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BMC Ophthalmology Feb 2024Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people...
BACKGROUND
Inherited retinal degenerations (IRDs) are a group of rare genetic conditions affecting retina of the eye that range in prevalence from 1 in 2000 to 1 in 4000 people globally. This review is based on a retrospective analysis of research articles reporting IRDs associated genetic findings in Pakistani families between 1999 and April 2023.
METHODS
Articles were retrieved through survey of online sources, notably, PubMed, Google Scholar, and Web of Science. Following a stringent selection criterion, a total of 126 research articles and conference abstracts were considered. All reported variants were cross-checked and validated for their correct genomic nomenclature using different online resources/databases, and their pathogenicity scores were explained as per ACMG guidelines.
RESULTS
A total of 277 unique sequence variants in 87 distinct genes, previously known to cause IRDs, were uncovered. In around 70% cases, parents of the index patient were consanguineously married, and approximately 88.81% of the detected variants were found in a homozygous state. Overall, more than 95% of the IRDs cases were recessively inherited. Missense variants were predominant (41.88%), followed by Indels/frameshift (26.35%), nonsense (19.13%), splice site (12.27%) and synonymous change (0.36%). Non-syndromic IRDs were significantly higher than syndromic IRDs (77.32% vs. 22.68%). Retinitis pigmentosa (RP) was the most frequently observed IRD followed by Leber's congenital amaurosis (LCA). Altogether, mutations in PDE6A gene was the leading cause of IRDs in Pakistani families followed by mutations in TULP1 gene.
CONCLUSION
In summary, Pakistani families are notable in expressing recessively inherited monogenic disorders including IRDs likely due to the highest prevalence of consanguinity in the country that leads to expression of rare pathogenic variants in homozygous state.
Topics: Humans; Pakistan; Retrospective Studies; Retinal Dystrophies; Retina; Retinitis Pigmentosa; Mutation; Pedigree; Eye Proteins; Cyclic Nucleotide Phosphodiesterases, Type 6
PubMed: 38317096
DOI: 10.1186/s12886-024-03319-7 -
Medicine Nov 2023Duhuo-Jisheng decoction (DJD) is a Chinese herb formula. Previous studies have reported that the clinical symptoms and laboratory indicators of rheumatoid arthritis (RA)... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Duhuo-Jisheng decoction (DJD) is a Chinese herb formula. Previous studies have reported that the clinical symptoms and laboratory indicators of rheumatoid arthritis (RA) patients could be improved by DJD. However, the existing evidence was not robust enough and controversial.
METHODS
Randomized controlled trials of DJD for RA were retrieved from Chinese and English databases from their inception to April 16, 2023. Meta-analysis was performed by Stata 17 software. We used subgroup analysis, meta-regression, and sensitivity analysis to identify potential sources of heterogeneity. The subgroup analysis and meta-regression were conducted from 6 aspects, including age, course of disease, course of treatment, interventions used in the experimental or control group, and random sequence generation. Galbraith plot was used to find studies with possible heterogeneity. Publication bias was assessed by Egger's test and funnel plots when the number of relevant studies was greater than or equal to 10.
RESULTS
Forty-two studies were included, involving 3635 patients and 19 outcome indicators. Meta-analysis showed that, compared with the routine disease-modifying antirheumatic drugs (rDMARDs), DJD could better improve the level of laboratory indicators, main symptoms and signs, and questionnaire scores of RA patients. The laboratory indicators included rheumatoid factor, T lymphocyte subpopulation (including CD4+, CD8+, and CD4+/CD8+), and inflammatory biomarkers (including erythrocyte sedimentation rate, C-reactive protein, tumor necrosis factor-α, interleukin 6, interleukin 1β, and interleukin 1). The main symptoms and signs included the duration of morning stiffness, the number of joint tenderness, the number of swollen joints, and the grip strength of both hands. The questionnaire included visual analogue scale, health assessment questionnaire, and disease activity score in 28 joints. In addition, the adverse events of DJD treatment were significantly lower than those of rDMARDs. However, the results of a few subgroup analyses differed from the overall results. Furthermore, the publication bias assessment showed that, out of 11 evaluated results, 4 had publication bias.
