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Clinics in Podiatric Medicine and... Oct 2021The chemical composition and thickness of nails are obstacles for treatments of various nail diseases, such as onychomycosis. Topical medications are currently the... (Review)
Review
The chemical composition and thickness of nails are obstacles for treatments of various nail diseases, such as onychomycosis. Topical medications are currently the preferred method of treatment because of reduced adverse systemic effects. However, penetration of the product from the nail plate into the nail bed continues to be an issue because of factors such as distance required to reach the target area, chemical barriers, and drug inactivation upon keratin binding. Beyond developing novel drugs, some studies have investigated mechanical and chemical methods to optimize drug delivery. The issue of nail diseases is still a challenge and requires multifactorial treatments.
Topics: Administration, Topical; Antifungal Agents; Humans; Nails; Onychomycosis; Penetrance
PubMed: 34538431
DOI: 10.1016/j.cpm.2021.06.004 -
JAMA May 2022
Topics: Genetic Predisposition to Disease; Humans; Mutation; Penetrance; Phenotype
PubMed: 35579644
DOI: 10.1001/jama.2022.4634 -
JAMA May 2022
Topics: Genetic Predisposition to Disease; Humans; Mutation; Penetrance; Phenotype
PubMed: 35579648
DOI: 10.1001/jama.2022.4631 -
Journal of Pediatric Ophthalmology and... 2024
Topics: Humans; Retinoblastoma; Penetrance; Retinal Neoplasms; Pedigree; Mutation
PubMed: 37489625
DOI: 10.3928/01913913-20230427-03 -
Genes Jun 2021The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants... (Review)
Review
The genetic landscape of Parkinson's disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.
Topics: Genetic Predisposition to Disease; Humans; Mutation; Parkinson Disease; Penetrance; Polymorphism, Single Nucleotide
PubMed: 34208795
DOI: 10.3390/genes12071006 -
American Journal of Human Genetics Jul 2012Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of...
Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer-susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes. We performed exome sequencing on 572 ClinSeq participants, and in 37 genes, we interpreted variants that cause high-penetrance cancer syndromes by using an algorithm that filtered results on the basis of mutation type, quality, and frequency and that filtered mutation-database entries on the basis of defined categories of causation. We identified 454 sequence variants that differed from the human reference. Exclusions were made on the basis of sequence quality (26 variants) and high frequency in the cohort (77 variants) or dbSNP (17 variants), leaving 334 variants of potential clinical importance. These were further filtered on the basis of curation of literature reports. Seven participants, four of whom were of Ashkenazi Jewish descent and three of whom did not meet family-history-based referral criteria, had deleterious BRCA1 or BRCA2 mutations. One participant had a deleterious SDHC mutation, which causes paragangliomas. Exome sequencing, coupled with multidisciplinary interpretation, detected clinically important mutations in cancer-susceptibility genes; four of such mutations were in individuals without a significant family history of disease. We conclude that secondary variants of high clinical importance will be detected at an appreciable frequency in exomes, and we suggest that priority be given to the development of more efficient modes of interpretation with trials in larger patient groups.
Topics: Aged; Algorithms; Atherosclerosis; Exome; Female; Genetic Predisposition to Disease; Genetic Variation; Humans; Incidental Findings; Male; Middle Aged; Mutation; Neoplasms; Pedigree; Penetrance; Sequence Analysis, DNA
PubMed: 22703879
DOI: 10.1016/j.ajhg.2012.05.021 -
Physiological Genomics Oct 2022Sequencing cancer predisposing genes (CPGs) in evocative patients (i.e., patients with personal and family history of multiple/early-onset/unusual cancers) allows... (Review)
Review
Sequencing cancer predisposing genes (CPGs) in evocative patients (i.e., patients with personal and family history of multiple/early-onset/unusual cancers) allows follow-up in their relatives to be adapted when a causative pathogenic variant is identified. Unfortunately, many evocative families remain unexplained. Part of this "missing heritability" could be due to CPG dysregulations caused by remote noncoding genomic alterations. Transcription levels are regulated through the ability of promoters to physically interact with their distant cis-regulatory elements. Three-dimensional chromatin contacts, mediated by a dynamic loop extrusion process, are uncovered by chromosome conformation capture (3C) and 3C-derived techniques, which have enabled the discovery of new pathological mechanisms in developmental diseases and cancers. High-penetrance cancer predisposition is caused by germline hereditary alterations otherwise found at the somatic level in sporadic cancers. Thus, data from both developmental diseases and cancers provide information about possible unknown cancer predisposition mechanisms. This mini-review aims to deduce from these data whether abnormal chromatin folding can cause high-penetrance cancer predisposition.
