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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 -
International Journal of Molecular... Jul 2021Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the...
BACKGROUND
Parkinson's disease (PD) is the second most frequent neurodegenerative disease, which creates a significant public health burden. There is a challenge for the optimization of therapies since patients not only respond differently to current treatment options but also develop different side effects to the treatment. Genetic variability in the human genome can serve as a biomarker for the metabolism, availability of drugs and stratification of patients for suitable therapies. The goal of this systematic review is to assess the current evidence for the clinical translation of pharmacogenomics in the personalization of treatment for Parkinson's disease.
METHODS
We performed a systematic search of Medline database for publications covering the topic of pharmacogenomics and genotype specific mutations in Parkinson's disease treatment, along with a manual search, and finally included a total of 116 publications in the review.
RESULTS
We analyzed 75 studies and 41 reviews published up to December of 2020. Most research is focused on levodopa pharmacogenomic properties and catechol-O-methyltransferase (COMT) enzymatic pathway polymorphisms, which have potential for clinical implementation due to changes in treatment response and side-effects. Likewise, there is some consistent evidence in the heritability of impulse control disorder via Opioid Receptor Kappa 1 (OPRK1), 5-Hydroxytryptamine Receptor 2A (HTR2a) and Dopa decarboxylase (DDC) genotypes, and hyperhomocysteinemia via the Methylenetetrahydrofolate reductase (MTHFR) gene. On the other hand, many available studies vary in design and methodology and lack in sample size, leading to inconsistent findings.
CONCLUSIONS
This systematic review demonstrated that the evidence for implementation of pharmacogenomics in clinical practice is still lacking and that further research needs to be done to enable a more personalized approach to therapy for each patient.
Topics: Antiparkinson Agents; Catechol O-Methyltransferase; Catechol O-Methyltransferase Inhibitors; Dopamine Agonists; Genotype; Humans; Levodopa; Monoamine Oxidase Inhibitors; Parkinson Disease; Pharmacogenetics; Pharmacogenomic Variants; Translational Research, Biomedical
PubMed: 34281267
DOI: 10.3390/ijms22137213 -
Neuro-oncology Advances 2021Glioblastoma (GB) is the most common malignant brain tumor with a dismal prognosis despite standard of care (SOC). Here we used a network meta-analysis on treatments... (Review)
Review
BACKGROUND
Glioblastoma (GB) is the most common malignant brain tumor with a dismal prognosis despite standard of care (SOC). Here we used a network meta-analysis on treatments from randomized control trials (RCTs) to assess the effect on overall survival (OS) and progression-free survival (PFS) beyond the SOC.
METHODS
We included RCTs that investigated the addition of a new treatment to the SOC in patients with newly diagnosed GB. Our primary outcome was OS, with secondary outcomes including PFS and adverse reactions. Hazard ratio (HR) and its 95% confidence interval (CI) regarding OS and PFS were extracted from each paper. We utilized a frequentist network meta-analysis. We planned a subgroup analysis based on O-methylguanine-DNA methyl-transferase () status. We followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses.
RESULTS
Twenty-one studies were included representing a total of 7403 patients with GB. There was significant heterogeneity among studies impacting important factors such as timing of randomization and sample size. A confidence analysis on the network meta-analysis results revealed a score of low or very low for all treatment comparisons, across subgroups. Allowing for the heterogeneity within the study population, alkylating nitrosoureas (Lomustine and ACNU) and tumor-treating field improved both OS (HR = 0.53, 95% CI 0.33-0.84 and HR = 0.63 95% CI 0.42-0.94, respectively) and PFS (HR = 0.88, 95% CI 0.77-1.00 and HR = 0.63 95% CI 0.52-0.76, respectively).
CONCLUSIONS
Our analysis highlights the numerous studies performed on newly diagnosed GB, with no proven consensus treatment that is superior to the current SOC. Intertrial heterogeneity raises the need for better standardization in neuro-oncology studies.
PubMed: 34042102
DOI: 10.1093/noajnl/vdab028 -
The Cochrane Database of Systematic... Mar 2021Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a... (Meta-Analysis)
Meta-Analysis
Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.
BACKGROUND
Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide.
OBJECTIVES
To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide.
SEARCH METHODS
We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014.
SELECTION CRITERIA
Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis.
DATA COLLECTION AND ANALYSIS
Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals.
MAIN RESULTS
We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status.
AUTHORS' CONCLUSIONS
PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.
