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The Cochrane Database of Systematic... Oct 2020Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014.
OBJECTIVES
To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia).
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE.
MAIN RESULTS
Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists.
AUTHORS' CONCLUSIONS
The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bias; Calcium Channel Blockers; Canrenone; Disease Progression; Eplerenone; Humans; Hyperkalemia; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Naphthyridines; Proteinuria; Randomized Controlled Trials as Topic; Spironolactone
PubMed: 33107592
DOI: 10.1002/14651858.CD007004.pub4 -
Scientific Reports Oct 2020The MITF(E318K) variant confers moderate risk for cutaneous melanoma. While there are small studies suggesting that this risk is associated with other malignancies (e.g.... (Meta-Analysis)
Meta-Analysis
The MITF(E318K) variant confers moderate risk for cutaneous melanoma. While there are small studies suggesting that this risk is associated with other malignancies (e.g. renal cell carcinoma), little is known about the role of this variant in specifying risk for other cancers. In this study, we perform a systematic review and meta-analysis of the published data as a backdrop to a whole-exome sequence(WES)-based characterization of MITF(E318K) risk for various cancers in sporadic samples from the TCGA and several genetically-enriched patient cohorts. We found minimal evidence of MITF(E318K)'s contribution to non-melanoma cancer risk among individuals with low inherited risks of melanoma (OR 1.168; 95% CI 0.78-1.74; p = 0.454), suggesting that earlier reports of an association between this variant and other malignancies may be related to shared environmental or polygenic risk factors rather than MITF(E318K). Interestingly, an association was observed with uterine carcinosarcoma, (OR 9.24; 95% CI 2.08-37.17; p = 0.024), which was not previously described. While more research needs to be completed, this study will help update cancer screening recommendations for patients with the MITF(E318K) variant.
Topics: Carcinoma, Renal Cell; Genetic Predisposition to Disease; Germ Cells; Germ-Line Mutation; Humans; Melanoma; Microphthalmia-Associated Transcription Factor; Neoplasms; Risk Factors; Skin Neoplasms; Exome Sequencing; Melanoma, Cutaneous Malignant
PubMed: 33051548
DOI: 10.1038/s41598-020-74237-z -
Vaccine Oct 202021 million pregnant women worldwide (18%) are estimated to carry Group B Streptococcus (GBS), which is a risk for invasive disease in newborns, pregnant women, and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
21 million pregnant women worldwide (18%) are estimated to carry Group B Streptococcus (GBS), which is a risk for invasive disease in newborns, pregnant women, and stillbirths. Adults ≥ 60 years or with underlying health conditions are also vulnerable to invasive GBS disease. We undertook systematic reviews on GBS organism characteristics including: capsular polysaccharide (serotype), sequence type (multi-locus sequence types (MLST)), and virulence proteins. We synthesised data by at-risk populations, to inform vaccine development.
METHODS
We conducted systematic reviews and meta-analyses to estimate proportions of GBS serotypes for at risk populations: maternal colonisation, invasive disease in pregnant women, stillbirths, infants 0-90 days age, and older adults (≥60 years). We considered regional variation and time trends (2001-2018). For these at-risk population groups, we summarised reported MLST and surface proteins.
RESULTS
Based on 198 studies (29247isolates), 93-99% of GBS isolates were serotypes Ia, Ib, II, III, IV and V. Regional variation is likely, but data gaps are apparent, even for maternal colonisation which has most data. Serotype III dominates for infant invasive disease (60%) and GBS-associated stillbirths (41%). ST17 accounted for a high proportion of infant invasive disease (41%; 95%CI: 35-47) and was found almost exclusively in serotype III strains, less present in maternal colonisation (9%; 95%CI:6-13),(4%; 95%CI:0-11) infant colonisation, and adult invasive disease (4%, 95%CI:2-6). Percentages of strains with at least one of alp 1, alp2/3, alpha C or Rib surface protein targets were 87% of maternal colonisation, 97% infant colonisation, 93% infant disease and 99% adult invasive disease. At least one of three pilus islands proteins were reported in all strains.
DISCUSSION
A hexavalent vaccine (serotypes Ia, Ib, II, III, IV and V) might provide comprehensive cover for all at-risk populations. Surveillance of circulating, disease-causing target proteins is useful to inform vaccines not targeting capsular polysaccharide. Addressing data gaps especially by world region and some at-risk populations (notably stillbirths) is fundamental to evidence-based decision-making during vaccine design.
