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American Journal of Epidemiology Feb 2008The authors performed a systematic review and meta-analysis to determine the effect of polymorphisms in genes encoding glutathione S-transferases (GSTs), phase II... (Meta-Analysis)
Meta-Analysis Review
The authors performed a systematic review and meta-analysis to determine the effect of polymorphisms in genes encoding glutathione S-transferases (GSTs), phase II isoenzymes involved in cellular detoxification, on risk of hepatocellular carcinoma (HCC). Fifteen eligible studies were identified: 14 evaluated GSTM1; 13, GSTT1; three, GSTP1; and one each evaluated GSTM2, GSTM3, GSTA1, GSTA4, GSTO1, and GSTO2, respectively. All were case-control studies performed in populations with high (Asian, African) and medium (European) HCC incidence rates. Random-effects meta-analyses suggested a small excess risk of HCC with GSTT1 null (odds ratio (OR) = 1.19, 95% confidence interval (CI): 0.99, 1.44) and possibly GSTM1 null (OR = 1.16, 95% CI: 0.89, 1.53) genotypes. Cumulative meta-analyses demonstrated that both pooled estimators generally trended toward a small excess risk with publication of more recent studies. Results for GSTP1 A313G suggested no excess risk (OR = 0.75, 95% CI: 0.50, 1.15). A number of potentially interesting gene-gene and gene-environment interactions were reported, but these were too few and inconsistent to allow meta-analysis. The overall results suggest that there may be a small excess risk of HCC in individuals with GSTT1 null and possibly also with GSTM1 null genotypes. However, given the relatively limited total number of subjects examined and observed between-study heterogeneity, chance could not be excluded.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Case-Control Studies; Confidence Intervals; Genetic Predisposition to Disease; Genotype; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Incidence; Isoenzymes; Liver Neoplasms; Odds Ratio; Polymorphism, Genetic; Risk Factors; United States
PubMed: 18065725
DOI: 10.1093/aje/kwm315 -
BMJ (Clinical Research Ed.) Oct 2004To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)--H2 receptor antagonists plus... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)--H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs--in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life.
DATA SOURCES
The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included.
REVIEW METHODS
Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or no review outcomes were measured. Quality assessment included allocation concealment and baseline similarity. Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed.
RESULTS
Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter).
CONCLUSIONS
Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Gastrointestinal Diseases; Humans; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 15475342
DOI: 10.1136/bmj.38232.680567.EB -
European Journal of Clinical Chemistry... Aug 1997The aim of this article is to describe guidelines for rational use of lactate dehydrogenase and its isoenzymes, in the diagnostic processes and during follow-up, based... (Review)
Review
The aim of this article is to describe guidelines for rational use of lactate dehydrogenase and its isoenzymes, in the diagnostic processes and during follow-up, based on a systematic review of relevant literature. Sources of data for this study were English-language scientific publications, obtained from the database of the National Library of Medicine (Medline), concerning the clinical application (diagnosis, monitoring or treatment of disease) of lactate dehydrogenase and lactate dehydrogenase isoenzyme measurements in serum in the following main clinical fields: cardiology, hepatology, haematology and oncology. For acceptance in the present review, studies had to include: a proper definition of the tested patient population, diagnostic criteria, sampling time, sampling frequency, and test characteristics. Estimation of the relation between lactate dehydrogenase or lactate dehydrogenase isoenzymes and specific diseases expressed as sensitivity, specificity, survival or remission rate were extracted. The application of serum lactate dehydrogenase is relevant in the diagnosis of myocardial infarction (late detection), haemolytic anaemia, ovarian dysgerminoma and testicular germ cell tumor. For monitoring the progress of a disease lactate dehydrogenase is relevant in establishing the survival duration and rate in Hodgkin's disease and non-Hodgkin's lymphoma, and in the follow-up of ovarian dysgerminoma. Rational use of lactate dehydrogenase can be achieved when requests for its determination are limited to the above mentioned conditions. No rationale could be found for measuring lactate dehydrogenase isoenzymes.
