.72) and 0.75 (CI 95% 0.71-0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74-0.82) and 0.74 (CI 95% 0.69-0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.
CONCLUSIONS
This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.
Topics: Female; Humans; Pregnancy; Uterine Cervical Neoplasms; DNA Methylation; Early Detection of Cancer; Colposcopy; Triage; Papillomavirus Infections; Referral and Consultation; Papillomaviridae; Cell Adhesion Molecule-1
PubMed: 37533074
DOI: 10.1186/s13148-023-01537-2 -
Genes Feb 2023Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND OBJECTIVE
Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric age. Despite its great impact, its molecular mechanisms have still not been completely unraveled. Focusing on the impact of epigenetics in the pain complex trait, we assessed the association between chronic pain and the methylation pattern of TRPA1, a key gene related to pain sensitivity.
METHODS
We conducted a systematic review retrieving articles from three different databases. After deduplication, 431 items were subjected to manual screening, and then 61 articles were selected and screened again. Of these, only six were maintained for meta-analysis and analyzed using specific R packages.
RESULTS
Six articles were divided into two groups (group 1: comparison of mean methylation levels between healthy subjects and patients with chronic pain; group 2: correlation between mean methylation levels and pain sensation). A non-significant mean difference was obtained from the analysis of group 1 with a value of 3.97 (95% C.I. -7.79; 15.73). Analysis of group 2 showed a high level of variability between studies (correlation = 0.35, 95% C.I. -0.12; 0.82) due to their heterogeneity (I = 97%, < 0.01).
CONCLUSIONS
Despite the high variability observed in the different studies analyzed, our results suggest that hypermethylation and increased pain sensitivity could be connected, possibly due to the variation of TRPA1 expression.
Topics: Adult; Child; Humans; Ankyrins; Chronic Pain; DNA Methylation; Epigenesis, Genetic; TRPA1 Cation Channel
PubMed: 36833338
DOI: 10.3390/genes14020411 -
Journal of Crohn's & Colitis Mar 2023Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease [IBD] patients. However, a comprehensive summary... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Over the past decade, the DNA methylome has been increasingly studied in peripheral blood of inflammatory bowel disease [IBD] patients. However, a comprehensive summary and meta-analysis of peripheral blood leukocyte [PBL] DNA methylation studies has thus far not been conducted. Here, we systematically reviewed all available literature up to February 2022 and summarized the observations by means of meta-analysis.
METHODS
We conducted a systematic search and critical appraisal of IBD-associated DNA methylation studies in PBL using the biomarker-based cross-sectional studies [BIOCROSS] tool. Subsequently, we performed meta-analyses on the summary statistics obtained from epigenome-wide association studies [EWAS] that included patients with Crohn's disease [CD], ulcerative colitis [UC] and/or healthy controls [HC].
RESULTS
Altogether, we included 15 studies for systematic review. Critical appraisal revealed large methodological and outcome heterogeneity between studies. Summary statistics were obtained from four studies based on a cumulative 552 samples [177 CD, 132 UC and 243 HC]. Consistent differential methylation was identified for 256 differentially methylated probes [DMPs; Bonferroni-adjusted p ≤ 0.05] when comparing CD with HC and 103 when comparing UC with HC. Comparing IBD [CD + UC] with HC resulted in 224 DMPs. Importantly, several of the previously identified DMPs, such as VMP1/TMEM49/MIR21 and RPS6KA2, were consistently differentially methylated across all studies.
CONCLUSION
Methodological homogenization of IBD epigenetic studies is needed to allow for easier aggregation and independent validation. Nonetheless, we were able to confirm previous observations. Our results can serve as the basis for future IBD epigenetic biomarker research in PBL.
Topics: Humans; DNA Methylation; Cross-Sectional Studies; Inflammatory Bowel Diseases; Crohn Disease; Colitis, Ulcerative; Membrane Proteins
PubMed: 35998097
DOI: 10.1093/ecco-jcc/jjac119 -
Frontiers in Cell and Developmental... 2021The association of opioid binding protein cell adhesion molecule-like (OPCML) gene methylation with ovarian cancer risk remains unclear. We identified eligible studies...