Topics: Aged; Female; Humans; Infant; Infant, Newborn; Membrane Proteins; Multilocus Sequence Typing; Pregnancy; Streptococcal Infections; Streptococcus agalactiae; Vaccines
PubMed: 32888741
DOI: 10.1016/j.vaccine.2020.08.052 -
Infection Apr 2021The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. We survey the...
PURPOSE
The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. We survey the history and mechanism of coronaviruses, and the structural characteristics of the spike protein and its key residues responsible for human transmissions.
METHODS
We have carried out a systematic review to summarize the origin, transmission and etiology of COVID-19. The structural analysis of the spike protein and its disordered residues explains the mechanism of the viral transmission. A meta-data analysis of the therapeutic compounds targeting the SARS-CoV-2 is also included.
RESULTS
Coronaviruses can cross the species barrier and infect humans with unexpected consequences for public health. The transmission rate of SARS-CoV-2 infection is higher compared to that of the closely related SARS-CoV infections. In SARS-CoV-2 infection, intrinsically disordered regions are observed at the interface of the spike protein and ACE2 receptor, providing a shape complementarity to the complex. The key residues of the spike protein have stronger binding affinity with ACE2. These can be probable reasons for the higher transmission rate of SARS-CoV-2. In addition, we have also discussed the therapeutic compounds and the vaccines to target SARS-CoV-2, which can help researchers to develop effective drugs/vaccines for COVID-19. The overall history and mechanism of entry of SARS-CoV-2 along with structural study of spike-ACE2 complex provide insights to understand disease pathogenesis and development of vaccines and drugs.
Topics: Amino Acid Sequence; Animals; COVID-19; Coronavirus Infections; Humans; Protein Binding; Protein Folding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; COVID-19 Drug Treatment
PubMed: 32886331
DOI: 10.1007/s15010-020-01516-2 -
International Journal of Molecular... Aug 2020Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to... (Review)
Review
Despite a number of reports in the literature on the role of epigenetic mechanisms in periodontal disease, a thorough assessment of the published studies is warranted to better comprehend the evidence on the relationship between epigenetic changes and periodontal disease and its treatment. Therefore, the aim of this systematic review is to identify and synthesize the evidence for an association between DNA methylation/histone modification and periodontal disease and its treatment in human adults. A systematic search was independently conducted to identify articles meeting the inclusion criteria. DNA methylation and histone modifications associated with periodontal diseases, gene expression, epigenetic changes after periodontal therapy, and the association between epigenetics and clinical parameters were evaluated. Sixteen studies were identified. All included studies examined DNA modifications in relation to periodontitis, and none of the studies examined histone modifications. Substantial variation regarding the reporting of sample sizes and patient characteristics, statistical analyses, and methodology, was found. There was some evidence, albeit inconsistent, for an association between DNA methylation and periodontal disease. , , , , , and were identified as candidate genes that have been assessed for DNA methylation in periodontitis. While several included studies found associations between methylation levels and periodontal disease risk, there is insufficient evidence to support or refute an association between DNA methylation and periodontal disease/therapy in human adults. Further research must be conducted to identify reproducible epigenetic markers and determine the extent to which DNA methylation can be applied as a clinical biomarker.
Topics: Cyclooxygenase 2; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Genetic Markers; Histone Code; Histones; Humans; Interferon-gamma; Interleukin-6; Periodontal Diseases; Receptors, Interleukin-6; Suppressor of Cytokine Signaling 1 Protein; Tumor Necrosis Factor-alpha
PubMed: 32867386
DOI: 10.3390/ijms21176217 -
The Cochrane Database of Systematic... Aug 2020In nephrotic syndrome protein leaks from blood into the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While most children with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
In nephrotic syndrome protein leaks from blood into the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the death rate to around 3%. However, corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, and 2015.
OBJECTIVES
The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children 1) children in their initial episode of SSNS, and 2) children who experience a relapsing course of SSNS.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 30 May 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) performed in children (one to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).
