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Clinical Neurology and Neurosurgery Apr 2024Levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced parkinson's... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Levodopa treatment requires the addition of other drugs, such as catechol-O-methyl transferase (COMT) inhibitors, to alleviate motor fluctuations in advanced parkinson's disease (PD). However, the optimal strategy, including the type and dose of COMT inhibitors remains unknown. This systematic review and network meta-analysis aimed to assess the efficacy and safety of different COMT inhibitors and for treating PD patients.
METHODS
PubMed, Embase, Cochrane Library and Web of Science were screened up to November 20, 2022. Randomized controlled trials (RCTs) of COMT inhibitors (entacapone, opicapone, tolcapone) for PD patients were included. Eligible outcomes were total ON-time, rate of ON-time >1 h, total daily dose of levodopa therapy, mean change from baseline to final follow up in Unified Parkinson's Disease Rating Scale (UPDRS) part III scores, adverse events and dyskinesia. Network meta-analyses integrated direct and indirect evidence with placebo as a common comparator.
RESULTS
We identified 18 studies with 7564 patients. Opicapone, entacapone, and tolcapone could increase total ON-time when compared with placebo. However, opicapone (25 mg, MD 4.0, 95%CrI: 1.1-7.5) and opicapone (50 mg, MD 5.1, 95%CrI: 2.2-8.7) statistically significant increase the total ON-time. opicapone and entacapone could increase the rate of ON-time >1 h when compared with placebo. Only opicapone (5 mg) showed no statistically significant with placebo (OR 1.4, 95%CrI: 0.74-2.4). We found that opicapone (50 mg, SURCA, 0.796) is the best option compared with other treatments. TOL (200 mg) was ranked highest in the rank probability test for total daily dose of levodopa therapy, followed by OPI (50 mg), TOL (400 mg) and TOL (100 mg) in order. SUCRA rankings identified TOL (200 mg) as the most likely therapy for increasing adverse events (SUCRA 27.19%), followed by TOL (400 mg, SUCRA 27.20%) and OPI (5 mg, SUCRA 30.81%). The SUCRA probabilities were 91.6%, 75.2%, 67.9%, 59.3%, 45.6%, 41.1%, 35.1%, 24.6% and 9.4% for PLA, TOL (400 mg), ENT (100 mg), ENT (200 mg), OPI (5 mg), TOL (100 mg), OPI (25 mg), OPI (50 mg), and TOL (200 mg) respectively.
CONCLUSION
In conclusion, opicapone (50 mg) may be a better choice for treatment PD when compared with other COMT inhibitors.
Topics: Humans; Parkinson Disease; Levodopa; Antiparkinson Agents; Tolcapone; Network Meta-Analysis; Catechol O-Methyltransferase Inhibitors; Catechols; Transferases; Randomized Controlled Trials as Topic; Nitriles
PubMed: 38437773
DOI: 10.1016/j.clineuro.2024.108189 -
Cancers Mar 2022Histone-lysine N-methyltransferase SETD7 regulates a variety of cancer-related processes, in a tissue-type and signalling context-dependent manner. To date, there is no... (Review)
Review
Histone-lysine N-methyltransferase SETD7 regulates a variety of cancer-related processes, in a tissue-type and signalling context-dependent manner. To date, there is no consensus regarding SETD7´s biological functions, or potential for cancer diagnostics and therapeutics. In this work, we summarised the literature on SETD7 expression and function in cancer, to identify the contexts where SETD7 expression and targeting can lead to improvements in cancer diagnosis and therapy. The most studied cancers were found to be lung and osteosarcoma followed by colorectal and breast cancers. SETD7 mRNA and/or protein expression in human cancer tissue was evaluated using public databases and/or in-house cohorts, but its prognostic significance remains inconclusive. The most studied cancer-related processes regulated by SETD7 were cell proliferation, apoptosis, epithelial-mesenchymal transition, migration and invasion with special relevance to the pRb/E2F-1 pathway. SETD7 consistently prevented epithelial to mesenchymal transition in different cancer types, and inhibition of its function appears to be associated with improved response to DNA-damaging agents in most of the analysed studies. Stabilising mutations in SETD7 target proteins prevent their methylation or promote other competing post-translational modifications that can override the SETD7 effect. This indicates that a clear discrimination of these mutations and competing signalling pathways must be considered in future functional studies.