The association of opioid binding protein cell adhesion molecule-like (OPCML) gene methylation with ovarian cancer risk remains unclear. We identified eligible studies by searching the PubMed, Web of Science, ScienceDirect, and Wanfang databases. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to determine the association of OPCML methylation with ovarian cancer risk. Meta-regression and subgroup analysis were used to assess the sources of heterogeneity. Additionally, we analyzed the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets to validate our findings. Our study included 476 ovarian cancer patients and 385 controls from eight eligible studies. The pooled OR was 33.47 (95% CI = 12.43-90.16) in the cancer group vs. the control group under the random-effects model. The association was still significant in subgroups according to sample type, control type, methods, and sample sizes (all < 0.05). Sensitivity analysis showed that the finding was robust. No publication bias was observed in Begg's ( = 0.458) and Egger's tests ( = 0.261). We further found that OPCML methylation was related to III/IV (OR = 4.20, 95% CI = 1.59-11.14) and poorly differentiated grade (OR = 4.37; 95% CI = 1.14-16.78). Based on GSE146552 and GSE155760, we validated that three CpG sites (cg16639665, cg23236270, cg15964611) in OPCML promoter region were significantly higher in cancer tissues compared to normal tissues. However, we did not observe the associations of OPCML methylation with clinicopathological parameters and overall survival based on TCGA ovarian cancer data. Our findings support that OPCML methylation is associated with an increased risk of ovarian cancer.
PubMed: 33777925
DOI: 10.3389/fcell.2021.570898 -
Drug Design, Development and Therapy 2023Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to... (Review)
Review
Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to chronic pain. Opioids have traditionally been the mainstay for treatment of moderate to severe acute pain. However, their use has been associated with opioid-related adverse events (ORAEs), such as respiratory depression, sedation, nausea, vomiting, pruritus, and decreased bowel motility. In addition, their liberal use has been implicated in the current opioid epidemic. As a result, there has been renewed interest in multimodal analgesia to target different mechanisms of action in order to achieve a synergistic effect and minimize opioid usage. Oliceridine is a novel mu-opioid receptor agonist that is part of a new class of biased ligands that selectively activate G-protein signaling and downregulate β-arrestin recruitment. Since G-protein signaling has been associated with analgesia while β-arrestin recruitment has been associated with ORAEs, there is potential for a wider therapeutic window. In this review, we will discuss the clinical evidence behind oliceridine and its potential role in acute postoperative pain management. We have systematically searched the PubMed database using the keywords , and . All articles identified were reviewed and evaluated, and all clinical trials were included.
Topics: Humans; Analgesics, Opioid; Morphine; Pain, Postoperative; GTP-Binding Proteins
PubMed: 36987403
DOI: 10.2147/DDDT.S372612 -
Developmental Neurobiology Mar 2021Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may... (Review)
Review
Ash1l potentially contributes to neurodevelopmental diseases. Although specific Ash1l mutations are rare, they have led to informative studies in animal models that may bring therapeutic advances. Ash1l is highly expressed in the brain and correlates with the neuropathology of Tourette syndrome (TS), autism spectrum disorder, and intellectual disability during development, implicating shared epigenetic factors and overlapping neuropathological mechanisms. Functional convergence of Ash1l generated several significant signaling pathways: chromatin remodeling and transcriptional regulation, protein synthesis and cellular metabolism, and synapse development and function. Here, we systematically review the literature on Ash1l, including its discovery, expression, function, regulation, implication in the nervous system, signaling pathway, mutations, and putative involvement in TS and other neurodevelopmental traits. Such findings highlight Ash1l pleiotropy and the necessity of transcending a single gene to complicated mechanisms of network convergence underlying these diseases. With the progress in functional genomic analysis (highlighted in this review), and although the importance and necessity of Ash1l becomes increasingly apparent in the medical field, further research is required to discover the precise function and molecular regulatory mechanisms related to Ash1l. Thus, a new perspective is proposed for basic scientific research and clinical interventions for cross-disorder diseases.
Topics: Animals; Autism Spectrum Disorder; DNA-Binding Proteins; Intellectual Disability; Neurodevelopmental Disorders; Tourette Syndrome
PubMed: 33258273
DOI: 10.1002/dneu.22795 -
Heliyon Oct 2022DNA methylation is an effective epigenetic process that is frequently linked to changes in gene expression. Zinc is a vital micronutrient that plays a crucial role in...
BACKGROUND
DNA methylation is an effective epigenetic process that is frequently linked to changes in gene expression. Zinc is a vital micronutrient that plays a crucial role in DNA methylation. Therefore, abnormal zinc levels may cause aberrant DNA methylation and other diseases.
OBJECTIVES
To investigate the influence of zinc on gene-specific and global DNA methylation in humans and rodents, their tissues and their cells.
