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International Journal of Molecular... May 2021Bicistronic reporter assays have been instrumental for transgene expression, understanding of internal ribosomal entry site (IRES) translation, and identification of...
Bicistronic reporter assays have been instrumental for transgene expression, understanding of internal ribosomal entry site (IRES) translation, and identification of novel cap-independent translational elements (CITE). We observed a large methodological variability in the use of bicistronic reporter assays and data presentation or normalization procedures. Therefore, we systematically searched the literature for bicistronic IRES reporter studies and analyzed methodological details, data visualization, and normalization procedures. Two hundred fifty-seven publications were identified using our search strategy (published 1994-2020). Experimental studies on eukaryotic adherent cell systems and the cell-free translation assay were included for further analysis. We evaluated the following methodological details for 176 full text articles: the bicistronic reporter design, the cell line or type, transfection methods, and time point of analyses post-transfection. For the cell-free translation assay, we focused on methods of in vitro transcription, type of translation lysate, and incubation times and assay temperature. Data can be presented in multiple ways: raw data from individual cistrons, a ratio of the two, or fold changes thereof. In addition, many different control experiments have been suggested when studying IRES-mediated translation. In addition, many different normalization and control experiments have been suggested when studying IRES-mediated translation. Therefore, we also categorized and summarized their use. Our unbiased analyses provide a representative overview of bicistronic IRES reporter use. We identified parameters that were reported inconsistently or incompletely, which could hamper data reproduction and interpretation. On the basis of our analyses, we encourage adhering to a number of practices that should improve transparency of bicistronic reporter data presentation and improve methodological descriptions to facilitate data replication.
Topics: Animals; Genes, Reporter; Humans; Internal Ribosome Entry Sites; Protein Biosynthesis; Regulatory Sequences, Nucleic Acid; Ribosomes
PubMed: 34068921
DOI: 10.3390/ijms22105193 -
Pharmacogenomics 2015Drug addiction is a serious disease with damaging effects on the brain and physical health. Despite the increase in the number of affected individuals, there are few... (Meta-Analysis)
Meta-Analysis Review
Drug addiction is a serious disease with damaging effects on the brain and physical health. Despite the increase in the number of affected individuals, there are few effective pharmacological treatment options for substance use disorders. The study of the influence of an individual's genetic features on the treatment response may help to identify more efficacious treatment options. This systematic review focuses on the serotonergic system because of its relevant role in mood and impulse control disorders, and its contribution to the development and maintenance of drug use disorders. In particular, we examine the role of serotonergic genes in the response to pharmacotherapy for alcohol, cocaine and nicotine addiction. Current evidence suggests that genetic variability of the serotonergic biosynthesis enzyme tryptophan hydroxylase 2 (TPH2) and the serotonin transporter (SLC6A4) genes mediates the efficacy of several addiction treatments, such as ondansetron and disulfiram, and the antidepressants bupropion, nortriptyline and sertraline.
Topics: Genetic Variation; Humans; Serotonin; Serotonin Agents; Serotonin Plasma Membrane Transport Proteins; Substance-Related Disorders; Tryptophan Hydroxylase
PubMed: 26265436
DOI: 10.2217/pgs.15.72 -
Signal Transduction and Targeted Therapy Oct 2020Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging virus that is highly pathogenic and has caused the recent worldwide pandemic officially named coronavirus disease (COVID-19). Currently, considerable efforts have been put into developing effective and safe drugs and vaccines against SARS-CoV-2. Vaccines, such as inactivated vaccines, nucleic acid-based vaccines, and vector vaccines, have already entered clinical trials. In this review, we provide an overview of the experimental and clinical data obtained from recent SARS-CoV-2 vaccines trials, and highlight certain potential safety issues that require consideration when developing vaccines. Furthermore, we summarize several strategies utilized in the development of vaccines against other infectious viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), with the aim of aiding in the design of effective therapeutic approaches against SARS-CoV-2.