PubMed: 35326563
DOI: 10.3390/cancers14061414 -
Epigenetics Dec 2022The aim of the present systematic review was to critically analyse the relationship between tumour suppressor genes (TSGs) promoter methylation, a potent mechanism of... (Meta-Analysis)
Meta-Analysis Review
The aim of the present systematic review was to critically analyse the relationship between tumour suppressor genes (TSGs) promoter methylation, a potent mechanism of gene silencing, and the development of salivary gland tumours, as well as the possible effect on clinical/histological characteristics. Review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (registration ID CRD42020218511). A comprehensive search of Web of Science, Scopus, PubMed, and Cochrane Central Register of Controlled Trials was performed utilizing relevant key terms, supplemented by a search of grey literature. Newcastle-Ottawa Quality Assessment Scale (NOQAS) was used for the quality assessment of included studies. Sixteen cross-sectional and 12 case-control studies were included in the review, predominantly dealing with methylation in TSGs related to DNA repair, cell cycle, and cell growth regulation and differentiation. Quantitative synthesis could be performed on P16 (inhibitor of cyclin-dependent kinase 4a), RASSF1A (Ras association domain family 1 isoform A) and MGMT (O6-methylguanine DNA methyltransferase) genes only. It showed that P16 and RASSF1A genes were more frequently methylated in salivary gland tumours compared to controls ( = .0002 and < .0001, respectively), while no significant difference was observed for MGMT. Additionally, P16 did not appear to be related to malignant transformation of pleomorphic adenomas ( = .330). In conclusion, TSG methylation is involved in salivary gland tumour pathogenesis and several genes might play a considerable role. Further studies are needed for a better understanding of complex epigenetic deregulation during salivary gland tumour development and progression.
Topics: Humans; Genes, Tumor Suppressor; DNA Methylation; Cross-Sectional Studies; Salivary Gland Neoplasms; Cyclin-Dependent Kinases; DNA
PubMed: 35287544
DOI: 10.1080/15592294.2022.2052426 -
International Journal of Molecular... Feb 2022Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase () may influence the risk for...
Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase () may influence the risk for psychopathy-related behaviors, while acting as a biomarker for predicting treatment response to dopaminergic medications. The literature shows inconsistent findings, making the interpretation of 's role difficult. The aims of this article are (i) to conduct a systematic review to analyze the effects of Val158Met on psychopathic traits in children and adolescents, and (ii) to present new evidence on the developmental trajectory of the association of Val158Met and youth psychopathic traits. For the systematic review, a literature search was conducted using PubMed, EMBASE, OVID Medline and PsychINFO with the search terms for psychopathic traits, Val158Met and age of interest. In our genotype study, the Val158Met genotype of 293 youth with European ancestry was analyzed in association with the psychopathy-related behavior scores from the Child Behavior Checklist and the Psychopathy Screening Device. To examine the potential influence of developmental changes, the sample was split into at or above and below age 13, and analyses were performed in males and females separately. The literature search yielded twenty-eight articles to be included in the systematic review, which demonstrated mixed results on the association depending on environmental factors, sex ratios, age groups and behavioral disorder diagnoses. The results from our genotype study revealed that Met homozygous youth in the below age 13 group and conversely Val carrier youth in the above age 13 group were more likely to display psychopathic traits. To our knowledge, this is the first study to systematically review the effects of Val158Met on psychopathic traits in childhood and adolescence, and to provide new evidence on the changing effects of Val158Met on psychopathy-related behaviors with development. Elucidating the role of the genotype in conjunction with the child versus adolescent stage of development for psychopathic traits may help predict treatment response, and may lead to early intervention and prevention strategies.