Topics: Animals; Clinical Enzyme Tests; Humans; Isoenzymes; L-Lactate Dehydrogenase
PubMed: 9298346
DOI: No ID Found -
Current Drug Metabolism Oct 2005The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible... (Review)
Review
The inhibition of human cytochrome P450s (CYPs) is one of the most common mechanisms which can lead to drug-drug interactions. The inhibition of CYPs can be reversible (competitive or non-competitive) or irreversible. Irreversible inhibition usually derives from activation of a drug by CYPs into a reactive metabolite, which tightly binds to the enzyme active site, leading to a long lasting inactivation. This process is called "mechanism based inhibition" or "suicide inhibition". The irreversible inactivation usually implies the formation of a covalent bond between the metabolite and the enzyme, which can lead to hapten formation and can in some cases trigger an autoimmune-response. For these reasons it is of utmost importance to study the mechanism of the CYP inhibition of new potential drugs as early as possible during the drug discovery process. The literature on CYPs is vast and covers numerous aspects of their biology and biochemistry, however to our knowledge there is no general and systematic review focusing on mechanism-based inhibitors; we have reviewed the literature and compiled all the available data on chemical entities, which are known to be CYP suicide inhibitors. Each compound is reported together with its chemical structure, the CYP isoform and the parameters describing the inactivation. Literature references are reported together with their PMID (PubMed ID number) to allow a fast retrieval of the papers. This review offers a quick reference to help predict liabilities of new chemical entities without carrying out extensive in vitro work, and will hopefully help in designing safer drugs.
Topics: Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Inhibitors; Humans; Isoenzymes; Structure-Activity Relationship; Terminology as Topic
PubMed: 16248836
DOI: 10.2174/138920005774330639 -
Prostate Cancer and Prostatic Diseases Sep 2020Approximately 10-30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays....
BACKGROUND
Approximately 10-30% of men with mCRPC will test positive for AR-V7 using one of two analytically and clinically validated circulating tumor cell (CTC)-based assays. These men have poor outcomes with approved AR-targeting therapies but may retain sensitivity to chemotherapy. Here, we discuss the clinical implications of testing and strategies that may benefit AR splice variant (AR-V)-positive men and discuss whether such variants are passengers or drivers of aggressive clinical behavior.
METHODS
We conducted a systemic review of the literature, covering updates since our 2016 review on androgen receptor variants in mCRPC, outcomes, and existing and novel approaches to therapy. We provide an expert opinion about management strategies for AR-V7-positive men and key unanswered research questions.
RESULTS
AR-V7-positive men, defined by Epic nuclear protein detection or the modified AdnaTest mRNA detection in CTCs, identify a subset of men with mCRPC that have a low probability of response to AR-targeting therapy with short progression-free and overall survival in multivariable analyses. AR-variants do not exist in isolation, but rather in the context of a complex, heterogeneous, and evolving mCRPC genome and phenotype as well as patient-specific clinical heterogeneity, and multiple mechanisms of resistance likely exist in patients regardless of AR-V7 detection. Efforts to develop broader resistance assays are needed, and effective treatment strategies beyond taxanes are needed to address the causal driver role of AR-variants and to benefit patients with AR-V-expressing prostate cancer.
CONCLUSIONS
CTC AR-V7 detection using the AdnaTest mRNA or Epic nuclear protein assays represents the first analytically and prospective clinically validated liquid biopsy assays that may inform treatment decisions in men with mCRPC, particularly after failure of first-line AR-therapy. The importance of AR-variants is likely to increase with the earlier use of AR-targeting strategies in other settings, and novel interventions for these men are needed.
Topics: Alternative Splicing; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Clinical Decision-Making; Drug Resistance, Neoplasm; Genetic Testing; Humans; Male; Precision Medicine; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen
PubMed: 32094489
DOI: 10.1038/s41391-020-0215-5 -
Mutation Research. Reviews in Mutation... 2020Cleft lip and palate (CL/P) is among the most common congenital malformations and affects 1 in 700 newborns. CL/P is caused by genetic and environmental factors...
UNLABELLED
Cleft lip and palate (CL/P) is among the most common congenital malformations and affects 1 in 700 newborns. CL/P is caused by genetic and environmental factors (maternal smoking, alcohol or drug use and others). Many genes and loci were associated with cleft lip/palate but the amount of heterogeneity justifies identifying new causal genes and variants. AHRR (Aryl-Hydrocarbon Receptor Repressor) gene has recently been related to CL/P however, few functional studies analyze the genotypephenotype interaction of AHRR with CL/P. Several studies associate the molecular pathway of AHRR to CL/P which indicates this gene as a functional candidate in CL/P etiology.
METHODS
Systematic Literature Review was performed using PUBMED database with the keywords cleft lip, cleft palate, orofacial cleft, AHRR and synonyms. SLR resulted in 37 included articles.
