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BMC Cancer Jan 2019Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings.
Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review.
BACKGROUND
Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings.
METHODS
The association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement.
RESULTS
In the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers.
CONCLUSIONS
Present research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context.
TRIAL REGISTRATION
Registration number: CRD42017057831 .
Topics: Adolescent; Analgesics, Opioid; Cancer Pain; Catechol O-Methyltransferase; Child; Child, Preschool; Cohort Studies; Dose-Response Relationship, Drug; Female; Genotype; Humans; Infant; Infant, Newborn; Italy; Male; Morphine; Pain Measurement; Polymorphism, Single Nucleotide
PubMed: 30704436
DOI: 10.1186/s12885-019-5310-4 -
Frontiers in Oncology 2024In the contemporary epoch, cancer stands as the predominant cause of premature global mortality, necessitating a focused exploration of molecular markers and advanced... (Review)
Review
In the contemporary epoch, cancer stands as the predominant cause of premature global mortality, necessitating a focused exploration of molecular markers and advanced therapeutic strategies. N6-methyladenosine (mA), the most prevalent mRNA modification, undergoes dynamic regulation by enzymes referred to as methyltransferases (writers), demethylases (erasers), and effective proteins (readers). Despite lacking methylation activity, RNA-binding motif protein 15 (RBM15), a member of the mA writer family, assumes a crucial role in recruiting the methyltransferase complex (MTC) and binding to mRNA. Although the impact of mA modifications on cancer has garnered widespread attention, RBM15 has been relatively overlooked. This review briefly outlines the structure and operational mechanism, and delineates the unique role of RBM15 in various cancers, shedding light on its molecular basis and providing a groundwork for potential tumor-targeted therapies.
PubMed: 38915367
DOI: 10.3389/fonc.2024.1375942 -
BMC Genetics Jan 2016Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on...
BACKGROUND
Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue. A systematic review was conducted to synthesise and evaluate the quality of available evidence for epigenetic modifications (specifically DNA methylation) in peripheral blood and saliva samples of schizophrenia and bipolar disorder patients in comparison to healthy controls.
METHODS
Original research articles using humans were identified using electronic databases. There were 33 included studies for which data were extracted and graded in duplicate on 22 items of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement, to assess methodological precision and quality of reporting.
RESULTS
There were 15 genome-wide and 18 exclusive candidate gene loci investigations for DNA methylation studies. A number of common genes were identified as differentially methylated in schizophrenia/bipolar disorder, which were related to reelin, brain-derived neurotrophic factor, dopamine (including the catechol-O-methyltransferase gene), serotonin and glutamate, despite inconsistent findings of hyper-, hypo-, or lack of methylation at these and other loci. The mean STROBE score of 59% suggested moderate quality of available evidence; however, wide methodological variability contributed to a lack of consistency in the way methylation levels were quantified, such that meta-analysis of the results was not possible.
CONCLUSIONS
Moderate quality of available evidence shows some convergence of differential methylation at some common genetic loci in schizophrenia and bipolar disorder, despite wide variation in methodology and reporting across studies. Improvement in the clarity of reporting clinical and other potential confounds would be useful in future studies of epigenetic processes in the context of exposure to environmental and other risk factors.
Topics: Bipolar Disorder; DNA Methylation; Humans; Reelin Protein; Saliva; Schizophrenia
PubMed: 26809779
DOI: 10.1186/s12863-016-0332-2 -
Oncotarget Jan 2016Enhancer of zeste homologue 2 (EZH2) is a potential independent mechanism for epigenetic silencing of tumor suppressor genes in cancer. We conducted an electronic search... (Meta-Analysis)
Meta-Analysis Review
Enhancer of zeste homologue 2 (EZH2) is a potential independent mechanism for epigenetic silencing of tumor suppressor genes in cancer. We conducted an electronic search on PubMed, EMBASE, Web of Science, and Cochrane library to perform this up-to-date meta-analysis. Fifty-one studies with a total of 9444 patients were included. The prevalence of high EZH2 expression was 0.54 (95% CI: 0.47-0.61). High EZH2 expression was significantly associated with poorer prognosis [overall survival: HR 1.54 (95% CI: 1.30-1.78), P < 0.000; disease free survival: HR 1.35 (95% CI: 1.00-1.71), P < 0.000]. In breast cancer, high EZH2 expression correlated with histological types [OR: 1.53 (95CI: 1.13-2.06); P < 0.006], histological grade [OR: 1.62 (95CI: 1.35-1.95); P < 0.000], estrogen receptor (ER) negativity [OR: 2.05 (95CI: 1.67-2.52); P < 0.000], progesterone receptor (PgR) negativity [OR: 1.42 (95CI: 1.03-1.96); P = 0.034], HER-2 positivity [OR: 1.35 (95CI: 1.08-1.69); P = 0.009], and high p53 expression [OR: 1.66 (95CI: 1.07-2.59); P = 0.024]. These results suggest that high EZH2 expression may be a promising prognostic factor to different cancers. High EZH2 expression tends to correlate with pathological types, histological grade, ER negativity, PgR negativity, HER-2 positivity and p53 high expression in breast cancer.
