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BMC Genomics Dec 2022Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as...
BACKGROUND
Modern human brains and skull shapes differ from other hominids. Brain growth disorders as micro- (ASPM, MCPH1) and macrocephaly (NFIX, GLI3) have been highlighted as relevant for the evolution in humans due to the impact in early brain development. Genes associated with macrocephaly have been reported to cause this change, for example NSD1 which causes Sotos syndrome.
RESULTS
In this study we performed a systematic literature review, located the reported variants associated to Sotos syndrome along the gene domains, compared the sequences with close primates, calculated their similarity, Ka/Ks ratios, nucleotide diversity and selection, and analyzed the sequence and structural conservation with distant primates. We aimed to understand if NSD1 in humans differs from other primates since the evolution of NSD1 has not been analyzed in primates, nor if the localization of the mutations is limited to humans. Our study found that most variations causing Sotos syndrome are in exon 19, 22 and 10. In the primate comparison we did not detect Ka/Ks ratios > 1, but a high nucleotide diversity with non-synonymous variations in exons 10, 5, 9, 11 and 23, and sites under episodic selection in exon 5 and 23, and human, macaque/colobus/tarsier/galago and tarsier/lemur/colobus. Most of the domains are conserved in distant primates with a particular progressive development from a simple PWWP1 in O. garnetti to a complex structure in Human.
CONCLUSION
NSD1 is a chromatin modifier that suggests that the selection could influence brain development during modern human evolution and is not present in other primates; however, nowadays the nucleotide diversity is associated with Sotos syndrome.
Topics: Humans; Animals; Sotos Syndrome; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Tarsiidae; Colobus; Nuclear Proteins; Mutation; Exons; Hominidae; Megalencephaly; Nucleotides; Cytoskeletal Proteins; Cell Cycle Proteins
PubMed: 36550402
DOI: 10.1186/s12864-022-09071-w -
Gut Microbes Nov 2020In this review, we highlight the variations of gut resistome studies, which may preclude comparisons and translational interpretations. Of 22 included studies, a range...
In this review, we highlight the variations of gut resistome studies, which may preclude comparisons and translational interpretations. Of 22 included studies, a range of 12 to 2000 antibiotic resistance (AR) genes were profiled. Overall, studies defined a healthy gut resistome as subjects who had not taken antibiotics in the last three to 12 months prior to sampling. In studies with assembly, AR genes were identified based on variable nucleotide or amino acid sequence similarities. Different marker genes were used for defining resistance to a given antibiotic class. Validation of phenotypic resistance in the laboratory is frequently lacking. Cryptic resistance, collateral sensitivity and the interaction with repressors or promotors were not investigated. International consensus is needed for selecting marker genes to define resistance to a given antibiotic class in addition to uniformity in phenotypic validation and bioinformatics pipelines.
Topics: Anti-Bacterial Agents; Bacteria; Drug Resistance, Bacterial; Gastrointestinal Microbiome; Gastrointestinal Tract; Genes, Bacterial; Humans
PubMed: 31942825
DOI: 10.1080/19490976.2019.1700755 -
Anesthesiology Feb 2022The dorsal root ganglion is widely recognized as a potential target to treat chronic pain. A fundamental understanding of quantitative molecular and genomic changes...
The dorsal root ganglion is widely recognized as a potential target to treat chronic pain. A fundamental understanding of quantitative molecular and genomic changes during the late phase of pain is therefore indispensable. The authors performed a systematic literature review on injury-induced pain in rodent dorsal root ganglions at minimally 3 weeks after injury. So far, slightly more than 300 molecules were quantified on the protein or messenger RNA level, of which about 60 were in more than one study. Only nine individual sequencing studies were performed in which the most up- or downregulated genes varied due to heterogeneity in study design. Neuropeptide Y and galanin were found to be consistently upregulated on both the gene and protein levels. The current knowledge regarding molecular changes in the dorsal root ganglion during the late phase of pain is limited. General conclusions are difficult to draw, making it hard to select specific molecules as a focus for treatment.
Topics: Animals; Galanin; Ganglia, Spinal; Mice; Neuropeptide Y; Pain Measurement; Peripheral Nerve Injuries; Rats; Rodentia; Sequence Analysis, RNA
PubMed: 34965284
DOI: 10.1097/ALN.0000000000004092 -
Viruses May 2022Live-attenuated SARS-CoV-2 vaccines received relatively little attention during the COVID-19 pandemic. Despite this, several methods of obtaining attenuated...
Live-attenuated SARS-CoV-2 vaccines received relatively little attention during the COVID-19 pandemic. Despite this, several methods of obtaining attenuated coronaviruses are known. In this systematic review, the strategies of coronavirus attenuation, which may potentially be applied to SARS-CoV-2, were identified. PubMed, Scopus, Web of Science and Embase databases were searched to identify relevant articles describing attenuating mutations tested in vivo. In case of coronaviruses other than SARS-CoV-2, sequence alignment was used to exclude attenuating mutations that cannot be applied to SARS-CoV-2. Potential immunogenicity, safety and efficacy of the attenuated SARS-CoV-2 vaccine were discussed based on animal studies data. A total of 27 attenuation strategies, used to create 101 different coronaviruses, have been described in 56 eligible articles. The disruption of the furin cleavage site in the SARS-CoV-2 spike protein was identified as the most promising strategy. The replacement of core sequences of transcriptional regulatory signals, which prevents recombination with wild-type viruses, also appears particularly advantageous. Other important attenuating mutations encompassed mostly the prevention of evasion of innate immunity. Sufficiently attenuated coronaviruses typically caused no meaningful disease in susceptible animals and protected them from challenges with virulent virus. This indicates that attenuated COVID-19 vaccines may be considered as a potential strategy to fight the threat posed by SARS-CoV-2.
