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Journal of Clinical Medicine Oct 2023This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active... (Review)
Review
This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.
PubMed: 37959208
DOI: 10.3390/jcm12216742 -
Indian Journal of Dental Research :... 2014Oral squamous cell carcinoma (OSCC) is a common cancer world-wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Oral squamous cell carcinoma (OSCC) is a common cancer world-wide that is highly lethal due to its recurrence and metastasis. Methylation is a common epigenetic mechanism that leads to gene silencing in tumors and could be a useful biomarker in OSCC. The prevalence of P16, death-associated protein kinase (DAPK) and O6-methylguanine-DNA-methyltransferase (MGMT) promoter hypermethylation in OSCC has been evaluated for several years while the results remain controversial.
OBJECTIVE
The aim of this systematic review is to critically analyze and perform a meta-analysis on the various studies in the literature that have reported the promoter hypermethylation of P16, DAPK and MGMT genes in OSCC.
SEARCH STRATEGY
Articles were searched and selected through PubMed. Hand search from the relevant journals was also performed. Articles were reviewed and analyzed.
RESULTS
The estimated prevalence of P16 methylation was 43%, DAPK methylation was 39.7% and MGMT methylation was 39.8%. Heterogeneity in methylation prevalences and correlations with the clinical outcomes of the disease prevailed in various studies.
CONCLUSION
We can conclude from our systematic review that a higher prevalence of methylation of P16, DAPK and MGMT occur in OSCC. Further studies are required to substantiate the role of methylation of P16, DAPK and MGMT as a marker in OSCC.
Topics: Carcinoma, Squamous Cell; Cyclin-Dependent Kinase Inhibitor p16; DNA Methylation; Death-Associated Protein Kinases; Humans; Mouth Neoplasms; O(6)-Methylguanine-DNA Methyltransferase; Promoter Regions, Genetic
PubMed: 25728117
DOI: 10.4103/0970-9290.152208 -
Medicine Jul 2016Several neuropathological, biochemical, and pharmacological data suggested a possible role of histamine in the etiopathogenesis of Parkinson disease (PD). The single... (Meta-Analysis)
Meta-Analysis Review
Thr105Ile (rs11558538) polymorphism in the histamine N-methyltransferase (HNMT) gene and risk for Parkinson disease: A PRISMA-compliant systematic review and meta-analysis.
BACKGROUND/AIMS
Several neuropathological, biochemical, and pharmacological data suggested a possible role of histamine in the etiopathogenesis of Parkinson disease (PD). The single nucleotide polymorphism (SNP) rs11558538 in the histamine N-methyltransferase (HNMT) gene has been associated with the risk of developing PD by several studies but not by some others. We carried out a systematic review that included all the studies published on PD risk related to the rs11558538 SNP, and we conducted a meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.
METHODS
We used several databases to perform the systematic review, the software Meta-DiSc 1.1.1 to perform the meta-analysis of the eligible studies, and the Q-statistic to test heterogeneity between studies.
RESULTS
The meta-analysis included 4 eligible case-control association studies for the HNMT rs11558538 SNP and the risk for PD (2108 patients, 2158 controls). The frequency of the minor allele positivity showed a statistically significant association with a decreased risk for PD, both in the total series and in Caucasians. Although homozygosity for the minor allele did not reach statistical significance, the test for trend indicates the occurrence of a gene-dose effect. Global diagnostic odds ratios (95% confidence intervals) for rs11558538T were 0.61 (0.46-0.81) for the total group, and 0.63 (0.45-0.88) for Caucasian patients.
CONCLUSION
The present meta-analysis confirms published evidence suggesting that the HNMT rs11558538 minor allele is related to a reduced risk of developing PD.
Topics: Histamine N-Methyltransferase; Humans; Parkinson Disease; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 27399132
DOI: 10.1097/MD.0000000000004147 -
World Neurosurgery Dec 2018Gliomatosis cerebri (GC) is a fatal diffusely infiltrating glioma. Because of its rarity, only scarce evidence is available regarding outcome predictors and the proper... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Gliomatosis cerebri (GC) is a fatal diffusely infiltrating glioma. Because of its rarity, only scarce evidence is available regarding outcome predictors and the proper management of GC.
METHODS
Reported studies of patients with histologically confirmed GC were systematically reviewed and individual patient-level data (n = 523) extracted. Multivariable Cox proportional hazard models were fit for overall survival (OS) and progression-free survival (PFS).