CONCLUSION
DJD could be a satisfactory complementary and alternative therapy for RA. However, due to a small number of subgroup analysis results being different from the overall results, it should be verified by further studies.
Topics: Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Hand Strength; Randomized Controlled Trials as Topic
PubMed: 37933004
DOI: 10.1097/MD.0000000000035513 -
Molecular Genetics & Genomic Medicine Nov 2023Among present reports, the T/G allelic variation at the rs2609255 locus of the family sequence similarity gene 13A (FAM13A) was considerable associated with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Among present reports, the T/G allelic variation at the rs2609255 locus of the family sequence similarity gene 13A (FAM13A) was considerable associated with susceptibility to interstitial lung diseases (ILDs). In this study, we summarized relevant studies and applied a meta-analysis to explore whether the polymorphism of rs2609255 site of the FAM13A gene can be utilized to predict susceptibility to idiopathic pulmonary fibrosis (IPF) patients or rheumatoid arthritis-associated interstitial lung disease (RA-ILD) or silicosis patients in different populations for the first time.
METHODS
We compared the frequency of G allele on rs2609255 site of FAM13A between the control subjects and IPF or RA-ILD or silicosis patients from different races by using meta-analysis. Nine studies were involved in this meta-analysis, including five IPF studies, two RA-ILD studies, and two silicosis studies, and containing 14 subgroups. We conducted separate meta-analyses for different races.
RESULTS
In all individuals, a substantial link between the G allele of the FAM13A rs2609255 polymorphism and IPF (OR: 1.47, 95% CI: 1.33-1.63, p < 0.00001) was indicated. After dividing by ethnicity, the G allele was illustrated to be considerable correlation with IPF in Asian (OR: 2.63, 95% CI: 1.81-3.81, p < 0.00001) and with RA-ILD individuals (OR: 3.27, 95% CI: 1.26-8.49, p = 0.01). Conversely, there was no correlation with the G allele and IPF in European individuals (OR: 1.27, 95% CI: 0.89-1.83, p = 0.13) or silicosis in Chinese individuals (OR: 1.20, 95% CI: 0.99-1.46, p = 0.07).
CONCLUSION
This is the first meta-analysis that provides evidence that the rs2609255 of FAM13A might increase susceptibility to RA-ILD, and IPF especially in Asian but not in European individuals, and not be correlated with silicosis in Chinese individuals, which indicated the differences in susceptibility to disease by race were noteworthy.
Topics: Humans; Lung Diseases, Interstitial; Idiopathic Pulmonary Fibrosis; Polymorphism, Genetic; Arthritis, Rheumatoid; Silicosis; GTPase-Activating Proteins
PubMed: 37786320
DOI: 10.1002/mgg3.2279 -
Viruses Jul 2023Whether RNA-RNA interactions of cytoplasmic RNA viruses, such as , might end in the biogenesis of putative virus-derived small RNAs as miRNA-like molecules has been...
Computational Prediction of RNA-RNA Interactions between Small RNA Tracks from Nonstructural Protein 3 and Neurotrophin Genes during Infection of an Epithelial Lung Cancer Cell Line: Potential Role of Novel Small Regulatory RNA.