Topics: Biomarkers, Tumor; Breast Neoplasms; Enhancer of Zeste Homolog 2 Protein; Female; Humans; Neoplasm Staging; Polycomb Repressive Complex 2; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Survival Rate
PubMed: 26683709
DOI: 10.18632/oncotarget.6612 -
Frontiers in Pharmacology 2022Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor, has demonstrated efficacy in Parkinson's Disease (PD) patients with end-of-dose motor...
Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor, has demonstrated efficacy in Parkinson's Disease (PD) patients with end-of-dose motor fluctuations. This study aimed to compare the short-term (<6 months) and long-term (≥6 months) tolerability of opicapone adjuvant treatment in PD patients. Electronic databases including PubMed, Embase, Web of Science and Cochrane library were searched for randomized controlled trials (RCTs) and observational studies. The end points included any treatment-related adverse events (TEAEs), serious TEAEs (SAEs) and treatment discontinuation. A random-effects model was used to generate overall incidences of TEAE. Three RCTs, three RCT extension studies and three open-label studies involving 2177 PD patients were evaluated. In the short-term studies, there were reports of TEAEs with an incidence of ≥5% in individuals treated with opicapone 50 mg, including dyskinesia (14.1%), elevated blood creatine phosphokinase levels (8.0%) and urinary tract infection (6.0%). Any TEAEs, SAEs and treatment discontinuation all occurred at rates of 62.9%, 4.8% and 9.3%, respectively. TEAEs with opicapone 50 mg that were reported by more than 5% of patients in long-term studies included dyskinesia (16.1%), dry mouth (12.1%), medication effect decreased (12.1%), PD exacerbated (7.8%), blood creatine phosphokinase level raised (7.4%), nausea (6.1%) and insomnia (5.1%). The incidence of any TEAEs, SAEs and treatment discontinuation were, correspondingly, 73.2%, 8.7% and 8.4%. These studies demonstrated that opicapone was generally well-tolerated and had a low risk of adverse events, suggesting that it could be a valuable therapeutic choice for people with PD.
PubMed: 36506576
DOI: 10.3389/fphar.2022.1042992 -
Frontiers in Neurology 2021Parkinson's disease (PD) is a common, chronic, progressive, debilitating neurodegenerative disease. The current levodopa treatment requires the addition of other drugs,...
Parkinson's disease (PD) is a common, chronic, progressive, debilitating neurodegenerative disease. The current levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced PD. Therefore, a theoretical reference for treatment is urgently needed. In this study, an appropriate search strategy was used to screen eligible studies on different drugs to treat patients with PD from the Embase, PubMed, and Cochrane Library. The publication dates were from January 1990 to June 2021. We integrated eligible randomized controlled trials, and statistical analysis was performed on three kinds of effectiveness outcomes and two types of safety outcomes. We assessed the average difference or odds ratio between each drug and placebo and summarized them as the average and 95% confidence interval (CI), respectively. In terms of efficacy, entacapone (mean difference [MD], 0.64 h; 95% CI, 0.29-1.0), opicapone (MD, 0.92 h; 95% CI, 0.35-1.5), and tolcapone (MD, 3.2 h; 95% CI, 2.1-4.2) increased patients' total ON-time compared to placebo. Tolcapone (MD, -100 mg; 95% CI -160 to -45) reduced the total daily dose of levodopa therapy. None of these three drugs was found to have statistical significance in mean change from baseline in UPDRS part III scores when compared with others. In terms of safety, tolcapone (MD, 3.8; 95% CI, 2.1-6.8), opicapone (MD, 3.7; 95% CI, 2-7.2), and entacapone (MD, 2.2; 95% CI, 1.5-3.3) increased the number of cases of dyskinesia compared to placebo. Entacapone (MD, 1.7; 95% CI, 1.3-2.2) and tolcapone (MD, 4.3; 95% CI, 1.3-15) were more likely to cause adverse events than placebo. In conclusion, opicapone showed higher efficiency and fewer safety problems in five indicators we selected when compared with the other two drugs.
PubMed: 34630283
DOI: 10.3389/fneur.2021.707723 -
Progress in Neuro-psychopharmacology &... Feb 2024SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous... (Review)
Review
OBJECTIVE
SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia.
METHODS
A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described.
RESULTS
The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations.
CONCLUSIONS
Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.
Topics: Humans; Genetic Predisposition to Disease; Intellectual Disability; Phenotype; Psychotic Disorders; Schizophrenia
PubMed: 37918557
DOI: 10.1016/j.pnpbp.2023.110888 -
Frontiers in Genetics 2019There is a continued debate and inconsistent findings in previous literature about the relationship of catechol-O-methyltransferase (COMT) and Parkinson's disease (PD)...