RESULTS
The median OS and PFS were 13 and 10 months, with 5-year rates of 18% and 13%, respectively. Age ≥65 years at diagnosis (hazard ratio for OS [HR], 2.32; 95% confidence interval [CI], 1.62-3.31), high-grade tumor (HR for grade III, 1.57; 95% CI, 1.02-2.40; HR for grade IV, 1.74; 95% CI, [0.98-3.10), GC type II (HR, 1.49; 95% CI, 1.12-1.98; HR, 1.56; 95% CI, 1.04-2.34), more central nervous system (CNS) regions involved (HR, 1.09; 95% CI, 1.01-1.18), focal neurological deficits (HR, 1.41; 95% CI, 1.07-1.86), cerebellar symptoms (HR, 2.20; 95% CI, 1.42-3.39), more symptoms at presentation (HR, 1.21; 95% CI, 1.05-1.40), Karnofsky performance scale score <70 (HR, 3.58; 95% CI, 1.73-7.39; HR, 4.48; 95% CI, 1.39-14.4), magnetic resonance imaging contrast enhancement (HR, 1.48; 95% CI, 1.12-1.96; HR, 1.74; 95% CI, 1.18-2.55), symmetric bilateral CNS invasion (HR, 1.42; 95% CI, 1.03-1.96), and high proliferation index (Ki-67 >5%; HR, 2.32; 95% CI, 1.11-4.86) were independent predictors of poor outcomes. In contrast, seizure occurrence (HR, 0.77; 95% CI, 0.60-1.00; HR, 0.68; 95% CI, 0.47-0.95), isocitrate dehydrogenase 1 mutation (HR, 0.16; 95% CI, 0.05-0.49), and O6-methylguanine-DNA-methyltransferase promoter methylation (HR, 0.23; 95% CI, 0.09-0.59) were associated with prolonged survival. Chemotherapy and surgical resection were associated with improved outcomes, but radiotherapy, whether monotherapy or combined with chemotherapy, was not superior to chemotherapy alone.
CONCLUSIONS
In the largest study to date on GC, we have identified clinical, imaging, and molecular outcome predictors that are similar to other gliomas and highlight the beneficial effect of chemotherapy and surgical resection, when feasible, on outcomes.
Topics: Central Nervous System Neoplasms; Humans; Neoplasms, Neuroepithelial; Prognosis
PubMed: 30172970
DOI: 10.1016/j.wneu.2018.08.173 -
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 -
Neuromolecular Medicine Jun 2016An association between a catechol-O-methyltransferase (COMT) Val156Met (rs4680) polymorphism and schizophrenia has been reported in the literature, although no... (Meta-Analysis)
Meta-Analysis Review
An association between a catechol-O-methyltransferase (COMT) Val156Met (rs4680) polymorphism and schizophrenia has been reported in the literature, although no conclusive outcomes have been attained. The aim of this study was to evaluate the association of the COMT Val108/158Met polymorphism with schizophrenia in a systematic review and meta-analysis. We performed a keyword search on PubMed and EBSCO databases. All English language case-control studies published up to April 2015 were selected. A total of 67 studies were selected for inclusion. The genotype distribution of subjects with schizophrenia was compared with healthy control subjects, using allelic, additive, dominant and recessive models. The pooled results from the meta-analysis (15,565 cases and 17,251 healthy subjects) after the elimination of heterogeneity showed an association between COMT Val108/158Met and schizophrenia [recessive model: OR 1.08 CI 95 % (1.01-1.15)]. We conducted subgroup analyses according to ethnicity. An association was observed in our Caucasian population in the additive model [OR 1.21 CI 95 % (1.06-1.37)] and in the recessive model [OR 1.21 CI 95 % (1.11-1.32)], but not in the allelic or dominant models. However, when we analysed our Asian population after the elimination of heterogeneity, no evidence of a significant association was found in any of the genetic models. Our analyses indicate that there is an association between COMT Val108/158Met and schizophrenia in the general population. Furthermore, in Caucasian populations, this risk could be increased.
Topics: Case-Control Studies; Catechol O-Methyltransferase; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Genetic; Schizophrenia
PubMed: 27020768
DOI: 10.1007/s12017-016-8392-z -
The Pharmacogenomics Journal Dec 2018Methotrexate (MTX), a structural analog of folic acid, is widely employed in the treatment of different cancers and autoimmune diseases. Despite the successful results...
Methotrexate (MTX), a structural analog of folic acid, is widely employed in the treatment of different cancers and autoimmune diseases. Despite the successful results observed, the main disadvantage lies in interpatient variability in the pharmacokinetic and pharmacodynamic parameters. In particular, adverse events and toxicities induced by MTX are a matter of concern and can be the cause of dose reduction or treatment discontinuation. Among the different approaches to reduce MTX therapeutic limitations, pharmacogenomics contributes by considering the effect of inherited genetic differences on those parameters. This review provides an update on MTX pharmacogenomics. It reports the contribution of main gene polymorphisms involved in the influx, efflux, cellular effect, and elimination on MTX toxicity and efficacy, on all the diseases treated with this drug. From the analysis of the data presented in this review, we concluded that only gene polymorphisms MTHFR rs1801133, SLC19A1 rs1051266, and TYMS rs34743033 could influence clinical decision-making.
Topics: Antimetabolites, Antineoplastic; Clinical Decision-Making; Humans; Immunosuppressive Agents; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Patient Selection; Pharmacogenetics; Pharmacogenomic Testing; Pharmacogenomic Variants; Polymorphism, Genetic; Precision Medicine; Predictive Value of Tests; Reduced Folate Carrier Protein; Risk Assessment; Thymidylate Synthase
PubMed: 30237581
DOI: 10.1038/s41397-018-0047-z -
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 -
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