Whether RNA-RNA interactions of cytoplasmic RNA viruses, such as , might end in the biogenesis of putative virus-derived small RNAs as miRNA-like molecules has been controversial. Even more, whether RNA-RNA interactions of wild animal viruses may act as virus-derived small RNAs is unknown. Here, we address these issues in four ways. First, we use conserved RNA structures undergoing negative selection in the genomes of SARS-CoV, MERS-CoV, and SARS-CoV-2 circulating in different bat species, intermediate animals, and human hosts. Second, a systematic literature review was conducted to identify -targeting hsa-miRNAs involved in lung cell infection. Third, we employed sophisticated long-range RNA-RNA interactions to refine the seed sequence homology of hsa-miRNAs with conserved RNA structures. Fourth, we used high-throughput RNA sequencing of a -infected epithelial lung cancer cell line (Calu-3) to validate the results. We proposed nine potential virus-derived small RNAs: two vsRNAs in SARS-CoV (Bats: SB-vsRNA-ORF1a-3p; SB-vsRNA-S-5p), one vsRNA in MERS-CoV (Bats: MB-vsRNA-ORF1b-3p), and six vsRNAs in SARS-CoV-2 (Bats: S2B-vsRNA-ORF1a-5p; intermediate animals: S2I-vsRNA-ORF1a-5p; and humans: S2H-vsRNA-ORF1a-5p, S2H-vsRNA-ORF1a-3p, S2H-vsRNA-ORF1b-3p, S2H-vsRNA-ORF3a-3p), mainly encoded by nonstructural protein 3. Notably, -derived small RNAs targeted 74 differentially expressed genes in infected human cells, of which 55 upregulate the molecular mechanisms underlying acute respiratory distress syndrome (ARDS), and the 19 downregulated genes might be implicated in neurotrophin signaling impairment. These results reveal a novel small RNA-based regulatory mechanism involved in neuropathogenesis that must be further studied to validate its therapeutic use.
Topics: Animals; Humans; Chiroptera; SARS-CoV-2; COVID-19; Lung Neoplasms; MicroRNAs; Middle East Respiratory Syndrome Coronavirus; Cell Line; Lung; Nerve Growth Factors
PubMed: 37631989
DOI: 10.3390/v15081647 -
Clinical Lung Cancer Jan 2024With the widespread application of immune checkpoint inhibitor (ICI) combined with radiotherapy (RT) for the treatment of lung cancer, increasing attention has been paid... (Meta-Analysis)
Meta-Analysis
Effect of Sequence of Radiotherapy Combined With Immunotherapy on the Incidence of Pneumonitis in Patients With Lung Cancer: A Systematic Review and Network Meta-Analysis.
BACKGROUND
With the widespread application of immune checkpoint inhibitor (ICI) combined with radiotherapy (RT) for the treatment of lung cancer, increasing attention has been paid to treatment-related pneumonitis. The effect of the treatment sequence on the incidence of pneumonitis remains unclear.
METHODS
We searched databases including PubMed, Embase, and ClinicalTrials.gov, meeting abstracts, and reference lists of relevant review articles for literature published on radio- and immunotherapy in lung cancer. Stata software (version 16.0) was used for meta-analysis. Data on the incidence of any grade and ≥ grade 3 pneumonitis was pooled using the random effects model. Bayesian network meta-analysis was used for arm-based pairwise comparisons. Subgroup analyses were performed to identify the potential influencing factors.
RESULTS
Thirty-eight studies met our inclusion criteria. The network meta-analysis showed no significant difference between the incidence of pneumonitis in concurrent ICI with RT (concurrent arm) and RT followed by ICI (RT-first arm) (odds ratio [OR]: 0.71, 95% confidence interval [CI]: 0.10-4.81). In the meta-analysis of single group rates, RT following ICI (ICI-first arm) exhibited higher incidence of any grade pneumonitis compared with concurrent- and RT-first arms, with 0.321 (95% CI: 0.260-0.386) for programmed cell death protein 1 (PD-1) inhibitors from clinical trials, and 0.480 (95% CI: 0.363-0.598) for PD-1 inhibitors from real-world retrospective data, respectively.
CONCLUSION
No significant difference in the incidence of any grade and grade ≥ 3 pneumonitis was found between RT-first and concurrent arms. The ICI-first arm exhibited a higher incidence of pneumonitis, which needs to be further confirmed by follow-up studies.