Topics: Adolescent; Antisocial Personality Disorder; Catechol O-Methyltransferase; Child; Female; Genetic Predisposition to Disease; Humans; Male; Polymorphism, Single Nucleotide
PubMed: 35163702
DOI: 10.3390/ijms23031782 -
Genetic Testing and Molecular Biomarkers Jun 2022Dysregulation of the SET and MYND domain-containing protein 3 () has been found in multiple cancers. This meta-analysis aimed to elucidate the association between... (Meta-Analysis)
Meta-Analysis
Dysregulation of the SET and MYND domain-containing protein 3 () has been found in multiple cancers. This meta-analysis aimed to elucidate the association between expression and clinical outcomes in cancer. A systematic search of Web of Science, Embase, PubMed, Cochrane Library, and CNKI was conducted. The relationship between expression and cancer patients' overall survival (OS) was evaluated using pooled hazard ratios (HRs) and their corresponding confidence intervals (95% CIs). The association between expression and clinicopathological features was assessed using odds ratios (ORs) with 95% CIs, including tumor size, lymph node metastasis (LNM), distance metastasis, and TNM stage. In total, 715 cancer patients with hepatocellular carcinoma, nonsmall cell lung carcinoma, esophageal squamous cell carcinoma, glioma, colorectal cancer, and/or bladder cancer from seven studies were included in our meta-analysis. overexpression was significantly associated with poor OS (HR = 1.81, 95% CI: 1.38-2.37, < 0.01) with no heterogeneity ( = 0.0%, = 0.929) in various cancers. Subgroup analysis showed that the prognostic value of across multiple tumors was constant as the tumor type, sample size, and methods of data extraction changed. Increased expression was positively associated with LNM (OR = 1.88, 95% CI = 1.33-2.66, < 0.001), tumor size (OR = 1.68, 95% CI: 1.09-2.60, = 0.019), and advanced TNM stage (OR = 1.84, 95% CI: 1.25-2.69, = 0.002). Upregulation of was significantly associated with poor prognosis in various cancers, suggesting that may be a useful prognostic biomarker.
Topics: Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Histone-Lysine N-Methyltransferase; Humans; Lymphatic Metastasis; Prognosis
PubMed: 35763383
DOI: 10.1089/gtmb.2021.0199 -
Frontiers in Oncology 2022Gynecological cancers seriously affect the reproductive system of females; diseases include ovarian tumors, uterine tumors, endometrial cancers, cervical cancers, and...
Gynecological cancers seriously affect the reproductive system of females; diseases include ovarian tumors, uterine tumors, endometrial cancers, cervical cancers, and vulva and vaginal tumors. At present, the diagnosis methods of gynecological cancer are insufficiently sensitive and specific, leading to failure of early disease detection. N-methyladenosine (mA) plays various biological functions in RNA modification and is currently studied extensively. mA modification controls the fate of transcripts and regulates RNA metabolism and biological processes through the interaction of mA methyltransferase ("writer") and demethylase ("erasers") and the binding protein decoding mA methylation ("readers"). In the field of epigenetics, mA modification is a dynamic process of reversible regulation of target RNA through its regulatory factors. It plays an important role in many diseases, especially cancer. However, its role in gynecologic cancers has not been fully investigated. Thus, we review the regulatory mechanism, biological functions, and therapeutic prospects of mA RNA methylation regulators in gynecological cancers.
PubMed: 35155260
DOI: 10.3389/fonc.2022.827956 -
BMJ Neurology Open 2024The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists...
BACKGROUND
The aim of this manuscript is to review the evidence and compare the efficacy and safety of catechol-O-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as adjunctive treatment to levodopa in patients with Parkinson's disease (PD) experiencing motor complications.
METHODS
In this systematic review and network meta-analysis, literature searches were performed in MEDLINE and Embase to identify eligible randomised controlled trials (RCTs) with a minimal follow-up of at least 4 weeks published in English between 1980 and 2021. RCTs were included if either a COMT-I, DRA or MAOB-I was evaluated as an adjunctive therapy to levodopa in patients with PD experiencing motor complications and dyskinesia. The main outcomes included daily off-medication time, motor and non-motor examination scales, and adverse events including dyskinesia.