There is a continued debate and inconsistent findings in previous literature about the relationship of catechol-O-methyltransferase (COMT) and Parkinson's disease (PD) susceptibility as well as cognitive dysfunction. To substantiate this existing gap, we comprehensively examine COMT genotype effects on the development of PD and test the hypothesis that the Met158 allele of the COMT gene is associated with cognitive dysfunction by conducting a meta-analysis review. PubMed/MEDLINE, Embase, Cochrane databases search (18/30/08) yielded 49 included studies. Data were extracted by two reviewers and included COMT genotype, publication year, diagnostic status, ancestry, the proportion of male participants, and whether genotype frequencies were consistent with Hardy-Weinberg equilibrium. Unadjusted odds ratios (ORs) were used to derive pooled estimates of PD risk overall and in subgroups defined by ethnicity, gender, and onset of disease. Moreover, the association of certain cognitive domains in PD and COMT gene type was explored. Meta-analyses were performed using random-effect models and value-based methods. All statistical tests were two-sided. The present study was registered with PROSPERO (CRD42018087323). In the current studies, we found no association between COMT Val158/108Met polymorphism and PD susceptibility. However, the gender-stratified analyses revealed marginally significant effects in heterozygote model analyses in women ( = 0.053). In addition, stratification according to onset of PD also shows significant effects of COMT Val158/108Met polymorphism on late-onset population both in recessive ( = 0.017) and allelic ( = 0.017) genetic models. For the intelligence quotient (IQ) score and Unified Parkinson Disease Rating Scale III (UPDRS III), there was no evidence for genetic association, except in subgroup analyses in Asian populations (IQ score, = 0.016; UPDRS III, < 0.001). The COMT Val158/108Met polymorphism is associated with the risk for PD in female or late-onset PD. Methionine/methionine carriers of Asian population performed significantly worse than the valine allele carriers in IQ score and UPDRS III.
PubMed: 31354790
DOI: 10.3389/fgene.2019.00644 -
Neuropsychiatric Disease and Treatment 2018It is accepted that there is a genetic factor that influences the risk of suicidal behavior. The () gene, especially the Val108/158Met polymorphism, has been associated...
BACKGROUND
It is accepted that there is a genetic factor that influences the risk of suicidal behavior. The () gene, especially the Val108/158Met polymorphism, has been associated with suicide; however, no conclusive outcome has been attained. Therefore, the aim of the present study was to assess the role of Val108/158Met in suicidal behavior throughout an updated meta-analysis.
METHODS
We performed an online search using PubMed and Web of Science (up to March 2017). Our systematic review included case-control studies of individuals who attempted suicide and completed suicide. We tested allelic, homozygous, heterozygous, dominant, and recessive inheritance models. The meta-analysis was performed in accordance with the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
RESULTS
The meta-analysis comprised 17 studies, which included 3,282 cases and 3,774 controls, and showed that when evaluating the overall population, the Val108/158Met polymorphism of was not associated with suicidal behavior in any of the inheritance models; however, the subanalyses showed that this polymorphism exhibits a risk factor in males and a protective effect in females. Additionally, it conveyed a risk factor in Asian populations when using the allelic (OR 1.25; CI: 1.04-1.51) and recessive models (OR 1.32; CI: 1.03-1.68).
CONCLUSION
Our updated meta-analysis suggests a possible association between Val108/158Met and suicidal behavior in Asian populations. However, in view of the small number of studies, these results should be considered exploratory. We recommend that more studies be performed with larger samples.
PubMed: 30319259
DOI: 10.2147/NDT.S172243 -
Cancer Control : Journal of the Moffitt... 2021Recent studies have shown that methyltransferase-like 3, a catalytic enzyme that is predominant in the N6-methyladenosine methyltransferase system, is abnormally... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Recent studies have shown that methyltransferase-like 3, a catalytic enzyme that is predominant in the N6-methyladenosine methyltransferase system, is abnormally expressed in various types of carcinoma and is correlated with poorer prognosis. However, the clinical functions of methyltransferase-like 3 in the prognosis of tumors are not fully understood.
METHODS
We identified studies by searching PubMed, Web of Science, and MedRvix for literature (up to June 30, 2020), and collected a total of 9 studies with 1257 patients for this meta-analysis. The cancer types included gastric cancer, breast cancer, non-small cell lung cancer, bladder cancer, colorectal cancer and ovarian. We further used The Cancer Genome Atlas dataset to validate the results.
RESULTS
High methyltransferase-like 3 expression clearly predicted a worse outcome (high vs. low methyltransferase-like 3 expression group; hazard ratio = 2.09, 95% confidence interval 1.53-2.89, = 0.0001). Moreover, methyltransferase-like 3 expression was associated with differentiation (moderate + poor vs. well, pooled odds ratio = 1.76, 95% confidence interval 1.32-2.35, = 0.0001), and gender (male vs. female, pooled odds ratio = 0.73, 95% confidence interval 0.55-0.97, = 0.029).
CONCLUSION
Our results suggest that methyltransferase-like 3 upregulation is significantly associated with poor prognosis and could potentially function as a tumor biomarker in cancer prognosis.
Topics: Adenosine; Female; Humans; Male; Methyltransferases; Neoplasms; Prognosis; Survival Analysis
PubMed: 33631954
DOI: 10.1177/1073274821997455