RESULTS
AHRR is a positional and functional candidate gene for CL/P. In silico analysis detected interactions with other genes previously associated to CL/P like ARNT and CYP1A1. AHRR protein regulates cellular toxicity through TCDD mediated AHR pathway. Exposure to TCDD in animal embryos is AHR mediated and lead to cleft palate due to palate fusion failure and post fusion rupture. AHRR regulates cellular growth and differentiation, fundamental to lip and palatogenesis. AHRR decreases carcinogenesis and recently a higher tumor risk has been described in CL/P patients and families. AHRR is also a smoking biomarker due to changed methylation sites found in smokers DNA although folate intake may partially revert these methylation alterations. This corroborates the role of maternal smoking and lack of folate supplementation as risk factors for CL/P.
CONCLUSION
This research identified the importance of AHRR in dioxin response and demonstrated an example of genetic and environmental interaction, indispensable in the development of many complex diseases.
Topics: Amino Acid Motifs; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Cleft Lip; Cleft Palate; DNA Methylation; Dietary Supplements; Female; Folic Acid; Genetic Association Studies; Humans; Infant, Newborn; Male; Models, Molecular; Protein Domains; RNA Isoforms; Repressor Proteins; Risk Factors; Smoking
PubMed: 32800270
DOI: 10.1016/j.mrrev.2020.108319 -
Korean Journal of Urology Jul 2014Prostate-specific antigen (PSA) is recognized as an organ-specific marker with low specificity and sensitivity in discriminating prostate cancer (PCa) from other benign... (Review)
Review
Prostate-specific antigen (PSA) is recognized as an organ-specific marker with low specificity and sensitivity in discriminating prostate cancer (PCa) from other benign conditions, such as prostatic hyperplasia or chronic prostatitis. Thus, in the case of clinical suspicion, a PCa diagnosis cannot be made without a prostate biopsy. [-2]proPSA (p2PSA), a precursor of PSA, has been investigated as a new marker to accurately detect PCa. The aim of this systematic review was to discuss the available literature regarding the clinical validity and utility of p2PSA and its derivatives, p2PSA/fPSA (%p2PSA) and the Prostate Health Index (PHI). A systematic search of the PubMed and Scopus electronic databases was performed in accordance with the PRISMA statement (http://www.prisma-statement.org), considering the time period from January 1990 to January 2014 and using the following search terms: proprostate specific antigen, proenzyme PSA, proPSA, [-2]proPSA, p2PSA, Prostate Health Index, and PHI. To date, 115 studies have been published, but only 35 were considered for the qualitative analysis. These studies suggested that p2PSA is the most cancer-specific form of PSA, being preferentially expressed in PCa tissue and being significantly elevated in the serum of men with PCa. It is now evident that p2PSA, %p2PSA, and PHI measurements improve the specificity of the available tests (PSA and derivatives) in detecting PCa. Moreover, increasing PHI values seem to correlate with more aggressive disease. Some studies have compared p2PSA and its derivatives with other new biomarkers and found p2PSA to be significantly more accurate. Indeed, the implementation of these tests in clinical practice has the potential to significantly increase the physician's ability to detect PCa and avoid unnecessary biopsies, while also having an effective impact on costs. Further studies in large, multicenter, prospective trials are required to confirm these encouraging results on the clinical utility of these new biomarkers.
Topics: Biomarkers, Tumor; Humans; Male; Prostate-Specific Antigen; Prostatectomy; Prostatic Neoplasms; Protein Isoforms; Protein Precursors; Sensitivity and Specificity; Severity of Illness Index
PubMed: 25045441
DOI: 10.4111/kju.2014.55.7.436 -
Frontiers in Physiology 2019Endurance is not only a key factor in many sports but endurance-related variables are also associated with good health and low mortality. Twin and family studies suggest... (Review)
Review
Endurance is not only a key factor in many sports but endurance-related variables are also associated with good health and low mortality. Twin and family studies suggest that several endurance-associated traits are ≈50% inherited. However, we still poorly understand what DNA sequence variants contribute to endurance heritability. To address this issue, we conducted a systematic review to identify genes whose experimental loss or gain-of-function increases endurance capacity in mice. We found 31 genes including two isoforms of whose manipulation increases running or swimming endurance performance by up to 1800%. Genes whose gain-of-function increases endurance are , (Pepck) (both the a and b isoforms of the protein Pgc-1α), (calcineurin) & . Genes whose loss-of-function increases endurance in mice are . Of these genes, human DNA sequence variants of , , , , , , , , and are also associated with endurance capacity and/or VOmax trainability suggesting evolutionary conservation between mice and humans. Bioinformatical analyses show that there are numerous amino acid or copy number-changing DNA variants of endurance genes in humans, suggesting that genetic variation of endurance genes contributes to the variation of human endurance capacity, too. Moreover, several of these genes/proteins change their expression or phosphorylation in skeletal muscle or the heart after endurance exercise, suggesting a role in the adaptation to endurance exercise.
