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Frontiers in Immunology 2022Glioblastoma (GBM) is the most common malignant brain tumor in adults, and immunotherapies and genetic therapies for GBM have evolved dramatically over the past decade,... (Review)
Review
Glioblastoma (GBM) is the most common malignant brain tumor in adults, and immunotherapies and genetic therapies for GBM have evolved dramatically over the past decade, but GBM therapy is still facing a dilemma due to the high recurrence rate. The inflammatory microenvironment is a general signature of tumors that accelerates epigenetic changes in GBM and helps tumors avoid immunological surveillance. GBM tumor cells and glioma-associated microglia/macrophages are the primary contributors to the inflammatory condition, meanwhile the modification of epigenetic events including DNA methylation, non-coding RNAs, and histone methylation and deacetylases involved in this pathological process of GBM, finally result in exacerbating the proliferation, invasion, and migration of GBM. On the other hand, histone deacetylase inhibitors, DNA methyltransferases inhibitors, and RNA interference could reverse the inflammatory landscapes and inhibit GBM growth and invasion. Here, we systematically review the inflammatory-associated epigenetic changes and regulations in the microenvironment of GBM, aiming to provide a comprehensive epigenetic profile underlying the recognition of inflammation in GBM.
Topics: Brain Neoplasms; Epigenesis, Genetic; Glioblastoma; Humans; Inflammation; Tumor Microenvironment
PubMed: 35572545
DOI: 10.3389/fimmu.2022.869307 -
Pharmacogenetics and Genomics Jun 2017Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Cisplatin ototoxicity affects 42-88% of treated children. Catechol-O-methyltransferase (COMT), thiopurine methyltransferase (TPMT) and AYCP2 genetic variants have been associated with ototoxicity, but the findings have been contradictory. The aims of the study were as follows: (a) to investigate these associations in a carefully phenotyped cohort of UK children and (b) to perform a systematic review and meta-analysis.
METHODS
We recruited 149 children from seven UK centres using a retrospective cohort study design. All participants were clinically phenotyped carefully. Genotyping was performed for one ACYP2 (rs1872328), three TPMT (rs12201199, rs1142345 and rs1800460) and two COMT (rs4646316 and rs9332377) variants.
RESULTS
For CTCAE grading, hearing loss was present in 91/120 (75.8%; worst ear) and 79/120 (65.8%; better ear). Using Chang grading, hearing loss was diagnosed in 85/119 (71.4%; worst ear) versus 75/119 (63.0%; better ear). No TPMT or COMT single-nucleotide polymorphisms (SNPs) were associated with ototoxicity. ACYP2 SNP rs1872328 was associated with ototoxicity (P=0.027; worst ear). Meta-analysis of our data with that reported in previous studies showed the pooled odds ratio (OR) to be statistically significant for both the COMT SNP rs4646316 (OR: 1.50; 95% confidence interval: 1.15-1.95) and the ACYP2 SNP rs1872328 (OR: 5.91; 95% confidence interval: 1.51-23.16).
CONCLUSION
We showed an association between the ACYP2 polymorphism and cisplatin-induced ototoxicity, but not with the TPMT and COMT. A meta-analysis was statistically significant for both the COMT rs4646316 and the ACYP2 rs1872328 SNPs. Grading the hearing of children with asymmetric hearing loss requires additional clarification.
Topics: Acid Anhydride Hydrolases; Adolescent; Antineoplastic Agents; Catechol O-Methyltransferase; Child; Child, Preschool; Cisplatin; Female; Genetic Association Studies; Hearing Loss; Humans; Infant; Male; Methyltransferases; Odds Ratio; Polymorphism, Single Nucleotide; Retrospective Studies; United Kingdom
PubMed: 28445188
DOI: 10.1097/FPC.0000000000000281 -
EBioMedicine Nov 2016Increasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Increasing studies showed that abnormal changes in single nucleotide polymorphisms (SNPs) of DNMTs (DNMT1, DNMT3A and DNMT3B) were associated with occurrence or decrease of various tumors. However, the associations between DNMTs variations and gastric cancer (GC) risk were still conflicting. We aimed to assess the effect of DNMTs polymorphisms on the susceptibility to GC.