Topics: Humans; Bayes Theorem; Immunotherapy; Incidence; Lung Neoplasms; Network Meta-Analysis; Pneumonia; Retrospective Studies
PubMed: 37612176
DOI: 10.1016/j.cllc.2023.08.008 -
Cureus Jul 2023Colorectal cancer (CRC) is a major global health concern, accounting for significant cancer-related morbidity and mortality worldwide. Despite advancements in early... (Review)
Review
Protective Effects of Long-Term Usage of Cyclo-Oxygenase-2 Inhibitors on Colorectal Cancer in Genetically Predisposed Individuals and Their Overall Effect on Prognosis: A Systematic Review.
Colorectal cancer (CRC) is a major global health concern, accounting for significant cancer-related morbidity and mortality worldwide. Despite advancements in early detection and treatment modalities, the prevention of CRC remains a critical goal. Cyclo-oxygenase-2 (COX-2) is an inducible enzyme involved in the production of pro-inflammatory prostaglandins, which play a crucial role in various cellular processes, including inflammation, cell proliferation, apoptosis, and angiogenesis. Elevated COX-2 expression has been consistently observed in colorectal tumors, indicating their role in the pathogenesis of cancer. COX-2 inhibitors, such as celecoxib and rofecoxib, have been studied as potentially effective treatment modalities due to their ability to decrease prostaglandin levels, which are generally higher in cancer patients. Aberrant prostaglandin production is linked to the adenoma-carcinoma sequence, during which adenomas turn dysplastic and accumulate enough damage to become malignant. COX-2 inhibitors have also been shown to modulate various signaling pathways involved in CRC development, such as wingless-related integration site/β-catenin (Wnt/β-catenin), mitogen-activated protein kinase (MAPK), and phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) pathways. This systematic review aimed to evaluate the protective effects of long-term usage of COX-2 inhibitors on CRC in genetically predisposed individuals and their overall effect on the prognosis of the disease. The researchers conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and collected data from several databases, including PubMed, PubMed Central, Cochrane Library, and Web of Science. The search strategy combined keywords related to CRC, COX-2 inhibitors, protective effects, and prognosis. They identified 1189 articles and shortlisted 26 full-text articles that met the eligibility criteria. Quality assessment tools, such as the Assessment of Multiple Systematic Review (AMSTAR) for systematic reviews, the Cochrane bias assessment tool for randomized control trials, the scale for the assessment of narrative review articles (SANRA) checklist for narrative reviews, and the Joanna Briggs Institute (JBI) tool for cross-sectional studies and case reports, are used. This review's conclusions will assist in determining the effectiveness of COX-2 inhibitors to prevent CRC. This review may also contribute to developing guidelines for clinicians to manage genetically predisposed individuals with CRC. Furthermore, the results of this review will shed light on the potential of COX-2 inhibitors as a preventive measure against CRC in genetically predisposed individuals.
PubMed: 37588311
DOI: 10.7759/cureus.41939 -
Vaccine Aug 2023Vaccines for avian influenza (AI) can protect poultry against disease, mortality, and virus transmission. Numerous factors, including: vaccine platform, immunogenicity,... (Meta-Analysis)
Meta-Analysis Review
Vaccines for avian influenza (AI) can protect poultry against disease, mortality, and virus transmission. Numerous factors, including: vaccine platform, immunogenicity, and relatedness to the field strain, are known to be important to achieving optimal AI vaccine efficacy. To better understand how these factors contribute to vaccine protection, a systematic meta-analysis was conducted to evaluate efficacy data for vaccines in chickens challenged with highly pathogenic (HP) AI. Data from a total of 120 individual trials from 25 publications were selected and evaluated. Two vaccine criteria were evaluated for their effects on two metrics of protection. The vaccine criteria were: 1) the relatedness of the vaccine antigen and challenge strain in the hemagglutinin 1 domain (HA1) protein sequence; 2) vaccine-induced antibody titers to the challenge virus (VIAC). The metrics of protection were: A) survival of vaccinated chickens vs unvaccinated controls; and B) reduction in oral virus-shedding by vaccinated vs unvaccinated controls 2-4 days post challenge. Three vaccine platforms were evaluated: oil-adjuvanted inactivated whole AI virus, recombinant herpes virus of turkeys (rHVT) vectored, and a non-replicating alpha-virus vectored RNA particle (RP) vaccine. Higher VIAC correlated with greater reduction of virus-shed and vaccine efficacy by all vaccine platforms. Both higher HA1 relatedness and higher VIAC using challenge virus as antigen correlated with better survival by inactivated vaccines and rHVT-vectored vaccines. However, rHVT-vectored and RP based vaccines were more tolerant of variation in the HA1; the relatedness of the HA1 of the vaccine and challenge virus did not significantly correlate with survival with rHVT-vectored vaccines. Protection was achieved with the lowest aa similarity for which there was data, 90-93 % for rHVT vaccines and 88 % for the RP vaccine.