Topics: Adult; Antineoplastic Agents, Alkylating; Bias; Brain Neoplasms; Cohort Studies; CpG Islands; DNA Methylation; DNA Modification Methylases; DNA Repair Enzymes; Glioblastoma; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; Promoter Regions, Genetic; Temozolomide; Tumor Suppressor Proteins
PubMed: 33710615
DOI: 10.1002/14651858.CD013316.pub2 -
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 -
European Journal of Clinical... Jun 2021Tolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson's disease (PD). However, safety issues hampered its use in clinical practice. We aimed...
PURPOSE
Tolcapone is an efficacious catechol-O-methyltransferase inhibitor for Parkinson's disease (PD). However, safety issues hampered its use in clinical practice. We aimed to provide evidence of safety and efficacy of tolcapone by a systematic literature review to support clinicians' choices in the use of an enlarging PD therapeutic armamentarium.
METHODS
We searched PubMed for studies on PD patients treated with tolcapone, documenting the following outcomes: liver enzyme, adverse events (AEs), daily Off-time, levodopa daily dose, unified Parkinson's disease rating scale (UPDRS) part-III, quality of life (QoL), and non-motor symptoms. FAERS and EudraVigilance databases for suspected AEs were interrogated for potential additional cases of hepatotoxicity.
RESULTS
Thirty-two studies were included, for a total of 4780 patients treated with tolcapone. Pertaining safety, 0.9% of patients showed liver enzyme elevation > 2. Over 23 years, we found 7 cases of severe liver injury related to tolcapone, 3 of which were fatal. All fatal cases did not follow the guidelines for liver function monitoring. FAERS and EudraVigilance database search yielded 61 reports of suspected liver AEs possibly related to tolcapone. Pertaining efficacy, the median reduction of hours/day spent in Off was 2.1 (range 1-3.2), of levodopa was 108.9 mg (1-251.5), of "On" UPDRS-III was 3.6 points (1.1-6.5). Most studies reported a significant improvement of QoL and non-motor symptoms.
CONCLUSION
Literature data showed the absence of relevant safety concerns of tolcapone when strict adherence to hepatic function monitoring is respected. Given its high efficacy on motor fluctuations, tolcapone is probably an underutilized tool in the therapeutic PD armamentarium.
Topics: Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Chemical and Drug Induced Liver Injury; Humans; Levodopa; Liver Function Tests; Parkinson Disease; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Tolcapone
PubMed: 33415500
DOI: 10.1007/s00228-020-03081-x -
Medicine Nov 2020The results of published articles on the relationship between the Val158Met polymorphism in the (Catechol-O-methyltransferase) COMT gene and the susceptibility of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The results of published articles on the relationship between the Val158Met polymorphism in the (Catechol-O-methyltransferase) COMT gene and the susceptibility of attention-deficit hyperactive disorder (ADHD) are controversial. We conducted an updated meta-analysis of case-control studies to assess the relationship between Val158Met polymorphism in COMT gene and ADHD susceptibility.
METHODS
A comprehensive literature search was conducted to identify all the case-control studies on the relationship between the COMT gene Val158Met polymorphism and ADHD susceptibility. According to the heterogeneity test results among studies evaluated with I, the fixed effect model or random effect model was selected as the pooling method. Meta-regression as well as sensitive analysis were used to explore possible causes of between-study heterogeneity. The funnel plot and Harbord test were used to estimate publication bias.
RESULTS
Finally, seventeen studies that met the inclusion criteria were included. The Val158Met genotype distributions of COMT gene in controls were in Hardy-Weinberg equilibrium in all studies. In general, there was no significant association between the COMT gene Val158Met polymorphism and ADHD susceptibility in dominant, recessive, and codominant models. The recessive genetic model (I = 60.8%) showed strong heterogeneity among studies, and still no significant association was found after sensitivity analysis. Subgroup analysis stratified by ethnicity (Asian and Caucasian) also showed that there was no significant association in the above-mentioned three models.
CONCLUSIONS
This updated meta-analysis indicated that the Val158Met polymorphism in the COMT gene may not be related to the risk of ADHD. Further researches are needed to confirm these results.
Topics: Attention Deficit Disorder with Hyperactivity; Catechol O-Methyltransferase; Genetic Predisposition to Disease; Genotype; Humans; Polymorphism, Single Nucleotide
PubMed: 33235119
DOI: 10.1097/MD.0000000000023400 -
Genes Nov 2020(1) Background: Although panic disorder (PD) is one of the most common anxiety disorders severely impacting quality of life, no effective genetic testing exists; known...