MAIN RESULTS
In this 2020 review update 16 new included studies were identified providing a total of 48 included studies with 3941 randomised participants. Risk of bias methodology was often poorly performed with only 25 studies and 22 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Only nine studies (19%) were at low risk of bias for performance (blinding of participants and personnel) and 11 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo-controlled RCTs. Twenty-two studies (fewer than 50%) were at low risk for attrition bias and 23 studies were at low risk for reporting bias (selective outcome reporting). In seven studies, which evaluated children in their initial episode of SSNS and were at low risk of bias for selection bias, there is little or no difference in the number of children with frequent relapses when comparing two months of prednisone with three months or more (RR 0.99, 95% CI 0.82 to 1.19; 585 participants, 4 studies; I2 = 0%) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 participants, 3 studies; I2 = 35%; high certainty evidence). In analyses of eight studies at low risk of selection bias, there is little or no difference in the number of children with any relapse by 12 to 24 months when comparing two months of prednisone with three months or more (RR 0.91, 95% CI 0.78 to 1.06; 637 participants; 5 studies; I2 = 47%) or when comparing three months with five to seven months of therapy (RR 0.88, 95% CI 0.70 to 1.11; 377 participants, 3 studies; I2 = 53%). Little or no difference was noted in adverse effects between the different treatment durations. Among children with relapsing SSNS, two small studies showed that time to remission did not differ between prednisone doses of 1 mg/kg compared with the conventional dose of 2 mg/kg (MD 0.71 days, 95% CI -0.43 to 1.86; 79 participants) and that the total prednisone dose administered was lower (MD -20.60 mg/kg, 95% CI -25.65 to -15.55; 20 participants). Two studies found little or no difference in the number with relapse at six months when comparing dosing by weight with dosing by surface area (RR 1.03, 95% CI 0.71 to 1.49; 146 participants). One study found a reduced risk of relapse with low daily dosing compared with alternate daily dosing (MD -0.90 number of relapses/year, 95% CI -1.33 to -0.47). Four studies found that in children with frequently relapsing disease, daily prednisone during viral infections compared with alternate-day prednisone or no treatment reduced the risk of relapse.
AUTHORS' CONCLUSIONS
There are now four well designed studies randomising 823 children which have clearly demonstrated that there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Small studies in children with relapsing disease have identified no differences in the times to remission using half the conventional induction dose of 2 mg/kg or 60 mg/m2. It is imperative that a much larger study be carried out to confirm these findings. Lower dose prednisone therapy administered daily during an upper respiratory infection or other infection reduces the risk of relapse compared with continuing alternate-day prednisone or no prednisone based on four small studies. The results of a much larger RCT enrolling more than 300 children are awaited to determine the relative efficacies and adverse effects of using alternate-day compared with daily prednisone to prevent relapse in children with intercurrent infections.
PubMed: 35659203
DOI: 10.1002/14651858.CD001533.pub6 -
The Cochrane Database of Systematic... Jul 2020Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Chronic lymphocytic leukaemia (CLL) is the most common cancer of the lymphatic system in Western countries. Several clinical and biological factors for CLL have been identified. However, it remains unclear which of the available prognostic models combining those factors can be used in clinical practice to predict long-term outcome in people newly-diagnosed with CLL.
OBJECTIVES
To identify, describe and appraise all prognostic models developed to predict overall survival (OS), progression-free survival (PFS) or treatment-free survival (TFS) in newly-diagnosed (previously untreated) adults with CLL, and meta-analyse their predictive performances.
SEARCH METHODS
We searched MEDLINE (from January 1950 to June 2019 via Ovid), Embase (from 1974 to June 2019) and registries of ongoing trials (to 5 March 2020) for development and validation studies of prognostic models for untreated adults with CLL. In addition, we screened the reference lists and citation indices of included studies.
SELECTION CRITERIA
We included all prognostic models developed for CLL which predict OS, PFS, or TFS, provided they combined prognostic factors known before treatment initiation, and any studies that tested the performance of these models in individuals other than the ones included in model development (i.e. 'external model validation studies'). We included studies of adults with confirmed B-cell CLL who had not received treatment prior to the start of the study. We did not restrict the search based on study design.
DATA COLLECTION AND ANALYSIS
We developed a data extraction form to collect information based on the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). Independent pairs of review authors screened references, extracted data and assessed risk of bias according to the Prediction model Risk Of Bias ASsessment Tool (PROBAST). For models that were externally validated at least three times, we aimed to perform a quantitative meta-analysis of their predictive performance, notably their calibration (proportion of people predicted to experience the outcome who do so) and discrimination (ability to differentiate between people with and without the event) using a random-effects model. When a model categorised individuals into risk categories, we pooled outcome frequencies per risk group (low, intermediate, high and very high). We did not apply GRADE as guidance is not yet available for reviews of prognostic models.