Topics: Animals; Chickens; Influenza Vaccines; Influenza in Birds; Influenza A Virus, H5N1 Subtype; Vaccines, Synthetic; Influenza A virus; Herpesvirus 1, Meleagrid
PubMed: 37537093
DOI: 10.1016/j.vaccine.2023.07.076 -
Frontiers in Immunology 2023The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins.... (Review)
Review
The peptidyl arginine deiminase (PADI) family is a calcium ion-dependent group of isozymes with sequence similarity that catalyze the citrullination of proteins. Histones can serve as the target substrate of PADI family isozymes, and therefore, the PADI family is involved in NETosis and the secretion of inflammatory cytokines. Thus, the PADI family is associated with the development of inflammatory autoimmune diseases and cancer, reproductive development, and other related diseases. In this review, we systematically discuss the role of the PADI family in the pathogenesis of various diseases based on studies from the past decade to provide a reference for future research.
Topics: Humans; Protein-Arginine Deiminases; Isoenzymes; Autoimmune Diseases; Histones; Neoplasms
PubMed: 37020554
DOI: 10.3389/fimmu.2023.1115794 -
The Cochrane Database of Systematic... Mar 2023Cystic fibrosis (CF) is a common, life-shortening, genetic disorder in populations of Northern European descent caused by the mutation of a single gene that codes for... (Review)
Review
BACKGROUND
Cystic fibrosis (CF) is a common, life-shortening, genetic disorder in populations of Northern European descent caused by the mutation of a single gene that codes for the production of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein coordinates the transport of salt (and bicarbonate) across cell surfaces, and the mutation most notably affects the airways. In the lungs of people with CF, the defective protein compromises mucociliary clearance and makes the airway prone to chronic infection and inflammation, damaging the structure of the airways and eventually leading to respiratory failure. In addition, abnormalities in the truncated CFTR protein lead to other systemic complications, including malnutrition, diabetes and subfertility. Five classes of mutation have been described, depending on the impact of the mutation on the processing of the CFTR protein in the cell. In class I mutations, premature termination codons prevent the production of any functional protein, resulting in severe CF. Therapies targeting class I mutations aim to enable the normal cellular mechanism to read through the mutation, potentially restoring the production of the CFTR protein. This could, in turn, normalise salt transport in the cells and decrease the chronic infection and inflammation that characterises lung disease in people with CF. This is an update of a previously published review.
OBJECTIVES
To evaluate the benefits and harms of ataluren and similar compounds on clinically important outcomes in people with CF with class I mutations (premature termination codons).
SEARCH METHODS
We searched the Cochrane Cystic Fibrosis Trials Register, which is compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles. The last search of the Cochrane Cystic Fibrosis Trials Register was conducted on 7 March 2022. We searched clinical trial registries maintained by the European Medicines Agency, the US National Institutes of Health and the World Health Organization. The last search of the clinical trials registries was conducted on 4 October 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of parallel design comparing ataluren and similar compounds (specific therapies for class I mutations) with placebo in people with CF who have at least one class I mutation.