Topics: Angiotensin-Converting Enzyme 2; Antibodies, Viral; Betacoronavirus; COVID-19; COVID-19 Vaccines; Clinical Trials as Topic; Coronavirus Infections; Gene Expression Regulation; Humans; Immunity, Innate; Immunization Schedule; Immunogenicity, Vaccine; Middle East Respiratory Syndrome Coronavirus; Pandemics; Patient Safety; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Receptors, Virus; Severe acute respiratory syndrome-related coronavirus; SARS-CoV-2; Severe Acute Respiratory Syndrome; Spike Glycoprotein, Coronavirus; Vaccines, Attenuated; Vaccines, DNA; Vaccines, Subunit; Vaccines, Virus-Like Particle; Viral Vaccines
PubMed: 33051445
DOI: 10.1038/s41392-020-00352-y -
Current Genomics Nov 2018Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests... (Review)
Review
Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
PubMed: 30386171
DOI: 10.2174/1389202919666171229145156 -
Scientific Reports Jul 2016Previous studies have elevated the prognostic value of survivin in renal cell carcinoma (RCC). To increase statistical power and improve translation, we systematically... (Meta-Analysis)
Meta-Analysis Review
Previous studies have elevated the prognostic value of survivin in renal cell carcinoma (RCC). To increase statistical power and improve translation, we systematically searched PubMed, Web of Science, and Embase to identify relevant studies until December 2015 and conducted a standard meta-analysis. Based on the inclusion and exclusion criteria, a total of 12 studies, including 2051 patients, were eligible for further analysis. Results showed that high survivin expression in RCC was associated with poor OS (HR = 2.84, 95% CI 1.68-4.79), CSS (HR = 2.36, 95% CI 1.41-3.95), and PFS (HR = 2.20, 95% CI 1.58-3.08). Survivin expression was also correlated with TNM stage (RR = 2.75, 95% CI 2.21-3.44), pathological T stage (RR = 2.19, 95% CI 1.75-2.75), lymph node metastasis (RR = 2.28, 95% CI 1.61-3.25), distant metastasis (RR = 1.56, 95% CI 1.16-2.08), Fuhrman grade (RR = 2.81, 95% CI 2.29-3.45), tumor size (RR = 1.49, 95% CI 1.24-1.78). Our study suggested that survivin was a prognostic marker in RCC. High survivin expression was correlated with poor prognosis and more advanced clinicopathological features, and it could serve as a biomarker for disease management.
Topics: Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Kidney Neoplasms; Lymphatic Metastasis; Neoplasm Staging; Prognosis; Survivin
PubMed: 27411378
DOI: 10.1038/srep29794 -
BMC Genomics Aug 2022The histidine metabolism and transport (his) genes are controlled by a variety of RNA-dependent regulatory systems among diverse taxonomic groups of bacteria including...
BACKGROUND
The histidine metabolism and transport (his) genes are controlled by a variety of RNA-dependent regulatory systems among diverse taxonomic groups of bacteria including T-box riboswitches in Firmicutes and Actinobacteria and RNA attenuators in Proteobacteria. Using a comparative genomic approach, we previously identified a novel DNA-binding transcription factor (named HisR) that controls the histidine metabolism genes in diverse Gram-positive bacteria from the Firmicutes phylum.
RESULTS
Here we report the identification of HisR-binding sites within the regulatory regions of the histidine metabolism and transport genes in 395 genomes representing the Bacilli, Clostridia, Negativicutes, and Tissierellia classes of Firmicutes, as well as in 97 other HisR-encoding genomes from the Actinobacteria, Proteobacteria, and Synergistetes phyla. HisR belongs to the TrpR family of transcription factors, and their predicted DNA binding motifs have a similar 20-bp palindromic structure but distinct lineage-specific consensus sequences. The predicted HisR-binding motif was validated in vitro using DNA binding assays with purified protein from the human gut bacterium Ruminococcus gnavus. To fill a knowledge gap in the regulation of histidine metabolism genes in Firmicutes genomes that lack a hisR repressor gene, we systematically searched their upstream regions for potential RNA regulatory elements. As result, we identified 158 T-box riboswitches preceding the histidine biosynthesis and/or transport genes in 129 Firmicutes genomes. Finally, novel candidate RNA attenuators were identified upstream of the histidine biosynthesis operons in six species from the Bacillus cereus group, as well as in five Eubacteriales and six Erysipelotrichales species.