METHODS
Firstly, we did a meta-analysis for 7 SNPs (rs16999593, rs2228611, rs8101866 in DNMT1, rs1550117, rs13420827 in DNMT3A, rs1569686, rs2424913 in DNMT3B). Four genetic models (homozygote, heterozygote, dominant and recessive model) were used. Moreover, a meta-sensitivity and subgroup analysis was performed to clarify heterogeneity source. Lastly, 17 SNPs that couldn't be meta-analyzed were presented in a systematic review.
FINDINGS
20 studies were included, 13 studies could be meta-analyzed and 7 ones could not. Firstly, a meta-analysis on 13 studies (3959 GC cases and 5992 controls) for 7 SNPs showed that GC risk increased in rs16999593 (heterozygote model: OR 1.36, 95%CI 1.14-1.61; dominant model: OR 1.36, 95%CI 1.15-1.60) and rs1550117 (homozygote model: OR 2.03, 95%CI 1.38-3.00; dominant model: OR 1.20, 95%CI 1.01-1.42; recessive model: OR 1.96, 95%CI 1.33-2.89) but decreased in rs1569686 (dominant model: OR 0.74, 95%CI 0.61-0.90). The remaining SNPs were not found associated with GC risk. Furthermore, the subgroup analysis indicated that for rs1550117 and rs1569686, the significant associations were particularly found in people from Chinese Jiangsu province (rs1550117, OR 1.77, 95%CI 1.25-2.51; rs1569686, OR 0.48, 95%CI 0.36-0.64) and that PCR-RFLP was a sensitive method to discover significant associations (rs1550117, OR 1.77, 95%CI 1.25-2.51; rs1569686, OR 0.49, 95%CI 0.37-0.65). Lastly, a systematic review on 7 studies for 17 SNPs suggested that rs36012910, rs7560488 and rs6087990 might have a potential effect on GC initiation.
CONCLUSION
This meta-analysis demonstrated that rs16999593 and rs1550117 could contribute to GC risk and that rs1569686 might be a protective factor against gastric carcinogenesis. By using these SNPs as biomarkers, it is feasible to estimate the risk of acquiring GC and thus formulate timely preventive strategy.
Topics: Alleles; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases; DNA Methyltransferase 3A; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Odds Ratio; Polymorphism, Single Nucleotide; Risk; Stomach Neoplasms; DNA Methyltransferase 3B
PubMed: 27789275
DOI: 10.1016/j.ebiom.2016.10.028 -
Medicine Apr 2023O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that maintains the stability of genetic information. MGMT is a strong prognostic biomarker in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that maintains the stability of genetic information. MGMT is a strong prognostic biomarker in patients with glioblastoma. However, the effect of its gene hypermethylation and expression on the survival rate of head and neck cancer (HNC) patients is still disputed. Therefore, we conducted a meta-analysis to evaluate the prognostic value of MGMT hypermethylation and expression in HNC patients.
METHODS
This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines and was registered at the International Prospective Register of Systematic Reviews (CRD42021274728). Literature related to the survival rate of HNC patients and MGMT was systematically searched in PubMed, Embase, The Cochrane Library and Web of Science electronic databases (published from inception to February 1, 2023). The association was evaluated by the combined hazard ratio (HR) and related 95% confidence interval (CI). Two authors independently screened all records and extracted the data. The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation system. All of the statistical tests used in this meta-analysis were conducted with Stata 12.0 software.
RESULTS
We included 5 studies with 564 HNC patients for the meta-analysis. All of the included patients were primary tumors and underwent surgical resection without prior radiotherapy or chemotherapy therapy. No significant heterogeneity was noted between MGMT and overall survival, MGMT and disease-free survival, and a fixed-effects model was used. HNC patients with MGMT hypermethylation and low expression had a poor prognosis, with pooled HR for overall survival (HR = 1.23, 95% CI: 1.10-1.38, P < .001) and disease-free survival (HR = 2.28, 95% CI: 1.45-3.58, P < .001). Subgroup analysis stratified by molecular abnormalities, such as hypermethylation or low expression, showed similar results. The insufficient number of trials included in our study encountered high risk of bias and may increase the deviation of the final meta-analysis results.
