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Frontiers in Bioscience (Landmark... Oct 2023In the past 10 years, significant progress has been made in understanding the pathogenic chain of events that causes Alzheimer's disease (AD). According to the most...
BACKGROUND
In the past 10 years, significant progress has been made in understanding the pathogenic chain of events that causes Alzheimer's disease (AD). According to the most widely accepted concept, the production and aggregation of β-amyloid (Aβ) peptides play a critical role in AD. As a result, therapeutic intervention with these processes is the focus of intense research. The Aβ peptide is cleaved by the α-secretase, β-secretase, and γ-secretase enzymes in a region near the pathogenic amyloid precursor protein (APP) and mutations occurring site.
METHODS
In the current review, a complete picture of the risk factors behind AD has been investigated. Mutations involved in AD progression have also been screened in various studies.
RESULTS
Most of the mutations in the amyloid precursor protein (APP) can lead to the accumulation of APP oligomers in the brain, leading to AD. Several point mutations in APP can cause familial AD (FAD), including the Swedish mutation (K>M670/671N>L) and the A673>V mutation. The pathogenic A673>V mutation and Swedish mutation (M670>K/N671>L) are present in the same region of amyloid precursor protein (). However, the A673>T mutation has been shown to confer protection against AD.
CONCLUSION
More investigations are needed from geographically distinct regions on mutations associated with AD development and applications of nanomedicines for better management of the disease burden in the future. Nanotechnology-produced metal nanoparticles (NPs) have gotten much attention because of their wide range of uses in the medicinal and agricultural industries. Nanomedicine containing potential phytochemicals, including GX-50 and curcumin conjugated with NPs, maybe a potential candidate for treating AD.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid beta-Peptides; Mutation; Amyloid Precursor Protein Secretases
PubMed: 37919079
DOI: 10.31083/j.fbl2810258 -
JCO Precision Oncology Aug 2022Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified... (Meta-Analysis)
Meta-Analysis
PURPOSE
Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.
METHODS
We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival.
RESULTS
A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors.
CONCLUSION
This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.
Topics: Humans; Lung Neoplasms; Melanoma; Mitogen-Activated Protein Kinases; Prospective Studies; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; United States
PubMed: 35977349
DOI: 10.1200/PO.22.00107 -
Neurogenetics May 2021Dravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients... (Comparative Study)
Comparative Study
Dravet syndrome (DS) is a rare and severe epileptic syndrome of childhood with prevalence between 1/22,000 and 1/49,900 of live births. Approximately 80% of patients with this syndrome present SCN1A pathogenic variants, which encodes an alpha subunit of a neural voltage-dependent sodium channel. There is a correlation between PCDH19 pathogenic variants, encodes the protocadherin 19, and a similar disease to DS known as DS-like phenotype. The present review aims to clarify the differences between DS and DS-like phenotype according to the SCN1A and PCDH19 variants. A systematic review was conducted in PubMed and Virtual Health Library (VHL) databases, using "Dravet Syndrome" and "Severe Myoclonic Epilepsy in Infancy (SMEI)" search words, selecting cohort of studies published in journal with impact factor of two or greater. The systematic review was according to the Preferred Reporting Items for Systematic Review and Meta-Analysis recommendations. Nineteen studies were included in the present review, and a significant proportion of patients with DS-carrying SCN1A was greater than patients with DS-like phenotype-harboring PCDH19 variants (76.6% versus 23.4%). When clinical and genetic data were correlated, autism was predominantly observed in patients with DS-like-carrying PCDH19 variants compared to SCN1A variant carriers (62.5% versus 37.5%, respectively, P-value = 0.044, P-value corrected = 0.198). In addition, it was noticed a significant predisposition to hyperthermia during epilepsy crisis in individuals carrying PCDH19 variants (P-value = 0.003; P-value corrected = 0.027). The present review is the first to point out differences between the DS and DS-like phenotype according to the SCN1A and PCDH19 variants.
Topics: Autistic Disorder; Epilepsies, Myoclonic; Genetic Heterogeneity; Humans; Hyperthermia; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Observational Studies as Topic; Phenotype; Protocadherins; Seizures, Febrile; Syndrome
PubMed: 33937968
DOI: 10.1007/s10048-021-00644-7 -
The Journal of Antimicrobial... Aug 2022To determine the prevalence of resistance to macrolides in Mycoplasma pneumoniae worldwide. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
To determine the prevalence of resistance to macrolides in Mycoplasma pneumoniae worldwide.
