-
Bioscience Reports Mar 2020O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients... (Meta-Analysis)
Meta-Analysis
BACKGROUND
O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA damage reversal repair protein. The influence of MGMT status on alkylating agent sensitivity in patients with neuroendocrine neoplasms (NENs) is controversial. We conducted a meta-analysis to assess the influence of MGMT status on the therapeutic sensitivity of alkylating agents in patients with NENs.
METHODS
We searched PubMed, EmBase, and Cochrane library public databases through 3 July 2019. The objective response rate (ORR) was the outcome data of interest. Subgroup analysis was performed according based on MGMT methylation and expression of MGMT protein.
RESULTS
Eleven studies were included in the meta-analysis. The proportion of patients with NENs that achieved an ORR after alkylating agent treatment was higher in the MGMT-deficient group than the non-deficient group (OR: 5.00; 95% CI: 3.04-8.22; P < 0.001; I2: 3%). Similar results were noted in the MGMT methylation and MGMT protein expression subgroups.
CONCLUSION
Patients with NENs and MGMT methylation or low protein expression had a higher ORR proportion than patients without MGMT methylation or high protein expression. The MGMT status can be used as a biological indicator of the response to alkylating agent treatment in patients with NENs.
Topics: Antineoplastic Agents, Alkylating; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Humans; Neuroendocrine Tumors; Promoter Regions, Genetic; Treatment Outcome; Tumor Suppressor Proteins
PubMed: 32141507
DOI: 10.1042/BSR20194127 -
Parkinson's Disease 2019Since the discovery of levodopa (L-dopa) in 1967, the range of medications available to treat Parkinson's disease has increased significantly and guidance on the use,... (Review)
Review
Since the discovery of levodopa (L-dopa) in 1967, the range of medications available to treat Parkinson's disease has increased significantly and guidance on the use, efficacy, and safety of these medications has evolved. To assess levels of adherence to national prescribing guidelines and awareness of changes in the efficacy and safety data published in the profiles of medications for the treatment of PD, we have reviewed studies on patterns and determinants of prescribing PD medications conducted in the last 50 years (since the discovery of L-dopa). A systematic literature review was conducted using EMBASE (1967 to March, 2018), Ovid MEDLINE(R) ALL (1967 to March 16, 2018), PsycINFO (1967 to the 2 week of March, 2018), and PubMed to identify all studies measuring prescribing patterns of PD medication between 1967 and 2017. Study design, source of data, country, year of study, number of patients and/or prescriptions, unit of analysis, prescribing determinants, and percentage utilisation of PD medications were extracted where possible. 44 studies examining prescribing patterns and/or prescribing determinants across 17 countries were identified. Unsurprisingly, L-dopa was the most commonly prescribed medication in all studies, accounting for 46.50% to 100% of all prescriptions for PD. In several studies, the prescribing rate of ergot-derived dopamine agonists (DAs) decreased over time in concordance with guidance. In contrast, the prescribing rates of non-ergot DAs increased over the last ten years in most of the included studies. In examining prescribing factors, two major categories were exemplified, patients' factors and prescribers' factors, with patients' age being the most common factor that affected the prescription in most studies. In conclusion, L-dopa is now the most commonly prescribed medication for cases of PD but there is large variation in the prescribing rates of catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase B (MAO-B) inhibitors, amantadine, and anticholinergics between countries. New studies examining the effects of recent clinical trials and measuring the prescribing rates of newly approved medications are warranted.
PubMed: 31781365
DOI: 10.1155/2019/9237181 -
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 -
Biological Psychiatry Oct 2019Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many polymorphisms in dopamine genes are reported to affect cognitive, imaging, or clinical phenotypes. It is often inferred or assumed that such associations are causal, mediated by a direct effect of the polymorphism on the gene product itself. However, the supporting evidence is not always clear.
METHODS
We conducted systematic reviews and meta-analyses to assess the empirical evidence for functional polymorphisms in genes encoding dopaminergic enzymes (COMT, DBH, DDC, MAOA, MAOB, and TH), dopamine receptors (DRD1, DRD2, DRD3, DRD4, and DRD5), the dopamine transporter (DAT), and vesicular transporters (VMAT1 and VMAT2). We defined functionality as an effect of the polymorphism on the expression, abundance, activity, or affinity of the gene product.