MAIN RESULTS
From 52 eligible studies, we identified 12 externally validated models: six were developed for OS, one for PFS and five for TFS. In general, reporting of the studies was poor, especially predictive performance measures for calibration and discrimination; but also basic information, such as eligibility criteria and the recruitment period of participants was often missing. We rated almost all studies at high or unclear risk of bias according to PROBAST. Overall, the applicability of the models and their validation studies was low or unclear; the most common reasons were inappropriate handling of missing data and serious reporting deficiencies concerning eligibility criteria, recruitment period, observation time and prediction performance measures. We report the results for three models predicting OS, which had available data from more than three external validation studies: CLL International Prognostic Index (CLL-IPI) This score includes five prognostic factors: age, clinical stage, IgHV mutational status, B2-microglobulin and TP53 status. Calibration: for the low-, intermediate- and high-risk groups, the pooled five-year survival per risk group from validation studies corresponded to the frequencies observed in the model development study. In the very high-risk group, predicted survival from CLL-IPI was lower than observed from external validation studies. Discrimination: the pooled c-statistic of seven external validation studies (3307 participants, 917 events) was 0.72 (95% confidence interval (CI) 0.67 to 0.77). The 95% prediction interval (PI) of this model for the c-statistic, which describes the expected interval for the model's discriminative ability in a new external validation study, ranged from 0.59 to 0.83. Barcelona-Brno score Aimed at simplifying the CLL-IPI, this score includes three prognostic factors: IgHV mutational status, del(17p) and del(11q). Calibration: for the low- and intermediate-risk group, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of four external validation studies (1755 participants, 416 events) was 0.64 (95% CI 0.60 to 0.67); 95% PI 0.59 to 0.68. MDACC 2007 index score The authors presented two versions of this model including six prognostic factors to predict OS: age, B2-microglobulin, absolute lymphocyte count, gender, clinical stage and number of nodal groups. Only one validation study was available for the more comprehensive version of the model, a formula with a nomogram, while seven studies (5127 participants, 994 events) validated the simplified version of the model, the index score. Calibration: for the low- and intermediate-risk groups, the pooled survival per risk group corresponded to the frequencies observed in the model development study, although the score seems to overestimate survival for the high-risk group. Discrimination: the pooled c-statistic of the seven external validation studies for the index score was 0.65 (95% CI 0.60 to 0.70); 95% PI 0.51 to 0.77.
AUTHORS' CONCLUSIONS
Despite the large number of published studies of prognostic models for OS, PFS or TFS for newly-diagnosed, untreated adults with CLL, only a minority of these (N = 12) have been externally validated for their respective primary outcome. Three models have undergone sufficient external validation to enable meta-analysis of the model's ability to predict survival outcomes. Lack of reporting prevented us from summarising calibration as recommended. Of the three models, the CLL-IPI shows the best discrimination, despite overestimation. However, performance of the models may change for individuals with CLL who receive improved treatment options, as the models included in this review were tested mostly on retrospective cohorts receiving a traditional treatment regimen. In conclusion, this review shows a clear need to improve the conducting and reporting of both prognostic model development and external validation studies. For prognostic models to be used as tools in clinical practice, the development of the models (and their subsequent validation studies) should adapt to include the latest therapy options to accurately predict performance. Adaptations should be timely.
Topics: Adult; Age Factors; Bias; Biomarkers, Tumor; Calibration; Confidence Intervals; Discriminant Analysis; Disease-Free Survival; Female; Genes, p53; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Models, Theoretical; Neoplasm Staging; Prognosis; Progression-Free Survival; Receptors, Antigen, B-Cell; Reproducibility of Results; Tumor Suppressor Protein p53
PubMed: 32735048
DOI: 10.1002/14651858.CD012022.pub2 -
Frontiers in Immunology 2020To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the...
To ultimately combat the emerging COVID-19 pandemic, it is desired to develop an effective and safe vaccine against this highly contagious disease caused by the SARS-CoV-2 coronavirus. Our literature and clinical trial survey showed that the whole virus, as well as the spike (S) protein, nucleocapsid (N) protein, and membrane (M) protein, have been tested for vaccine development against SARS and MERS. However, these vaccine candidates might lack the induction of complete protection and have safety concerns. We then applied the Vaxign and the newly developed machine learning-based Vaxign-ML reverse vaccinology tools to predict COVID-19 vaccine candidates. Our Vaxign analysis found that the SARS-CoV-2 N protein sequence is conserved with SARS-CoV and MERS-CoV but not from the other four human coronaviruses causing mild symptoms. By investigating the entire proteome of SARS-CoV-2, six proteins, including the S protein and five non-structural proteins (nsp3, 3CL-pro, and nsp8-10), were predicted to be adhesins, which are crucial to the viral adhering and host invasion. The S, nsp3, and nsp8 proteins were also predicted by Vaxign-ML to induce high protective antigenicity. Besides the commonly used S protein, the nsp3 protein has not been tested in any coronavirus vaccine studies and was selected for further investigation. The nsp3 was found to be more conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV than among 15 coronaviruses infecting human and other animals. The protein was also predicted to contain promiscuous MHC-I and MHC-II T-cell epitopes, and the predicted linear B-cell epitopes were found to be localized on the surface of the protein. Our predicted vaccine targets have the potential for effective and safe COVID-19 vaccine development. We also propose that an "Sp/Nsp cocktail vaccine" containing a structural protein(s) (Sp) and a non-structural protein(s) (Nsp) would stimulate effective complementary immune responses.