METHODS
Prior to 12 December 2020, PubMed, Web of Science, Scopus and Embase databases were searched for epidemiological studies of M. pneumoniae resistance. Two reviewers independently extracted data from included studies. The extracted data include sampling population, total sampling number, the number of resistant strains and the molecular subtype of resistant strains. The estimate of resistance prevalence was calculated using the random-effects model.
RESULTS
A total of 17 873 strains were obtained from five continents and reported in 98 investigations between 2000 and 2020, with 8836 strains characterized as macrolide resistant. In summary, macrolide-resistant M. pneumoniae was most common in Asia (63% [95% CI 56, 69]). In Europe, North America, South America and Oceania, the prevalence was 3% [2, 7], 8.6% [6, 11], 0% and 3.3%, respectively. Over the last 20 years, the prevalence of macrolide-resistant M. pneumoniae has remained high in China (81% [73, 87]), with a significant increasing trend in South Korea (4% [1, 9] to 78% [49, 93], P < 0.0001). Furthermore, a point mutation at 2063 from A to G was mostly related to M. pneumoniae macrolide resistance. In terms of clinical outcomes, longer cough (mean difference [MD]: 2.93 [0.26, 5.60]) and febrile days (MD: 1.52 [1.12, 1.92]), and prolonged hospital stays (MD: 0.76 [0.05, 1.46]) might be induced by macrolide-resistant M. pneumoniae pneumonia.
CONCLUSIONS
The incidence of macrolide-resistant M. pneumoniae varies globally, with eastern Asia having a greater degree of resistance. However, attention is also required in other areas, and antibiotic alternatives should be considered for treatment in high-prevalence countries.
Topics: Anti-Bacterial Agents; Drug Resistance, Bacterial; Humans; Macrolides; Mycoplasma pneumoniae; Pneumonia, Mycoplasma; Prevalence; RNA, Ribosomal, 23S
PubMed: 35678262
DOI: 10.1093/jac/dkac170 -
Future Oncology (London, England) Sep 2022To review safety and efficacy outcomes in studies of first-line maintenance therapies for advanced ovarian cancer. A systematic literature review was performed (27... (Review)
Review
To review safety and efficacy outcomes in studies of first-line maintenance therapies for advanced ovarian cancer. A systematic literature review was performed (27 February 2020) to identify clinical outcomes including progression-free survival (PFS), overall survival (OS) and Grade ≥3 adverse events. Overall 50 references met prespecified criteria; 18 studies evaluated 10 different agents, including PARP inhibitors. PFS was an end point in 16 trials and OS in 12 trials. PARP inhibitors reported better PFS hazard ratios (HRs: 0.59-0.68) compared with other classes; no mature OS data were identified. Safety reporting was inconsistent. Reported PFS HRs were better for PARP inhibitors than for other ovarian cancer maintenance therapies; overall survival data remain immature.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Progression-Free Survival
PubMed: 36102225
DOI: 10.2217/fon-2022-0578 -
Osong Public Health and Research... Feb 2022Yersinia pestis, the cause of plague and a potential biological weapon, has always been a threatening pathogen. Some strains of Y. pestis have varying degrees of...
Yersinia pestis, the cause of plague and a potential biological weapon, has always been a threatening pathogen. Some strains of Y. pestis have varying degrees of antibiotic resistance. Thus, this systematic review was conducted to alert clinicians to this pathogen's potential antimicrobial resistance. A review of the literature was conducted for experimental reports and systematic reviews on the topics of plague, Y. pestis, and antibiotic resistance. From 1995 to 2021, 7 Y. pestis isolates with 4 antibiotic resistance mechanisms were reported. In Y. pestis 17/95, 16/95, and 2180H, resistance was mediated by transferable plasmids. Each plasmid contained resistance genes encoded within specific transposons. Strain 17/95 presented multiple drug resistance, since plasmid 1202 contained 10 resistance determinants. Strains 16/95 and 2180H showed single antibiotic resistance because both additional plasmids in these strains carried only 1 antimicrobial determinant. Strains 12/87, S19960127, 56/13, and 59/13 exhibited streptomycin resistance due to an rpsl gene mutation, a novel mechanism that was discovered recently. Y. pestis can acquire antibiotic resistance in nature not only via conjugative transfer of antimicrobial-resistant plasmids from other bacteria, but also by gene point mutations. Global surveillance should be strengthened to identify antibiotic-resistant Y. pestis strains by whole-genome sequencing and drug susceptibility testing.
PubMed: 35255676
DOI: 10.24171/j.phrp.2021.0288 -
Journal of Pediatric Endocrinology &... Jun 2022Differentiated thyroid cancers (DTCs) in the paediatric population differ from that of their adult counterparts in terms of clinicopathological characteristics and... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Differentiated thyroid cancers (DTCs) in the paediatric population differ from that of their adult counterparts in terms of clinicopathological characteristics and treatment outcomes. This systematic review and meta-analysis was conducted to comprehensively evaluate the prevalence of various genetic alterations underlying the pathogenesis of sporadic paediatric DTCs.