CONCLUSION
HNC patients with MGMT hypermethylation and low expression were more likely to exhibit poorer survival. MGMT hypermethylation and low expression can predict survival in patients with HNC.
Topics: Humans; Prognosis; DNA Methylation; O(6)-Methylguanine-DNA Methyltransferase; DNA Repair Enzymes; Head and Neck Neoplasms; DNA
PubMed: 37026932
DOI: 10.1097/MD.0000000000033472 -
The British Journal of Radiology Jul 2018The management of elderly patients with glioblastoma-multiforme (GBM) remains poorly defined with many experts in the past advocating best supportive care, in view of... (Review)
Review
The management of elderly patients with glioblastoma-multiforme (GBM) remains poorly defined with many experts in the past advocating best supportive care, in view of limited evidence on efficacy of more aggressive treatment protocols. There is randomised evidence (NORDIC and NA-O8 studies) to support the use of surgery followed by adjuvant monotherapy with either radiotherapy (RT) using hypofractionated regimes (e.g. 36 Gy in 6 fractions OR 40 Gy in 15 fractions) or chemotherapy with temozolomide (TMZ) in patients expressing methylation of promoter for O-methylguanine-DNA methyltransferase enzyme. However, the role of combined-modality therapy involving the use of combined RT and TMZ protocols has remained controversial with data from the EORTC (European Organisation for Research and Treatment of Cancer)-NCIC (National Cancer Institute of Canada) studies indicating that patients more than 65 years of age may not benefit significantly from combining standard RT fractionation using 60 Gy in 30 fractions with concurrent and adjuvant TMZ. More recently, randomised data has emerged on combining hypofractionated RT with concurrent and adjuvant TMZ. We provide a comprehensive review of literature with the aim of defining an evidence-based algorithm for management of elderly glioblastoma-multiforme population.
Topics: Aged; Brain Neoplasms; Glioblastoma; Humans
PubMed: 29376741
DOI: 10.1259/bjr.20170271 -
Pain Physician Sep 2023Responsiveness to opioid analgesics differs among patients with acute postoperative pain. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Responsiveness to opioid analgesics differs among patients with acute postoperative pain.
OBJECTIVE
Our study presents the most recent evidence on the effect of genetic variations on postoperative pain, opioid consumption, nausea, and vomiting in patients treated with opioids.
STUDY DESIGN
An updated systematic review and meta-analysis on the association between single-nucleotide polymorphisms and opioids administered to patients with acute postoperative pain.
METHODS
PubMed, Embase, ISI Web of Science, and the Cochrane Library databases were searched for articles published from February 1, 2014, through December 31, 2021.
RESULTS
Added to the previous meta-analysis, 39 studies (a total of 7,455 patients) were included in the final meta-analysis. Highlights of the findings include: 1) human μ-opioid receptor gene 118G allele carriers required more opioids during the first postoperative 24 hours (standard mean difference [SMD] = -0.27; 95% CI,-0.40 to -0.14; P < 0.0001) and 48 hours (SMD = -0.52; 95% CI, -0.83 to -0.20; P = 0.001), and reported higher pain scores during the first 24 hours but not at the 48-hour postoperative period (SMD = -0.09, 95% CI, -0.15 to -0.03; P = 0.002) compared to homozygous 118AA patients. 2) patients with the CYP3A4 *1G allele required fewer opioids during the first 24-hour postoperative period (SMD = 0.59; 95% CI, 0.05 to 1.14; P = 0.03) compared to patients with the homozygous CYP3A4*1/*1 allele. 3) Adenosine triphosphate-binding cassette subfamily B member-1 (ABCB1) 3435T allele carriers required more opioids during the 48-hour postoperative period (SMD = -0.21; 95% CI, -0.38 to -0.04; P = 0.02) compared to homozygous CC carriers. 4) Catechol-O-methyl transferase 158A allele carriers required fewer opioids during the first 24-hour postoperative period (SMD = 0.33; 95% CI, 0.15 to 0.51; P = 0.0004) compared to homozygous GG carriers. No significant differences were observed in patients with CYP2D6*10 and ABCB1 G2677A/T genetic polymorphisms.
