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Cells Jun 2022In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 () knockout mouse models, we have learnt much about the structure of this... (Review)
Review
In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 () knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver-Russell and Beckwith-Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of -linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of defects in these patients.
Topics: Animals; Beckwith-Wiedemann Syndrome; Epigenomics; Genomic Imprinting; Humans; Insulin-Like Growth Factor II; Mice; Silver-Russell Syndrome
PubMed: 35741015
DOI: 10.3390/cells11121886 -
Current Opinion in Pediatrics Dec 2020Mammals have two complete sets of chromosomes, one from each parent with equal autosomal gene expression. Less than one percentage of human genes are imprinted or show... (Review)
Review
PURPOSE OF REVIEW
Mammals have two complete sets of chromosomes, one from each parent with equal autosomal gene expression. Less than one percentage of human genes are imprinted or show expression from only one parent without changing gene structure, usually by DNA methylation, but reversible in gametogenesis. Many imprinted genes affect fetal growth and development accounting for several human disorders reviewed in this report.
RECENT FINDINGS
Disorders include Prader-Willi and Angelman syndromes, the first examples of imprinting errors in humans, chromosome 15q11.2-q13.3 duplication, Silver-Russell syndrome, Beckwith-Weidemann syndrome, GNAS gene-related inactivation disorders (e.g. Albright hereditary osteodystrophy), uniparental chromosome 14 disomy, chromosome 6q24-related transient neonatal diabetes mellitus, parent of origin effects in 15q11.2 BP1-BP2 deletion (Burnside-Butler) syndrome and 15q11-q13 single gene imprinted disorders.
SUMMARY
Periconceptional and intrauterine life can be influenced by environmental factors and nutrition impacting DNA methylation. This process not only alters development of the fetus, but pregnancy complications may result from large fetal size. Epigenetic processes control imprinted gene functions and regulation with susceptibility to diseases as described. A better understanding of these processes will impact on care and treatment of affected individuals.
Topics: Chromosome Disorders; Humans
PubMed: 33148967
DOI: 10.1097/MOP.0000000000000965 -
The New England Journal of Medicine Feb 2021Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.
METHODS
This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2.
RESULTS
The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.
CONCLUSIONS
The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
Topics: 2019-nCoV Vaccine mRNA-1273; Adolescent; Adult; Aged; COVID-19; COVID-19 Vaccines; Female; Humans; Incidence; Male; Middle Aged; Patient Acuity; SARS-CoV-2; Single-Blind Method; Spike Glycoprotein, Coronavirus; Treatment Outcome; Young Adult
PubMed: 33378609
DOI: 10.1056/NEJMoa2035389 -
The New England Journal of Medicine Sep 2009Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.
METHODS
In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.
RESULTS
At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.
CONCLUSIONS
In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)
Topics: Acute Coronary Syndrome; Adenosine; Aged; Clopidogrel; Double-Blind Method; Dyspnea; Electrocardiography; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2 Receptor Antagonists; Stroke; Ticagrelor; Ticlopidine
PubMed: 19717846
DOI: 10.1056/NEJMoa0904327 -
Molecular Syndromology Jul 2016Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting... (Review)
Review
Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting disorders. The expression of both syndromes usually depends on the parental origin of the chromosome in which the imprinted genes reside. SRS is characterized by severe intrauterine and postnatal growth retardation with various additional clinical features such as hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies. BWS is an overgrowth syndrome with many additional clinical features such as macroglossia, organomegaly, and an increased risk of childhood tumors. Both SRS and BWS are clinically and genetically heterogeneous, and for clinical diagnosis, different diagnostic scoring systems have been developed. Six diagnostic scoring systems for SRS and 4 for BWS have been previously published. However, neither syndrome has common consensus diagnostic criteria yet. Most cases of SRS and BWS are associated with opposite epigenetic or genetic abnormalities in the 11p15 chromosomal region leading to opposite imbalances in the expression of imprinted genes. SRS is also caused by maternal uniparental disomy 7, which is usually identified in 5-10% of the cases, and is therefore the first imprinting disorder that affects 2 different chromosomes. In this review, we describe in detail the clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS.
PubMed: 27587987
DOI: 10.1159/000447413 -
The New England Journal of Medicine Jun 2015Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.
METHODS
We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.
RESULTS
The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.
CONCLUSIONS
When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).
Topics: Acute Coronary Syndrome; Aged; Anticholesteremic Agents; Azetidines; Cardiovascular Diseases; Cholesterol, LDL; Double-Blind Method; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kaplan-Meier Estimate; Male; Middle Aged; Simvastatin; Triglycerides
PubMed: 26039521
DOI: 10.1056/NEJMoa1410489 -
Epigenomics Apr 2016Silver-Russell syndrome is a clinically and genetically heterogeneous disorder, characterized by prenatal and postnatal growth restriction, relative macrocephaly, body... (Review)
Review
Silver-Russell syndrome is a clinically and genetically heterogeneous disorder, characterized by prenatal and postnatal growth restriction, relative macrocephaly, body asymmetry and characteristic facial features. It is one of the imprinting disorders, which results as a consequence of aberrant imprinted gene expressions. Currently, maternal uniparental disomy of chromosome 7 accounts for approximately 10% of Silver-Russell syndrome cases, while ~50% of patients have hypomethylation at imprinting control region 1 at chromosome 11p15.5 locus, leaving ~40% of cases with unknown etiologies. This review aims to provide a comprehensive list of molecular defects in Silver-Russell syndrome reported to date and to highlight the importance of multiple-loci/tissue testing and trio (both parents and proband) screening. The epigenetic and phenotypic overlaps with other imprinting disorders will also be discussed.
Topics: Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 7; DNA Methylation; Genomic Imprinting; Humans; Silver-Russell Syndrome; Uniparental Disomy
PubMed: 27066913
DOI: 10.2217/epi-2015-0010 -
Pediatric Endocrinology, Diabetes, and... 2015Silver-Russell syndrome (SRS) is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alternations. It is characterized by prenatal and... (Review)
Review
Silver-Russell syndrome (SRS) is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alternations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry. About 40-60% of cases are caused by hypomethylation of 11p.15.5 Imprinting Centre Region 1 (ICR1) on the paternal chromosome, and maternal uniparental disomy for chromosome 7 (UPD(7)mat) is found in 5-10% of cases. There are suggested correlations between genotype and the phenotype. Psychomotor development may be delayed, usually mildly, with school difficulties and speech delay more common in patients with UPD(7)mat. Children with 11p15 hypomethylation are shorter and lighter at birth in comparison to children with UPD(7)mat, however further deceleration tends to be more apparent in the latter group. The onset of puberty tends to occur early, with acceleration of bone age, resulting in less apparent growth spurt. Failure to thrive and feeding problems are characteristic for the infant period, and further development of a child may be conditioned by additional congenital defects.
Topics: Adolescent; Child; Child, Preschool; Chromosomes, Human, Pair 11; Chromosomes, Human, Pair 7; Epigenomics; Female; Genetic Background; Genetic Predisposition to Disease; Genomic Imprinting; Humans; Infant; Male; Silver-Russell Syndrome
PubMed: 26615046
DOI: 10.18544/PEDM-20.03.0009