DATA COLLECTION AND ANALYSIS
For the included trials, the review authors independently extracted data, assessed the risk of bias and evaluated the certainty of the evidence using GRADE; trial authors were contacted for additional data.
MAIN RESULTS
Our searches identified 56 references to 20 trials; of these, 18 trials were excluded. Both the included parallel RCTs compared ataluren to placebo for 48 weeks in 517 participants (males and females; age range six to 53 years) with CF who had at least one nonsense mutation (a type of class I mutation). The certainty of evidence and risk of bias assessments for the trials were moderate overall. Random sequence generation, allocation concealment and blinding of trial personnel were well documented; participant blinding was less clear. Some participant data were excluded from the analysis in one trial that also had a high risk of bias for selective outcome reporting. PTC Therapeutics Incorporated sponsored both trials with grant support from the Cystic Fibrosis Foundation, the US Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health. The trials reported no difference between treatment groups in terms of quality of life, and no improvement in respiratory function measures. Ataluren was associated with a higher rate of episodes of renal impairment (risk ratio 12.81, 95% confidence interval 2.46 to 66.65; P = 0.002; I = 0%; 2 trials, 517 participants). The trials reported no treatment effect for ataluren for the review's secondary outcomes of pulmonary exacerbation, computed tomography score, weight, body mass index and sweat chloride. No deaths were reported in the trials. The earlier trial performed a post hoc subgroup analysis of participants not receiving concomitant chronic inhaled tobramycin (n = 146). This analysis demonstrated favourable results for ataluren (n = 72) for the relative change in forced expiratory volume in one second (FEV) per cent (%) predicted and pulmonary exacerbation rate. The later trial aimed to prospectively assess the efficacy of ataluren in participants not concomitantly receiving inhaled aminoglycosides, and found no difference between ataluren and placebo in FEV % predicted and pulmonary exacerbation rate. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with CF with class I mutations. One trial reported favourable results for ataluren in a post hoc subgroup analysis of participants not receiving chronic inhaled aminoglycosides, but these were not reproduced in the later trial, suggesting that the earlier results may have occurred by chance. Future trials should carefully assess for adverse events, notably renal impairment, and consider the possibility of drug interactions. Cross-over trials should be avoided, given the potential for the treatment to change the natural history of CF.
Topics: Adolescent; Adult; Child; Female; Humans; Male; Middle Aged; Young Adult; Aminoglycosides; Anti-Bacterial Agents; Codon, Nonsense; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Mutation; Persistent Infection
PubMed: 36866921
DOI: 10.1002/14651858.CD012040.pub3 -
Genes Jan 2023The ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif, defined by the consensus sequence patterns LxLxL or DLNx(x)P, is found in a... (Review)
Review
The ethylene-responsive element binding factor-associated amphiphilic repression (EAR) motif, defined by the consensus sequence patterns LxLxL or DLNx(x)P, is found in a diverse range of plant species. It is the most predominant form of active transcriptional repression motif identified so far in plants. Despite its small size (5 to 6 amino acids), the EAR motif is primarily involved in the negative regulation of developmental, physiological and metabolic functions in response to abiotic and biotic stresses. Through an extensive literature review, we identified 119 genes belonging to 23 different plant species that contain an EAR motif and function as negative regulators of gene expression in various biological processes, including plant growth and morphology, metabolism and homeostasis, abiotic stress response, biotic stress response, hormonal pathways and signalling, fertility, and ripening. Positive gene regulation and transcriptional activation are studied extensively, but there remains much more to be discovered about negative gene regulation and the role it plays in plant development, health, and reproduction. This review aims to fill the knowledge gap and provide insights into the role that the EAR motif plays in negative gene regulation, and provoke further research on other protein motifs specific to repressors.
Topics: Arabidopsis; Plants, Genetically Modified; Transcription Factors; Amino Acid Motifs; Transcriptional Activation
PubMed: 36833197
DOI: 10.3390/genes14020270