RESULTS
We screened 22,728 articles and identified 255 eligible studies. We found robust and medium to large effects for polymorphisms in 4 genes. For catechol-O-methyltransferase (COMT), the ValMet polymorphism (rs4680) markedly affected enzyme activity, protein abundance, and protein stability. Dopamine β-hydroxylase (DBH) activity was associated with rs1611115, rs2519152, and the DBH-STR polymorphism. Monoamine oxidase A (MAOA) activity was associated with a 5' VNTR polymorphism. Dopamine D receptor (DRD2) binding was influenced by the Taq1A (rs1800497) polymorphism, and rs1076560 affected DRD2 splicing.
CONCLUSIONS
Some widely studied dopaminergic polymorphisms clearly and substantially affect the abundance or activity of the encoded gene product. However, for other polymorphisms, evidence of such an association is negative, inconclusive, or lacking. These findings are relevant when selecting polymorphisms as "markers" of dopamine function, and for interpreting the biological plausibility of associations between these polymorphisms and aspects of brain function or dysfunction.
Topics: Brain; Dopamine; Dopamine Plasma Membrane Transport Proteins; Humans; Polymorphism, Single Nucleotide; Receptors, Dopamine
PubMed: 31303260
DOI: 10.1016/j.biopsych.2019.05.014 -
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 Physiology 2018Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes N-methylation of pyridine-containing compounds. NNMT is upregulated in many types of solid tumors,...
Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes N-methylation of pyridine-containing compounds. NNMT is upregulated in many types of solid tumors, suggesting the potential for its use as a tumor biomarker. However, the prognostic value of NNMT in solid tumors is still unclear. We therefore conducted a meta-analysis to investigate the association between NNMT expression and survival in patients with solid tumors. We focused on patients with solid tumors, using high NNMT expression levels as the intervention and low NNMT expression levels as the comparison, according to Patient, Intervention, Comparison, and Outcome (PICO) guidelines. Electronic databases (up to June 7, 2018) were comprehensively searched to collect relevant cohort studies regarding the associations between NNMT expression levels and survival outcomes (overall survival [OS], disease-specific survival [DSS] including cancer-specific survival [CSS], and time to tumor progression [TTP] including disease-free survival [DFS], progression-free survival [PFS], and metastasis-free survival [MeFS]). Publication biases were also examined. All analyses were performed using STATA 12.0 software. A total of 3340 patients with solid tumors from nine published studies were included. The combined hazard ratio (HR) identified high NNMT expression levels as a poor prognostic predictor of OS (HR = 1.67, 95% CI = 1.23-2.26). However, NNMT levels had no significant association with DSS (HR = 1.47, 95% CI = 0.95-2.28) and TTP (HR = 1.13, 95%CI = 0.39-3.25). High NNMT expression levels may be a poor prognostic biomarker for patients with solid tumors.
PubMed: 30349486
DOI: 10.3389/fphys.2018.01407 -
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 -
Molecular Genetics & Genomic Medicine Sep 2018There are many studies with different results that examine the association between Catechol-O-MethylTransferase (COMT) gene single-nucleotide polymorphisms (SNPs) and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
There are many studies with different results that examine the association between Catechol-O-MethylTransferase (COMT) gene single-nucleotide polymorphisms (SNPs) and schizophrenia. In this study, the aim was to conduct a meta-analysis to achieve a pooled effect size of the association between COMT gene rs165599 SNP and schizophrenia.
METHODS
Odds ratio (OR) was used as an effect size to determine the association between schizophrenia and the SNP. The pooled ORs were achieved under four different genetic models. When the heterogeneity among studies was high the DerSimonian-Laird random-effects model, otherwise the Mantel-Haenszel fixed-effects model was used. Publication bias was evaluated by Egger's test.
RESULTS
Under different genetic models no statistically significant association was found between rs165599 SNP and schizophrenia by meta-analyses consist of 20 independent studies. There was high heterogeneity among studies, for the possible reason the population differences, although the subgroup analyzes reduced the heterogeneity, no association was obtained. However, the sex-specific estimation of the females showed that to be a G allele carrier is a risk factor for schizophrenia (OR = 1.366 [95% confidence interval = 1.094-1.706]) compared to AA homozygous.