CONCLUSIONS
The obtained distribution of the HisR transcription factor and two RNA-mediated regulatory mechanisms for histidine metabolism genes across over 600 species of Firmicutes is discussed from functional and evolutionary points of view.
Topics: Actinobacteria; Bacteria; DNA; Gene Expression Regulation, Bacterial; Gram-Positive Bacteria; Histidine; Humans; Phylogeny; Riboswitch; Transcription Factors
PubMed: 36008760
DOI: 10.1186/s12864-022-08796-y -
Frontiers in Endocrinology 2021To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To comprehensively evaluate and compare the therapeutic effects of various hypoglycemic agents in NAFLD patients with or without diabetes.
METHODS
All literature from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, and Clinical Trials was searched, and the language was limited to English. Two reviewers independently assessed study eligibility, continuous data extraction, and independent assessment of bias risk. Our primary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST) and triglyceride levels, while our secondary outcomes were high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, body weight, BMI, and fasting glucose and glycosylated hemoglobin (HbA1c) levels.
RESULTS
The review identified 20 eligible trials that met the inclusion criteria. We found that, compared to other drugs, thiazolidinediones, especially pioglitazone, had a greater effect on the levels of ALT (-8.01 (95% CI -14.3 to 2.02)) and AST (-5.0 (95% CI -9.21 to -1,22)) and other biological indicators, but they were also associated with an increased risk of weight gain (3.62 (95% CI 2.25 to 4.99) and increased BMI (0.59 (95% Cl -0.13 to 1.29). GLP1 RAs and metformin also had better therapeutic effects than other drugs as measured by the levels of ALT (liraglutide: -9.36 (95% Cl -18 to -0.34), metformin: -2.84 (95% CI -11.09 to 5.28)) and AST (liraglutide: -5.14 (95% CI -10.69 to 0.37), metformin: -2.39 (95% CI -7.55, 2.49)) and other biological indicators.
CONCLUSION
Despite the significant risk of weight gain, thiazolidinediones, especially pioglitazone, are beneficial in normalizing liver and glucose metabolism in NAFLD patients. In clinical practice, we believe that GLP1 RAs such as liraglutide and exenatide or metformin can be used in combination to offset the risk of weight gain associated with thiazolidinediones. However, long-term studies are still needed to verify the efficacy and safety of individual hypoglycemic agents.
SYSTEMATIC REVIEW REGISTRATION
[PROSPERO], identifier [CRD42020212025].
Topics: Alanine Transaminase; Aspartate Aminotransferases; Bayes Theorem; Blood Glucose; Body Mass Index; Body Weight; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Glycated Hemoglobin; Glycosylation; Humans; Hypoglycemic Agents; Lipoproteins, HDL; Lipoproteins, LDL; Metformin; Network Meta-Analysis; Non-alcoholic Fatty Liver Disease; Pioglitazone; Reproducibility of Results; Risk; Treatment Outcome
PubMed: 33841337
DOI: 10.3389/fendo.2021.649018 -
Medicine Aug 2018Several studies have shown that B7-H4 expression is significantly increased in ovarian cancer. However, the role of B7-H4 expression in ovarian cancer remains unclear,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Several studies have shown that B7-H4 expression is significantly increased in ovarian cancer. However, the role of B7-H4 expression in ovarian cancer remains unclear, and some studies reporting conflicting results. A systematic review of the literature and meta-analysis were conducted to assess the clinicopathologic characteristics and prognostic significance of B7-H4 in ovarian cancer.