METHODS
This study followed the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. Systematic searches were made on the PubMed and Embase databases using relevant keywords, and articles published until October 15, 2021 were selected. Data on the prevalence of various genetic alterations were extracted from the individual articles. Random-effects model was employed for meta-analysis to generate pooled estimates and their 95% confidence intervals (95% CIs).
RESULTS
Thirty-three articles comprising 1,380 paediatric patients were included. rearrangement (pooled prevalence: 24.4%, 95% CI: 19.1-30.1) was observed to be the most common genetic alteration in sporadic paediatric DTCs, closely followed by point mutation (pooled prevalence: 21.2%, 95% CI: 17.2-25.5). Other common alterations included: rearrangement (pooled prevalence: 13.5%, 95% CI: 9.5-17.9) and mutation (pooled prevalence: 12.5%, 95% CI: 3.6-25.7). and mutations were observed to be relatively uncommon (pooled prevalence: 5.7%, 95% CI: 2.9-9.3, and 2.2%, 95% CI: 0.4-5.5, respectively). There was no evidence of publication bias.
CONCLUSIONS
Fusion oncogenes are noted to be the major oncogenic drivers in sporadic paediatric DTCs and underlie their unique behaviour. However, despite the relatively lower frequency of point mutation compared to adults, it remains a major player in childhood DTCs.
Topics: Adult; Child; DEAD-box RNA Helicases; Genomics; Humans; Mutation; Point Mutation; Proto-Oncogene Proteins B-raf; Ribonuclease III; Thyroid Neoplasms
PubMed: 35434981
DOI: 10.1515/jpem-2021-0741 -
International Journal of Pediatric... May 2023Hearing loss is one of the most common heterogeneous complicated disorders worldwide. We previously analyzed the results of published data on non-syndromic hearing loss... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Hearing loss is one of the most common heterogeneous complicated disorders worldwide. We previously analyzed the results of published data on non-syndromic hearing loss in the Iranian population systematically. A broad range of genes is a challenge for molecular screening and clinical diagnosis in our populations on the ground of distinct genetics. The aim of this study was to analyze the role and frequency of the variants accountable for non-syndromic hearing loss (NSHL) in the Iranian population. These were identified with different methods including whole exome sequencing (WES), next-generation sequencing (NGS), targeted genomic enrichment and massively parallel sequencing (TGE + MPS), autozygosity mapping, STR markers, linkage analysis, and direct sequencing. This is the comprehensively study focusing on classifying 13 common NSHL genes according to their frequencies. Previous studies have not studied different regions and the Iranian population, and this is the definitive study on the topic.
METHODS
We searched Scopus, PubMed, Science Direct databases, and Google Scholar. After a systematic review of the evidence 95 studies were considered then 31 studies were eligible for meta-analysis. In total, 6995 families, 358 variants, and 117 novel variants were included. Statistical analyses were conducted using Stata SE version 11 software. The inverse variance method enjoyed combining data. Heterogeneity of the preliminary results was assessed using Q (Cochrane test), and I square index. Random effects or fixed models were applied to combine the results, relying on the degree of heterogeneity. Point and pooled prevalence of variants acting on different regions were illustrated by forest plots.
RESULTS
The total prevalence of at least one variant of GJB2 and SLC26A genes was estimated at 26% and 5%, respectively. Variant c.35delG accounted for 18% of the GJB2 variants while 1% of these variants were novel ones. The next most common variants in the GJB2 gene were c.109G>A at 3.5% and c.-23+1G>A at 2.3%. Moreover, the prevalence of GJB2 gene variants varied on average 0.002% from one region to another in Iran (p=0.849). Our meta-analysis also showed that the frequency of at least one variant of MYO15A varied between 1.2% and 12.5%. Corresponding prevalences for the other variants were as follows: ILDR1 (3.5%-3.7%), CDH23 (2%-10%), PJVK (1.4%-33%), TECTA (1.3%-6.7%), MYO6 (2%-4.8%), TMC1 (1.8%-2%), MYO7A (0.7%-5%), MARVELD2 (0.7-5%), OTOF (0.7%-4%), LRTOMT (0.7%-2.5%). Finally, we did not find any relationship between geographic area and the presence of these variants.
CONCLUSION
GJB2 gene variants were the most common cause of NSHL in Iran. Understanding the prevalence of NSHL gene frequency in Iran may be the foundation for future studies in an Iranian population which may lead to future NSHL therapy.