PubMed: 30967789
DOI: 10.3389/fphys.2019.00262 -
Cancer Medicine Feb 2020A meta-analysis was formulated to appraise the diagnostic accuracy of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC). (Meta-Analysis)
Meta-Analysis
PURPOSE
A meta-analysis was formulated to appraise the diagnostic accuracy of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
We enrolled all relevant studies published until September 2019. Four primary subgroups were investigated: the subgroup of quantitative or qualitative analysis of ctDNA, the subgroup of Ras association domain family 1 isoform A (RASSF1A) methylation in ctDNA and the subgroup of the combined alpha-fetoprotein (AFP) and ctDNA assay. We analyzed the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) as well as the area under the curve (AUC).
RESULTS
A total of 33 qualified articles with 4113 subjects were incorporated into our meta-analysis. The combined SEN, SPE, and DOR in quantitative studies were 0.722 (95% confidence interval (95% CI): 0.686-0.756), 0.823 (95% CI: 0.789-0.854), 18.532 (95% CI: 8.245-41.657), respectively, yielding an AUC of 0.880. For qualitative studies, the corresponding value was 0.568 (95% CI: 0.548-0.587), 0.882 (95% CI: 0.867-0.897), 10.457 (95% CI: 7.270-15.040) and 0.787, respectively. Detection of RASSF1A methylation yielded an AUC of 0.841, with a SEN of 0.644 (95% CI: 0.608-0.678) and a SPE of 0.875 (95% CI: 0.847-0.900). AFP combined with ctDNA assay achieved an AUC of 0.944, with a SEN of 0.760 (95% CI: 0.728-00.790) and a SPE of 0.920 (95% CI: 0.893-00.942).
CONCLUSION
Circulating tumor DNA displays a promising diagnostic potential in HCC. However, it is not independently sufficient and can serve as an assistant tool combined with AFP for HCC screening and detection.
Topics: Carcinoma, Hepatocellular; Circulating Tumor DNA; DNA Methylation; Humans; Liver Neoplasms; Mass Screening; Predictive Value of Tests; ROC Curve; Tumor Suppressor Proteins; alpha-Fetoproteins
PubMed: 31876977
DOI: 10.1002/cam4.2799 -
International Journal of Molecular... Oct 2022Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform.... (Review)
Review
Adult skeletal muscle fibres are classified as type 1, 2A, 2X, and 2B. These classifications are based on the expression of the dominant myosin heavy chain isoform. Muscle fibre-specific gene expression and proportions of muscle fibre types change during development and in response to exercise, chronic electrical stimulation, or inactivity. To identify genes whose gain or loss-of-function alters type 1, 2A, 2X, or 2B muscle fibre proportions in mice, we conducted a systematic review of transgenic mouse studies. The systematic review was conducted in accordance with the 2009 PRISMA guidelines and the PICO framework. We identified 25 "muscle fibre genes" (, , , , , , , , , , , , , , , , , , , , , , , and ) whose gain or loss-of-function significantly changes type 1, 2A, 2X or 2B muscle fibre proportions in mice. The fact that 15 of the 25 muscle fibre genes are transcriptional regulators suggests that muscle fibre-specific gene expression is primarily regulated transcriptionally. A reanalysis of existing datasets revealed that the expression of and increases and decreases after exercise, respectively. This suggests that these genes help to regulate the muscle fibre adaptation to exercise. Finally, there are many known DNA sequence variants of muscle fibre genes. It seems likely that such DNA sequence variants contribute to the large variation of muscle fibre type proportions in the human population.
Topics: Adult; Mice; Animals; Humans; Muscle Fibers, Skeletal; Myosin Heavy Chains; Protein Isoforms; Electric Stimulation; Muscle, Skeletal; RNA-Binding Proteins; Forkhead Transcription Factors; Nuclear Receptor Co-Repressor 1
PubMed: 36361732
DOI: 10.3390/ijms232112933