METHODS
Eligible studies were searched in the PubMed, MEDLINE, Cochrane Library, and the China National Knowledge Infrastructure databases. The included studies assessed the relationship between B7-H4 expression and clinicopathologic features or prognosis in patients with ovarian cancer through September 2017. A total of 1045 patients in 10 studies were included in the meta-analysis. Stata software version 12.0 was used to analyze the data. We used an odds ratio (OR) or hazard ratio (HR) with a 95% confidence interval (CI) to assess the risk or hazard association.
RESULTS
B7-H4 expression in ovarian cancer patients was significantly increased (OR: 4.20, 95% CI: 2.85-6.18, Z = 6.91, P < .05), and heterogeneity was low between studies (I = 8.2%, P = .366). With respect to the clinicopathologic features, no relation was detected between B7-H4 expression and International Federation of Gynaecology and Obstetricsstages stages (OR: 0.81, 95% CI: 0.64-1.03, Z = 1.70, P = .09), pathologic grade (OR: 0.91, 95% CI: 0.72-1.16, Z = 0.76, P = .45), tumor metastasis (OR: 1.25, 95% CI: 0.90-1.74, Z = 1.34, P = .18), or histologic type (OR: 1.17, 95% CI: 0.85-1.60, Z = 0.96, P = .34) in ovarian cancer. Furthermore, B7-H4 expression was significantly associated with a worse progression-free survival (PFS) (HR: 1.30, 95% CI: 1.17-1.45, Z = 4.79, P < .05).
CONCLUSION
B7-H4 expression was related to ovarian cancer, but not to patients' clinicopathologic characteristics. High B7-H4 expression was negatively correlated with survival outcome, suggesting that B7-H4 plays an essential role in poor prognosis in ovarian cancer patients.
Topics: Biomarkers, Tumor; China; Disease-Free Survival; Female; Humans; Neoplasm Staging; Ovarian Neoplasms; Prognosis; T-Lymphocytes; V-Set Domain-Containing T-Cell Activation Inhibitor 1
PubMed: 30095655
DOI: 10.1097/MD.0000000000011821 -
BMJ Open Aug 2019Liver kinase B1 (LKB1) is considered a tumour suppressor that can control cell growth and metabolism. Whether LKB1 expression levels are related to clinicopathology and... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Liver kinase B1 (LKB1) is considered a tumour suppressor that can control cell growth and metabolism. Whether LKB1 expression levels are related to clinicopathology and prognosis is controversial. This review aimed to quantitatively examine the latest evidence on this question.
DESIGN
An updated systematic review and meta-analysis on the association between LKB1 expression and prognosis of patients with solid tumours were performed.
DATA SOURCES
Eligible studies were identified through literature searches from database establishment until 15 June 2018 in the following databases: Embase, PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure and Wan Fang databases.
ELIGIBILITY CRITERIA
The association between LKB1 expression and clinicopathological characteristics, overall survival (OS), disease-free survival (DFS) and relapse-free survival (RFS) of patients with solid tumours were reported. Sufficient data were available to calculate the OR or HR and 95% CI.
DATA EXTRACTION AND SYNTHESIS
Relevant data were meta-analysed for OS, DFS, RFS and various clinical parameters.
RESULTS
The systematic review included 25 studies containing 6012 patients with solid tumours. Compared with patients with high LKB1 expression, patients with low expression showed significantly shorter OS in univariate analysis (HR=1.63, 95% CI 1.35 to 1.97, p<0.01) and multivariate analysis (HR=1.61, 95% CI 1.26 to 2.06, p<0.01). In contrast, the two groups showed similar DFS in univariate analysis (HR=1.49, 95% CI 0.73 to 3.01, p=0.27) as well as similar RFS in univariate analysis (HR=1.44, 95% CI 0.65 to 3.17, p=0.37) and multivariate analysis (HR=1.02, 95% CI 0.42 to 2.47, p=0.97). Patients with low LKB1 expression showed significantly worse tumour differentiation (OR=1.71, 95% CI 1.14 to 2.55, p<0.01), larger tumours (OR=1.68, 95% CI 1.24 to 2.27, p<0.01), earlier lymph node metastasis (OR=1.43, 95% CI 1.26 to 1.62, p<0.01) and more advanced tumour, node, metastases (TNM) stage (OR=1.80, 95% CI 1.56 to 2.07, p<0.01).