RESULTS
74 RCTs reporting on 18 693 patients were included. All three studied drug classes decreased daily off-medication time compared with placebo (COMT-Is mean -0.8 hours (95% CI -1.0 to -0.6), DRAs -1.1 hours (95% CI -1.4 to -0.8), MAOB-Is -0.9 hours (95% CI -1.2 to -0.6)). Safety analysis showed an increased risk of dyskinesia for all three drug classes (COMT-Is OR 3.3 (95% CI 2.7 to 4.0), DRAs 3.0 (95% CI 2.5 to 3.5), MAOB-Is 1.6 (95% CI 1.2 to 2.2)). According to surface under the cumulative ranking curve scores, pramipexole IR was associated with the most favourable benefit-risk profile.
CONCLUSIONS
COMT-Is, DRAs and MAOB-Is effectively reduce motor complications and increase incidence of dyskinesia. In the network meta-analysis, adjunctive use of DRAs appeared most effective.
PubMed: 38352047
DOI: 10.1136/bmjno-2023-000573 -
Neuro-oncology Advances 2023Glioblastoma is the most aggressive primary brain cancer with a poor prognosis. Despite numerous studies in the past 17 years, effective treatment options for... (Review)
Review
BACKGROUND
Glioblastoma is the most aggressive primary brain cancer with a poor prognosis. Despite numerous studies in the past 17 years, effective treatment options for glioblastoma remain limited. In this study, we aimed to identify and compare phase III clinical trials for glioblastoma in terms of efficacy and baseline characteristics.
METHODS
A systematic literature search was conducted using PubMed and ClinicalTrials.gov to identify phase III clinical trials for glioblastoma in adult patients. The target population included adult patients aged 18 years and above (younger cohort) and patients ≥60 years of age (elderly cohort). The search results were screened based on predefined inclusion criteria, and the included trials were analyzed for their study design, baseline characteristics, and survival results.
RESULTS
Eleven trials met the inclusion criteria in the younger cohort. Of these, three reported a statistically significant improvement in overall survival (OS), including the EORTC/NCIC study (NCT00006353), EF-14 (NCT00916409), and CeTeG (NCT01149109). Of the 11 trials, eight were open-label randomized trials, including all of the positive ones, while three negative trials employed treatment blinding and a placebo control. The baseline characteristics of the trials [such as extent of resection, age, gender, and (6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status] did not significantly differ between positive and negative trials. Isocitrate dehydrogenase (IDH) mutation status was analyzed in only two trials, with a small percentage of IDH-mutated tumors in each. Additionally, three more trials in the elderly cohort showed a statistically significant improvement of OS, the NOA-08 trial, the ISRCTN81470623-trial by Malmström et al. and NCT00482677-trial by Perry et al. Their baseline characteristics and implications are also analyzed.
CONCLUSION
This analysis of phase III clinical trials for glioblastoma conducted since 2005 showed that the majority of trials did not result in a significant improvement in OS. Among the trials included in this analysis, only the EORTC/NCIC, EF-14, and CeTeG studies demonstrated a positive OS outcome in the younger cohort.