(1) Background: Although panic disorder (PD) is one of the most common anxiety disorders severely impacting quality of life, no effective genetic testing exists; known data on possible genetic biomarkers is often scattered and unsystematic which complicates further studies. (2) Methods: We used PathwayStudio 12.3 (Elsivier, Netherlands) to acquire literature data for further manual review and analysis. 229 articles were extracted, 55 articles reporting associations, and 32 articles reporting no associations were finally selected. (3) Results: We provide exhaustive information on genetic biomarkers associated with PD known in the scientific literature. Data is presented in two tables. Genes and may be considered the most promising for PD diagnostic to date. (4) Conclusions: This review illustrates current progress in association studies of PD and may indicate possible molecular mechanisms of its pathogenesis. This is a possible basis for data analysis, novel experimental studies, or developing test systems and personalized treatment approaches.
Topics: Anxiety Disorders; Biomarkers; Catechol O-Methyltransferase; Genetic Markers; Genetic Testing; Humans; Panic Disorder; Serotonin Plasma Membrane Transport Proteins
PubMed: 33158196
DOI: 10.3390/genes11111310 -
Clinical Kidney Journal Oct 2020Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that... (Review)
Review
Despite the extensive efforts of scientists, the genetic background of diabetic nephropathy (DN) has not yet been clarified. To elucidate the genetic variants that predispose to the development of DN, we conducted a systematic review and meta-analysis of all available genetic association studies (GAS) of DN. We searched in the Human Genome Epidemiology Navigator (HuGE Navigator) and PubMed for available GAS of DN. The threshold for meta-analysis was three studies per genetic variant. The association between genotype distribution and DN was examined using the generalized linear odds ratio (OR). For variants with available allele frequencies, the examined model was the allele contrast. The pooled OR was estimated using the DerSimonian and Laird random effects model. The publication bias was assessed with Egger's test. We performed pathway analysis of significant genes with DAVID 6.7. Genetic data of 606 variants located in 228 genes were retrieved from 360 GASs and were synthesized with meta-analytic methods. , (), , , , , , , , , , , , (), , , (), , , , , , , , (, , , , , , (), (), (), , , , , , , , , , , , as well as and three intergenic polymorphisms showed significant association with DN. Pathway analysis revealed the overrepresentation of six signalling pathways. The significant findings provide further evidence for genetic factors implication in DN offering new perspectives in discovery of new therapies.
PubMed: 33123356
DOI: 10.1093/ckj/sfaa077 -
Clinical Epigenetics May 2020Assessing long-term health effects from a potentially harmful environment is challenging. Endocrine-disrupting compounds (EDCs) have become omnipresent in our...
Assessing long-term health effects from a potentially harmful environment is challenging. Endocrine-disrupting compounds (EDCs) have become omnipresent in our environment. Individuals may or may not experience clinical health issues from being exposed to the increasing environmental pollution in daily life, but an issue of high concern is that also the non-exposed progeny may encounter consequences of these ancestral exposures. Progress in understanding epigenetic mechanisms opens new perspectives to estimate the risk of man-made EDCs. However, the field of epigenetic toxicology is new and its application in public health or in the understanding of disease etiology is almost non-existent, especially if it concerns future generations. In this review, we investigate the literature on transgenerational inheritance of diseases, published in the past 10 years. We question whether persistent epigenetic changes occur in the male germ line after exposure to synthesized EDCs. Our systematic search led to an inclusion of 43 articles, exploring the effects of commonly used synthetic EDCs, such as plasticizers (phthalates and bisphenol A), pesticides (dichlorodiphenyltrichloroethane, atrazine, vinclozin, methoxychlor), dioxins, and polycyclic aromatic hydrocarbons (PAHs, such as benzo(a)pyrene). Most studies found transgenerational epigenetic effects, often linked to puberty- or adult-onset diseases, such as testicular or prostate abnormalities, metabolic disorders, behavioral anomalies, and tumor development. The affected epigenetic mechanisms included changes in DNA methylation patterns, transcriptome, and expression of DNA methyltransferases. Studies involved experiments in animal models and none were based on human data. In the future, human studies are needed to confirm animal findings. If not transgenerational, at least intergenerational human studies and studies on EDC-induced epigenetic effects on germ cells could help to understand early processes of inheritance. Next, toxicity tests of new chemicals need a more comprehensive approach before they are introduced on the market. We further point to the relevance of epigenetic toxicity tests in regard to public health of the current population but also of future generations. Finally, this review sheds a light on how the interplay of genetics and epigenetics may explain the current knowledge gap on transgenerational inheritance.
Topics: Animals; Atrazine; Benzhydryl Compounds; Benzo(a)pyrene; DDT; Dioxins; Endocrine Disruptors; Epigenesis, Genetic; Male; Mammals; Mice; Paternal Inheritance; Phenols; Phthalic Acids
PubMed: 32398147
DOI: 10.1186/s13148-020-00845-1