LIMITATIONS
Several loci were not analyzed in detail due to insufficient clinical data. Furthermore, nongenetic factors that affected analgesic efficacy and the clinical outcome of postoperative pain were not discussed and were not the aim of this meta-analysis.
CONCLUSIONS
In combination with previous systematic reviews and meta-analyses, our results indicate that the A118G allele variant of OPRM1 and the *1*1G allele variant of CYP3A4 have a profound influence on individual differences in opioid reactivity in patients with postoperative pain. Our results, together with the identification of additional single nucleotide polymorphisms in future studies, may provide a theoretical basis for precise clinical analgesia.
KEY WORDS
Single nucleotide polymorphism, postoperative pain, opioid, meta-analysis.
Topics: Humans; Analgesics, Opioid; Catechol O-Methyltransferase; Cytochrome P-450 CYP3A; Pain, Postoperative; Polymorphism, Single Nucleotide
PubMed: 37774182
DOI: No ID Found -
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 -
Food Science & Nutrition Jul 2023This systematic review identified various bioactive compounds which have the potential to serve as novel drugs or leads against acute myeloid leukemia. Acute myeloid...
This systematic review identified various bioactive compounds which have the potential to serve as novel drugs or leads against acute myeloid leukemia. Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy that arises from the dysregulation of cell differentiation, proliferation, and cell death. The risk factors associated with the onset of AML include long-term exposure to radiation and chemicals such as benzene, smoking, genetic disorders, blood disorders, advancement in age, and others. Although novel strategies to manage AML, including a refinement of the conventional chemotherapy regimens, hypomethylating agents, and molecular targeted drugs, have been developed in recent years, resistance and relapse remain the main clinical problems. In this study, three databases, PubMed/MEDLINE, ScienceDirect, and Google Scholar, were systematically searched to identify various bioactive compounds with antileukemic properties. A total of 518 articles were identified, out of which 59 were viewed as eligible for the current report. From the data extracted, over 60 bioactive compounds were identified and divided into five major groups: flavonoids, alkaloids, organosulfur compounds, terpenes, and terpenoids, and other known and emerging bioactive compounds. The mechanism of actions of the analyzed individual bioactive molecules differs remarkably and includes disrupting chromatin structure, upregulating the synthesis of certain DNA repair proteins, inducing cell cycle arrest and apoptosis, and inhibiting/regulating Hsp90 activities, DNA methyltransferase 1, and histone deacetylase 1.
PubMed: 37457145
DOI: 10.1002/fsn3.3420 -
ESMO Open 2016Despite decades of intense research, the complex biology of glioblastoma (GBM) is not completely understood. Progression-free survival and overall survival have remained...
Despite decades of intense research, the complex biology of glioblastoma (GBM) is not completely understood. Progression-free survival and overall survival have remained unchanged since the implementation of the STUPP regimen in 2005 with concomitant radio-/chemotherapy and adjuvant chemotherapy with temozolomide. In the context of Hanahan and Weinberg's six hallmarks and two emerging hallmarks of cancer, we discuss up-to-date status and recent research in the biology of GBM. We discuss the clinical impact of the research results with the most promising being in the hallmarks 'enabling replicative immortality', 'inducing angiogenesis', 'reprogramming cellular energetics' and 'evading immune destruction'. This includes the importance of molecular diagnostics according to the new WHO classification and how next generation sequencing is being implemented in the clinical daily life. Molecular results linked together with clinical outcome have revealed the importance of the prognostic biomarker isocitratedehydrogenase (IDH), which is now part of the diagnostic criteria in brain tumours. IDH is discussed in the context of the hallmark 'reprogramming cellular energetics'. O-6-methylguanine-DNA methyltransferase status predicts a more favourable response to treatment and is thus a predictive marker. Based on genomic aberrations, Verhaak have suggested a division of GBM into three subgroups, namely, proneural, classical and mesenchymal, which could be meaningful in the clinic and could help guide and differentiate treatment decisions according to the specific subgroup. The information achieved will develop and improve precision medicine in the future.
PubMed: 28912963
DOI: 10.1136/esmoopen-2016-000144 -
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