PubMed: 37811538
DOI: 10.1093/noajnl/vdad105 -
PsyCh Journal Dec 2022The catechol-O-methyltransferase (COMT) gene is thought to have an important role in the etiopathogenesis of schizophrenia, but there are conflicting results regarding... (Meta-Analysis)
Meta-Analysis Review
The catechol-O-methyltransferase (COMT) gene is thought to have an important role in the etiopathogenesis of schizophrenia, but there are conflicting results regarding its role in clinical presentation. We aimed to elucidate the relationship between the single nucleotide polymorphisms (SNPs) in the COMT gene and the severity of positive and negative symptoms. In order to investigate the relationship, the PubMed, PubMed Central, Scopus, and Cochrane CENTRAL databases were screened for eligible articles. Thirty-eight studies, including 4443 adult patients with schizophrenia, were included in the quantitative analyses, and four studies were qualitatively assessed. Quantitative analyses were performed for acutely ill and clinically stable patient subgroups regarding the different genotypes of rs4680 SNP. Our results showed that the severity of negative symptoms was higher in patients who were rs4680 Met homozygous compared to Val/Met heterozygotes only in acutely ill samples. There was no other significant difference between genotypes. Meta-regression did not reveal any significant moderator effect on the difference in negative symptoms. General psychopathology, positive, negative, and total psychotic symptom levels also were similar between Val homozygotes and Met carriers. Nonetheless, there are some limitations in the study. First, SNPs except for rs4680 were under-researched because of the limited number of studies. Second, high heterogeneity across studies was the main concern. Our results suggested that the COMT rs4680 Met allele was associated with higher levels of negative symptoms within acutely ill patients. Future studies should focus on specific patient subgroups to reveal the moderating effects of SNPs.
Topics: Adult; Humans; Catechol O-Methyltransferase; Genotype; Polymorphism, Single Nucleotide; Psychotic Disorders; Schizophrenia
PubMed: 35642295
DOI: 10.1002/pchj.562 -
Journal of Thoracic Disease Jul 2021An increasing number of original studies suggest that estrogen receptor beta (ERβ) expression may be related to non-small cell lung cancer (NSCLC) prognosis; however,...
Upregulation of estrogen receptor beta protein but not mRNA predicts poor prognosis and may be associated with enhanced translation in non-small cell lung cancer: a systematic review and meta-analysis.
BACKGROUND
An increasing number of original studies suggest that estrogen receptor beta (ERβ) expression may be related to non-small cell lung cancer (NSCLC) prognosis; however, the evidence remains inconclusive and conflicting. We aimed to systematically evaluate the expression and prognostic value of ERβ in NSCLC, and to explain the inconsistency between ERβ protein and mRNA level.
METHODS
PubMed, Embase, and Web of Science databases were searched for studies (published before October 6, 2020) reporting the prognostic value of ERβ protein expression in NSCLC. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) were calculated. Transcriptome and survival data of lung adenocarcinoma patients were obtained from public databases for differential expression and survival analyses. Immunohistochemistry (IHC) was performed to examine the ERβ protein expression in 39 NSCLC patients. Western blotting and RT-qPCR were performed to analyze ERβ expression in two paired NSCLC and normal adjacent tissue samples. The effect of methyltransferase-like 13 (METTL3) on ERβ expression was investigated in a lung cancer cell line.
RESULTS
Meta-analysis of 23 studies with a total of 3744 patients demonstrated that high protein expression of overall ERβ and cytoplasmic ERβ indicated poor OS (HR: 1.05, 95% CI: 1.00 to 1.10; HR: 1.48, 95% CI: 1.13 to 1.95) in NSCLC. For lung adenocarcinoma especially, high protein expression of both overall/cytoplasmic ERβ and nuclear ERβ suggested poor OS (HR: 1.54, 95% CI: 1.05 to 2.25; HR: 1.36, 95% CI: 1.03 to 1.80). Bioinformatics analysis indicated the expression of ERβ mRNA was not associated with the prognosis of lung adenocarcinoma. Analysis of public databases showed that ERβ mRNA is not highly expressed in tumor tissues, however, IHC results revealed that ERβ protein is highly expressed in NSCLC tissues. We validated this inconsistency in ERβ expression in paired tumors and normal adjacent tissues from patients. Moreover, METTL3 knockdown in the A549 cell line downregulated ERβ protein expression but not ERβ mRNA expression.
CONCLUSIONS
Our study elucidated the inconsistency between ERβ protein and mRNA expression levels and their prognostic values. The results indicated that METTL3-driven enhanced translation in NSCLC may cause this inconsistency.
PubMed: 34422356
DOI: 10.21037/jtd-21-658