Topics: Animals; COVID-19; COVID-19 Vaccines; Humans; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Vaccine Development; Vaccines, Attenuated
PubMed: 35632736
DOI: 10.3390/v14050991 -
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 -
BMC Endocrine Disorders Nov 2021Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms...
BACKGROUND
Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant type of diabetes. Pathogenic variants in fourteen genes are reported as causes of MODY. Its symptoms overlap with type 1 and type 2 diabetes. Reviews for clinical characteristics, diagnosis and treatments are available but a comprehensive list of genetic variants, is lacking. Therefore this study was designed to collect all the causal variants involved in MODY, reported to date.
METHODS
We searched PubMed from its date of inception to December 2019. The search terms we used included disease names and name of all the known genes involved. The ClinVar database was also searched for causal variants in the known 14 MODY genes.
RESULTS
The record revealed 1647 studies and among them, 326 studies were accessed for full-text. Finally, 239 studies were included, as per our inclusion criteria. A total of 1017 variants were identified through literature review and 74 unpublished variants from Clinvar database. The gene most commonly affected was GCK, followed by HNF1a. The traditional Sanger sequencing was used in 76 % of the cases and 65 % of the studies were conducted in last 10 years. Variants from countries like Jordan, Oman and Tunisia reported that the MODY types prevalent worldwide were not common in their countries.
CONCLUSIONS
We expect that this paper will help clinicians interpret MODY genetics results with greater confidence. Discrepancies in certain middle-eastern countries need to be investigated as other genes or factors, like consanguinity may be involved in developing diabetes.
Topics: Adaptor Proteins, Signal Transducing; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 2; Glucokinase; Hepatocyte Nuclear Factor 1-alpha; Hepatocyte Nuclear Factor 1-beta; Hepatocyte Nuclear Factor 4; High-Throughput Nucleotide Sequencing; Homeodomain Proteins; Humans; Insulin; Lipase; Paired Box Transcription Factors; Potassium Channels, Inwardly Rectifying; Repressor Proteins; Sequence Analysis, DNA; Sulfonylurea Receptors; Trans-Activators; src-Family Kinases
PubMed: 34763692
DOI: 10.1186/s12902-021-00891-7 -
International Journal of Molecular... Nov 2021The inflammatory reaction in rheumatoid arthritis (RA) is controlled by major epigenetic modifications that modulate the phenotype of synovial and immune cells. The aim...
The inflammatory reaction in rheumatoid arthritis (RA) is controlled by major epigenetic modifications that modulate the phenotype of synovial and immune cells. The aim of this work was to perform a systematic review focusing on miR expression, DNA methylation and histone modifications in RA. We demonstrated that, in human samples, the expressions of miR-155, miR-146a and miR-150 were significantly decreased while the expression of miR-410-3p was significantly increased in the RA group. Moreover, miR-146a significantly decreased pro-autoimmune IL-17 cytokine expression in RA. In a murine model, miR-34a inhibition can ameliorate the arthritis score. However, this evidence remain critically insufficient to support current therapeutic applications in RA patients.
Topics: Animals; Arthritis, Rheumatoid; DNA Methylation; Epigenesis, Genetic; Histone Code; Humans; MicroRNAs
PubMed: 34830057
DOI: 10.3390/ijms222212170 -
International Journal of Molecular... Nov 2021Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC)...
Epigenetic alterations (including DNA methylation or miRNAs) influence oncogene/oncosuppressor gene expression without changing the DNA sequence. Prostate cancer (PC) displays a complex genetic and epigenetic regulation of cell-growth pathways and tumor progression. We performed a systematic literature review (following PRISMA guidelines) focused on the epigenetic regulation of PD-L1 expression in PC. In PC cell lines, CpG island methylation of the promoter negatively regulated PD-L1 expression. Histone modifiers also influence the PD-L1 transcription rate: the deletion or silencing of the histone modifiers MLL3/MML1 can positively regulate PD-L1 expression. Epigenetic drugs (EDs) may be promising in reprogramming tumor cells, reversing epigenetic modifications, and cancer immune evasion. EDs promoting a chromatin-inactive transcriptional state (such as bromodomain or p300/CBP inhibitors) downregulated PD-L1, while EDs favoring a chromatin-active state (i.e., histone deacetylase inhibitors) increased PD-L1 expression. miRNAs can regulate PD-L1 at a post-transcriptional level. miR-195/miR-16 were negatively associated with PD-L1 expression and positively correlated to longer biochemical recurrence-free survival; they also enhanced the radiotherapy efficacy in PC cell lines. miR-197 and miR-200a-c positively correlated to PD-L1 mRNA levels and inversely correlated to the methylation of PD-L1 promoter in a large series. miR-570, miR-34a and miR-513 may also be involved in epigenetic regulation.
Topics: Animals; B7-H1 Antigen; Cell Line, Tumor; CpG Islands; DNA Methylation; Epigenesis, Genetic; Gene Expression; Gene Expression Regulation, Neoplastic; Histone Code; Histones; Humans; Male; MicroRNAs; Promoter Regions, Genetic; Prostatic Neoplasms
PubMed: 34830196
DOI: 10.3390/ijms222212314 -
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 -
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