Topics: Animals; Betacoronavirus; COVID-19; COVID-19 Vaccines; Coronavirus Infections; Epitopes, B-Lymphocyte; Humans; Immunogenicity, Vaccine; Machine Learning; Middle East Respiratory Syndrome Coronavirus; Pandemics; Pneumonia, Viral; SARS-CoV-2; Viral Proteins; Viral Vaccines
PubMed: 32719684
DOI: 10.3389/fimmu.2020.01581 -
Journal of Immunology Research 2020Unbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Unbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative colitis (UC). However, clinical translation has been proven difficult. Here, we hypothesized that one reason could be differences between inflammatory responses in an inflamed gut and in peripheral blood cells.
METHODS
We performed meta-analysis of gene expression microarray data from intestinal biopsies and whole blood cells (WBC) from pediatric patients with UC and healthy controls in order to identify overlapping pathways, predicted upstream regulators, and potential biomarkers.
RESULTS
Analyses of profiling datasets from colonic biopsies showed good agreement between different studies regarding pathways and predicted upstream regulators. The most activated predicted upstream regulators included TNF, which is known to have a key pathogenic and therapeutic role in pediatric UC. Despite this, the expression levels of were increased in neither colonic biopsies nor WBC. A potential explanation was increased expression of , one of the membrane-bound receptors of TNF in the inflamed colon. Further analyses showed a similar pattern of complex relations between the expression levels of the regulators and their receptors. We also found limited overlap between pathways and predicted upstream regulators in colonic biopsies and WBC. An extended search including all differentially expressed genes that overlapped between colonic biopsies and WBC only resulted in identification of three potential biomarkers involved in the regulation of intestinal inflammation. However, two had been previously proposed in adult inflammatory bowel diseases (IBD), namely, MMP9 and PROK2.
CONCLUSIONS
Our findings indicate that biomarker identification in pediatric UC is complicated by the involvement of multiple pathways, each of which includes many different types of genes in the blood or inflamed intestine. Therefore, further studies for identification of combinatorial biomarkers are warranted. Our study may provide candidate biomarkers for such studies.
Topics: Biomarkers; Biopsy; Child; Colitis, Ulcerative; Colon; Gastrointestinal Hormones; Gene Expression Profiling; Humans; Intestinal Mucosa; Matrix Metalloproteinase 9; Neuropeptides; Oligonucleotide Array Sequence Analysis; Receptors, Tumor Necrosis Factor, Type II; Treatment Outcome
PubMed: 32411805
DOI: 10.1155/2020/8279619 -
Systematic Reviews May 2020Environmental factors such as pollution, pesticide exposure and socio-demographic location have been implicated as a pressure capable of altering genetic make-up....
Environmental factors such as pollution, pesticide exposure and socio-demographic location have been implicated as a pressure capable of altering genetic make-up. Altered genetic sequence of genes encoding enzymes may result in single nucleotide polymorphism (SNP). Of peculiar interest is the genetic variance on the paraoxonase-1 gene induced by pre- and postnatal exposure to pesticides. SNP have been reported on the paraoxonase-1 gene and post-xenobiotic exposure and are presumed to alter gene sequence and ultimately enzymatic activity. The altered enzymatic activity may facilitate neurodevelopment disorders. Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are among the neurodevelopment disorders of which prevalence is concurrently associated with increasing environmental xenobiotic exposure. The variance on xenobiotic metabolising genes is associated with altered neurodevelopment outcome and ultimately altered neurobehavioural outcome. Prime interests of this systematic review were to establish an understanding of the sequences on the paraoxonase-1 gene associated with adverse neurobehavioural outcome. An in-depth literature search was conducted using the term combination "pesticide exposure, pre- and postnatal exposure, organophosphates/organophosphorus, single nucleotide polymorphism, paraoxonase-1 (PON-1), neurodevelopment/neurobehavioural outcome in child/infant". Articles published from the year 2000 to 2018 were considered for review. The result showed that variance on the PON1-108 and 192 alleles could be implicated in the development of altered neurobehavioural outcomes.
Topics: Aryldialkylphosphatase; Child; Environmental Exposure; Humans; Organophosphates; Pesticides; Polymorphism, Single Nucleotide
PubMed: 32386510
DOI: 10.1186/s13643-020-01330-9