METHOD
Systematic literature searches were conducted using Medline, Scopus, Google Scholar, and Web of Science databases. Studies that met the inclusion criteria and were published in English language were included. Data including the first author, sample size, subjects, targeted genes, tissue types or cells analysed, zinc level, molecular techniques, DNA methylation outcomes, and consequences were extracted.
RESULTS
From a total of 2360 articles screened by title and abstract, 15 met the inclusion criteria. Qualitative analysis indicates that there are associations between zinc deficiency and gene-specific hypomethylation in humans and between zinc deficiency and hypermethylation in rodents. Zinc did not influence LINE-1 methylation in humans. Depending on cell type, zinc could have a positive or negative effect on global methylation in humans and rodents. As predicted, in general, gene expression was elevated by DNA hypomethylation and the corresponding protein levels were also upregulated. However, some studies showed that zinc deficiency led to reduced gene expression or no alteration in mRNA levels and corresponding protein levels.
CONCLUSION
Our study shows links between zinc levels and DNA methylation. However, greater significance may be achieved if more than one independent investigator analyses the same set of genes in the same cell type. Therefore, gene-cell and animal-specific investigations are recommended to reduce variability and allow comparisons across studies.
PubMed: 36203899
DOI: 10.1016/j.heliyon.2022.e10815 -
Journal of Cachexia, Sarcopenia and... Dec 2022Lower limb muscle dysfunction is a key driver for impaired physical capacity and frailty status, both characteristics of sarcopenia. Sarcopenia is the key pathway... (Review)
Review
Lower limb muscle dysfunction is a key driver for impaired physical capacity and frailty status, both characteristics of sarcopenia. Sarcopenia is the key pathway between frailty and disability. Identifying biological markers for early diagnosis, treatment, and prevention may be key to early intervention and prevention of disability particularly mobility issues. To identify biological markers associated with lower limb muscle (dys)function in adults with sarcopenia, a systematic literature search was conducted in AMED, CINAHL, Cochrane Library, EMBASE, Medline, PubMed, Scopus, SPORTDiscus, and Web of Science databases from inception to 17 November 2021. Title, abstract, and full-text screening, data extraction, and methodological quality assessment were performed by two reviewers independently and verified by a third reviewer. Depending on available data, associations are reported as either Pearson's correlations, regression R or partial R , P value, and sample size (n). Twenty eligible studies including 3306 participants were included (females: 79%, males: 15%, unreported: 6%; mean age ranged from 53 to 92 years) with 36% in a distinct sarcopenic subgroup (females: 73%, males: 19%, unreported: 8%; mean age range 55-92 years). A total of 119 biomarkers were reported, categorized into: genetic and microRNAs (n = 64), oxidative stress (n = 10), energy metabolism (n = 18), inflammation (n = 7), enzyme (n = 4), hormone (n = 7), bone (n = 3), vitamin (n = 2), and cytokine (n = 4) markers) and seven lower limb muscle measures predominately focused on strength. Seven studies reported associations between lower limb muscle measures including (e.g. power, force, and torque) and biomarkers. In individuals with sarcopenia, muscle strength was positively associated with free testosterone (r = 0.40, P = 0.01; n = 46). In analysis with combined sarcopenic and non-sarcopenic individuals, muscle strength was positively associated with combined genetic and methylation score (partial R = 0.122, P = 0.03; n = 48) and negatively associated with sarcopenia-driven methylation score (partial R = 0.401, P < 0.01; n = 48). Biomarkers related to genetics (R = 0.001-0.014, partial R = 0.013-0.122, P > 0.05; n = 48), oxidative stress (r = 0.061, P > 0.05; n ≥ 77), hormone (r = 0.01, ρ = 0.052 p > 0.05, n ≥ 46) and combined protein, oxidative stress, muscle performance, and hormones (R = 22.0, P > 0.05; n ≥ 82) did not report significant associations with lower limb muscle strength. Several biomarkers demonstrated associations with lower limb muscle dysfunction. The current literature remains difficult to draw clear conclusions on the relationship between biomarkers and lower limb muscle dysfunction in adults with sarcopenia. Heterogeneity of biomarkers and lower limb muscle function precluded direct comparison. Use of international classification of sarcopenia and a set of core standardized outcome measures should be adopted to aid future investigation and recommendations to be made.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Biomarkers; Frailty; Hormones; Lower Extremity; Muscle, Skeletal; Sarcopenia
PubMed: 35977879
DOI: 10.1002/jcsm.13064 -
Frontiers in Allergy 2023Epigenetics facilitates insights on the impact of host environment on the genesis of chronic rhinosinusitis (CRS) through modulations of host gene expression and... (Review)
Review
BACKGROUND
Epigenetics facilitates insights on the impact of host environment on the genesis of chronic rhinosinusitis (CRS) through modulations of host gene expression and activity. Epigenetic mechanisms such as DNA methylation cause reversible but heritable changes in gene expression over generations of progeny, without altering the DNA base-pair sequences. These studies offer a critical understanding of the environment-induced changes that result in host predisposition to disease and may help in developing novel biomarkers and therapeutics. The goal of this systematic review is to summarize the current evidence on epigenetics of CRS with a focus on chronic rhinosinusitis with nasal polyps (CRSwNP) and highlight gaps that merit further research.