Topics: Humans; Iran; Mutation; Deafness; Hearing Loss; Connexin 26; Connexins; MARVEL Domain Containing 2 Protein
PubMed: 37086676
DOI: 10.1016/j.ijporl.2023.111512 -
Gastrointestinal Endoscopy May 2021Although molecular analysis of pancreatic cyst fluid may aid pancreatic cyst classification, clinical practice remains highly variable. Therefore, we performed a... (Meta-Analysis)
Meta-Analysis
Molecular analysis of EUS-acquired pancreatic cyst fluid for KRAS and GNAS mutations for diagnosis of intraductal papillary mucinous neoplasia and mucinous cystic lesions: a systematic review and meta-analysis.
BACKGROUND AND AIMS
Although molecular analysis of pancreatic cyst fluid may aid pancreatic cyst classification, clinical practice remains highly variable. Therefore, we performed a systematic review and meta-analysis to evaluate the diagnostic performance of KRAS and GNAS mutations in EUS-acquired pancreatic cyst fluid for diagnosis of intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic lesions (MCLs).
METHODS
Individualized searches were developed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and meta-analysis analyzed according to the Cochrane Diagnostic Test Accuracy working group methodology. A bivariate model was used to compute the pooled sensitivity and specificity and to plot the summary receiver operating characteristics curve with summary point and corresponding 95% confidence interval (95% CI).
RESULTS
Six studies (785 lesions) were included. For IPMNs and MCLs, KRAS + GNAS (combination) had significantly higher diagnostic accuracy than KRAS alone and GNAS alone (all P < .001). The pooled sensitivity, specificity, and diagnostic accuracy of KRAS + GNAS mutations for diagnosis of IPMNs were 94% (95% CI, 72-99; I = 86.74%), 91% (95% CI, 72-98; I = 89.83), and 97% (95% CI, 95-98), respectively, with each significantly higher compared with carcinoembryonic antigen (CEA) alone (all P < .001). For diagnosis of MCLs, KRAS + GNAS had a similar sensitivity and specificity compared with CEA alone; however, diagnostic accuracy was significantly improved (97% [95% CI, 95-98] vs 89% [95% CI, 86-91]; P < .001).
CONCLUSIONS
Molecular analysis for KRAS + GNAS mutations in EUS-acquired pancreatic cyst fluid has high sensitivity and specificity with significantly improved diagnostic accuracy for diagnosis of IPMNs and MCLs when compared with CEA alone.
Topics: Biomarkers, Tumor; Chromogranins; Cyst Fluid; GTP-Binding Protein alpha Subunits, Gs; Humans; Mutation; Pancreatic Cyst; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras)
PubMed: 33359054
DOI: 10.1016/j.gie.2020.12.014 -
European Journal of Clinical... May 2015Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare genetic condition characterized by end-organ insensitivity to glucocorticoids owing to... (Review)
Review
BACKGROUND
Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare genetic condition characterized by end-organ insensitivity to glucocorticoids owing to inactivating mutations of the NR3C1 gene.
MATERIALS AND METHODS
We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through November 2014) to identify original articles and reviews on this topic. The search terms included 'primary generalized glucocorticoid resistance', 'Chrousos syndrome', 'glucocorticoid receptor gene' and 'glucocorticoid receptor mutations'.
RESULTS
Only a few cases of Chrousos syndrome have been described to date, ranging from asymptomatic to severe forms of mineralocorticoid and/or androgen excess. All reported cases have been associated with point mutations or deletions in the NR3C1 gene. The tremendous progress of molecular biology has enabled us to apply standard methods to investigate the molecular mechanisms of action of the mutant glucocorticoid receptors (GRs). We and others have identified and functionally characterized novel mutations causing Chrousos syndrome, while structural biology has enabled us to have a better understanding of how conformational changes of the receptor cause glucocorticoid resistance. In this review, we also present our results of the functional characterization of two recently described mutations, and we discuss the diagnostic approaches and therapeutic management of patients with Chrousos syndrome.
CONCLUSIONS
Although Chrousos syndrome is a rare condition, many clinical cases remain unrecognized for a long time. We recommend determination of the 24-h urinary free cortisol excretion and sequencing of the NR3C1 gene in patients with hyperandrogenism and/or hypertension of unknown origin.
Topics: Adrenocorticotropic Hormone; Dexamethasone; Glucocorticoids; Humans; Hydrocortisone; Metabolism, Inborn Errors; Mutation; Receptors, Glucocorticoid
PubMed: 25715669
DOI: 10.1111/eci.12426