CONCLUSION
Low LKB1 expression predicts shorter OS, worse tumour differentiation, larger tumours, earlier lymph node metastasis and more advanced TNM stage. Low LKB1 expression may be a useful biomarker of poor clinicopathology and prognosis.
Topics: AMP-Activated Protein Kinase Kinases; Disease-Free Survival; Humans; Neoplasms; Prognosis; Protein Serine-Threonine Kinases; Survival Rate
PubMed: 31383697
DOI: 10.1136/bmjopen-2018-027185 -
BMC Cancer Nov 2016Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase responsible for regulating ribosomal biogenesis and protein synthesis. Dysregulation of mTOR... (Meta-Analysis)
Meta-Analysis Review
Clinicopathological and prognostic significance of mTOR and phosphorylated mTOR expression in patients with esophageal squamous cell carcinoma: a systematic review and meta-analysis.
BACKGROUND
Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase responsible for regulating ribosomal biogenesis and protein synthesis. Dysregulation of mTOR contributes to tumorigenesis, angiogenesis, cellular growth and metastasis but its roles in esophageal squamous cell carcinoma (ESCC) are controversial. Therefore, the objective of this study is to evaluate the prognostic and clinicopathological significance of mTOR/p-mTOR expression in ESCC.
METHODS
Literature retrieval was conducted by searching PubMed, EMBASE and the Web of Science for full-text papers that met our eligibility criteria. Odds ratio (OR) and hazard ratio (HR) with 95 % confidence interval (CI) served as the appropriate summarized statistics for assessments of clinicopathological and prognostic significance, respectively. Cochrane Q-test and I-statistic were adopted to estimate the heterogeneity level between studies. Potential publication bias was detected by Begg's test and Egger's test.
RESULTS
A total of 915 ESCC patients from nine original articles were included into this meta-analysis. The pooled analyses suggested that mTOR/p-mTOR expression was significantly correlated with the unfavorable outcomes of differentiation degree (OR: 2.63; 95 % CI: 1.71-4.05; P = 0.001), tumor invasion (OR: 1.48; 95 % CI: 1.02-2.13; P = 0.037), TNM stage (OR: 2.25; 95 % CI: 1.05-4.82; P = 0.037) and lymph node metastasis (OR: 1.82; 95 % CI: 1.06-3.11; P = 0.029), but had no significant relationship to the genders (OR: 0.81; 95 % CI: 0.50-1.32; P = 0.396). Moreover, mTOR/p-mTOR expression could independently predict the worse overall survival (HR: 2.04; 95 % CI: 1.58-2.62; P < 0.001), disease-free survival (HR: 2.39; 95 % CI: 1.64-3.49; P < 0.001) and cancer-specific survival (HR: 1.62; 95 % CI: 1.18-2.23; P = 0.003) of patients with ESCC. Such prognostic value of mTOR was not substantially altered by further subgroup analyses.
CONCLUSIONS
Positive expression of mTOR and p-mTOR was significantly associated with the unfavorable conditions on the depth of tumor invasion, TNM stage, differentiation degree and lymph node metastasis. mTOR and p-mTOR could serve as a valuable predictor for the poor prognosis of ESCC. More high-quality worldwide studies performing a multivariate analysis based on larger sample size are urgently required for further verifying and modifying our findings in the future.
Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Esophageal Neoplasms; Humans; Lymphatic Metastasis; Neoplasm Invasiveness; Phosphoproteins; Phosphorylation; Prognosis; Protein Processing, Post-Translational; Survival Analysis; TOR Serine-Threonine Kinases
PubMed: 27835987
DOI: 10.1186/s12885-016-2940-7