METHODS
A systematic review of the English language literature was performed to identify investigations related to epigenetic studies in subjects with CRS.
RESULTS
The review identified 65 studies. These have focused on DNA methylation and non-coding RNAs, with only a few on histone deacetylation, alternative polyadenylation, and chromatin accessibility. Studies include those investigating and changes or both. Studies also include animal models of CRS. Almost all have been conducted in Asia. The genome-wide studies of DNA methylation found differences in global methylation between CRSwNP and controls, while others specifically found significant differences in methylation of the CpG sites of the thymic stromal lymphopoietin (), , and . In addition, DNA methyltransferase inhibitors and histone deacetylase inhibitors were studied as potential therapeutic agents. Majority of the studies investigating non-coding RNAs focused on micro-RNAs (miRNA) and found differences in global expression of miRNA levels. These studies also revealed some previously known as well as novel targets and pathways such as tumor necrosis factor alpha, TGF beta-1, IL-10, , aryl hydrocarbon receptor, PI3K/AKT pathway, mucin secretion, and vascular permeability. Overall, the studies have found a dysregulation in pathways/genes involving inflammation, immune regulation, tissue remodeling, structural proteins, mucin secretion, arachidonic acid metabolism, and transcription.
CONCLUSIONS
Epigenetic studies in CRS subjects suggest that there is likely a major impact of the environment. However, these are association studies and do not directly imply pathogenesis. Longitudinal studies in geographically and racially diverse population cohorts are necessary to quantify genetic vs. environmental risks for CRSwNP and CRS without nasal polyps and assess heritability risk, as well as develop novel biomarkers and therapeutic agents.
PubMed: 37284022
DOI: 10.3389/falgy.2023.1165271 -
International Journal of Molecular... Oct 2022The characteristic epigenetic profile of periodontitis found in peripheral leukocytes denotes its impact on systemic immunity. In fact, this profile not only stands for... (Review)
Review
The characteristic epigenetic profile of periodontitis found in peripheral leukocytes denotes its impact on systemic immunity. In fact, this profile not only stands for periodontitis as a low-grade inflammatory disease with systemic effects but also as an important source of potentially valuable clinical biomarkers of its systemic effects and susceptibility to other inflammatory conditions. Thus, we aimed to identify relevant genes tested as epigenetic systemic biomarkers in patients with periodontitis, based on the DNA methylation patterns and RNA expression profiles in peripheral immune cells. A detailed protocol was designed following the Preferred Reporting Items for Systematic Review and Meta-analysis -PRISMA guideline. Only cross-sectional and case-control studies that reported potential systemic biomarkers of periodontitis in peripheral immune cell types were included. DNA methylation was analyzed in leukocytes, and gene expression was in polymorphonuclear and mononuclear cells. Hypermethylation was found in TLR regulators genes: , , , , , , and in early stages of periodontitis, while advanced stages presented hypomethylation of these genes. , , , and genes were differentially expressed in lymphocytes and monocytes of subjects with poorly controlled diabetes mellitus, dyslipidemia, and periodontitis in comparison with controls. The gene was differentially overexpressed in periodontitis and dyslipidemia. Peripheral blood neutrophils in periodontitis showed differential expression in 163 genes. Periodontitis showed an increase in ceruloplasmin gene expression in polymorphonuclears in comparison with controls. Several genes highlight the role of the epigenetics of peripheral inflammatory cells in periodontitis that could be explored in blood as a source of biomarkers for routine testing.
Topics: Biomarkers; Ceruloplasmin; Cross-Sectional Studies; DNA Methylation; Dyslipidemias; Gene Expression; Humans; Myeloid Differentiation Factor 88; Periodontitis; RNA
PubMed: 36233348
DOI: 10.3390/ijms231912042