CONCLUSION
The COMT gene rs165599 SNP does not appear to be a single-risk factor for schizophrenia.
Topics: Case-Control Studies; Catechol O-Methyltransferase; Female; Humans; Male; Polymorphism, Single Nucleotide; Risk Factors; Schizophrenia
PubMed: 30165727
DOI: 10.1002/mgg3.468 -
Neuroepidemiology 2018Pain in Parkinson's disease (PD) is a debilitating symptom with a prevalence of 68%, yet is untreated 50% of the time. What is unclear, however, is which treatment is... (Meta-Analysis)
Meta-Analysis
Pain in Parkinson's disease (PD) is a debilitating symptom with a prevalence of 68%, yet is untreated 50% of the time. What is unclear, however, is which treatment is optimal for minimizing pain severity in PD. Thus, the objective of this systematic review and meta-analysis was to investigate the efficacy of a variety of novel, complimentary, and conventional treatments for pain in PD and elucidate which therapy is the most effective. A systematic search was performed using MEDLINE, PsycINFO, Embase, CINAHL, and CENTRAL databases. To identify additional articles, manual searches of reference lists of included trials were also searched. Major neurology conference proceedings occurring between January 2014 and February 2018 were also searched to identify unpublished studies that may be potentially eligible. Twenty-five randomized controlled trials that encompassed medical, surgical, and complementary therapies met our inclusion criteria and exhibited moderate quality evidence. Two reviewers conducted assessments for study eligibility, risk of bias, data extraction, and quality of evidence rating. A conservative random-effects model was used to pool effect estimates of pain severity. The greatest reductions in pain were found with safinamide (Standardized mean difference = -4.83, 95% CI [-5.07 to -4.59], p < 0.0001), followed by cannabinoids and opioids, multidisciplinary team care, catechol-O-methyltransferase inhibitors, and electrical and Chinese therapies. Moderate effects in reducing pain were in pardoprunox and surgery, while the weakest effects were in dopaminergic agonists and miscellaneous therapies. Safinamide is an important adjunct to standard parkinsonian medication for alleviating pain in PD.
Topics: Alanine; Analgesics; Benzylamines; Electric Stimulation Therapy; Humans; Pain; Pain Management; Parkinson Disease
PubMed: 30153669
DOI: 10.1159/000492221 -
AJNR. American Journal of Neuroradiology Aug 2018() promoter methylation status has been reported as a prognostic biomarker in clinical trials. (Meta-Analysis)
Meta-Analysis
BACKGROUND
() promoter methylation status has been reported as a prognostic biomarker in clinical trials.
PURPOSE
Our aim was to systematically evaluate imaging features of promoter methylated glioblastoma and to determine the diagnostic performance of MR imaging for prediction of promoter methylation in patients with newly diagnosed glioblastoma.
DATA SOURCES
A computerized search of Ovid MEDLINE and EMBASE up to February 27, 2018, was conducted.
STUDY SELECTION
We selected studies evaluating imaging features of promoter methylated glioblastoma and the diagnostic performance of MR imaging for prediction of promoter methylation.
DATA ANALYSIS
Pooled estimates of sensitivity and specificity were calculated using a hierarchic logistic regression model. Meta-regression and sensitivity analysis were performed.
DATA SYNTHESIS
Twenty-two articles including 2199 patients were included. promoter methylated glioblastoma is likely to show less edema, high ADC, and low perfusion. Ten articles including 753 patients were included in the meta-analysis. The summary sensitivity was 79% (95% CI, 72%-85%), and the summary specificity was 78% (95% CI, 71%-84%). In the meta-regression, promoter methylation and mean age were associated with heterogeneity. Sensitivity analysis excluding 1 study resolved the heterogeneity.
LIMITATIONS
Included studies used a variety of different MR imaging techniques to predict promoter methylation.
CONCLUSIONS
promotor methylated glioblastoma is likely to show less aggressive imaging features than promotor unmethylated glioblastoma. Despite the variety of different MR imaging techniques used, MR imaging in patients with newly diagnosed glioblastoma was shown to have the potential to predict promoter methylation noninvasively.
Topics: Aged; Brain Neoplasms; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuroimaging; Promoter Regions, Genetic; Sensitivity and Specificity; Tumor Suppressor Proteins
PubMed: 30002055
DOI: 10.3174/ajnr.A5711