Topics: Chromatin; Genome; Humans; Neoplasms; Penetrance; Promoter Regions, Genetic
PubMed: 36036457
DOI: 10.1152/physiolgenomics.00052.2022 -
Genetics in Medicine : Official Journal... 2003Penetrance and expressivity have been defined through clinical experience. Although penetrance is often seen as the end of the spectrum of expressivity, penetrance and... (Review)
Review
Penetrance and expressivity have been defined through clinical experience. Although penetrance is often seen as the end of the spectrum of expressivity, penetrance and expressivity are considered as distinct phenomena. A review of the known mechanisms underlying either penetrance or expressivity reveals that in most of the cases the same explanation is true for both phenomena. Some of the known mechanisms include modifier genes, the influence of the allele in trans, sex, and environmental factors. Although rapid progress has been made in understanding of the basis of incomplete penetrance and the differences of expressivity, they still remain unknown for most of the genetic disorders. In recent years, it has become evident that there is much in common between the classical Mendelian traits in which the inheritance has been seen as "simple" and most of the common diseases in which the inheritance is "complex." In both cases genetic and/or environmental factors are acting in a complex way.
Topics: Environment; Gene Expression; Genetic Predisposition to Disease; Genomic Imprinting; Models, Genetic; Mosaicism; Penetrance; Polymorphism, Genetic; Sex Characteristics
PubMed: 14501829
DOI: 10.1097/01.gim.0000086478.87623.69 -
Advances in Experimental Medicine and... 2021Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance...
Susceptibility genes involved in disease etiology and prognosis are categorized into two groups: high penetrance genes (i.e., BRCA1, CHEK2, ATM, etc.) and low penetrance genes (i.e., NATs, GSTs, CYPs, etc., and variants identified by genome-wide association studies). Since low penetrance genes have high population attributable risk, the usefulness of those genes to research on breast cancer prevention is not small. In this chapter, the previous studies on low-penetrance genetic susceptibility through a candidate gene approach and genome-wide association of breast cancer were summarized. The contribution of low-penetrance susceptibility genes to the breast cancer risk prediction models will also be discussed on the utility in clinical or public health application.
Topics: Breast Neoplasms; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Penetrance
PubMed: 33983592
DOI: 10.1007/978-981-32-9620-6_22 -
Pulmonary Pharmacology & Therapeutics Feb 2020Plasma drug concentrations, spectrum of antibacterial activity and minimum inhibitory concentration (MIC) had been widely considered as markers of the efficacy of... (Review)
Review
Plasma drug concentrations, spectrum of antibacterial activity and minimum inhibitory concentration (MIC) had been widely considered as markers of the efficacy of antibiotics. Nonetheless, in several cases, antibiotics characterized by all these features were ineffective for the treatment of respiratory tract infections. A typical paradigm represented the case of patients with bronchiectasis who do not always benefit from antibiotics and thus experiencing increased sputum production, worse quality of life, more rapid forced expiratory volume in the first second (FEV1) decline, more frequent exacerbations and increased mortality rates, especially those with Pseudomonas aeruginosa (P. aeruginosa) chronic infection. Subsequently, penetrance of antibiotics in the epithelial lining fluid has gradually emerged as another key factor for the outcome of antibiotic treatment. Given that a plethora of antibiotics presented with poor or intermediate penetrance in the epithelial lining fluid, inhaled antibiotics targeting directly the site of infection emerged as a new option for patients with respiratory disorders including patients with bronchiectasis. This review article intends to summarize the current state of knowledge for the penetrance of antibiotics in the epithelial lining fluid and present results from clinical trials of inhaled antibiotics in patients with bronchiectasis of etiology other than cystic fibrosis.
Topics: Administration, Inhalation; Anti-Bacterial Agents; Bronchiectasis; Clinical Trials as Topic; Humans; Lung; Penetrance; Pseudomonas Infections; Respiratory Tract Infections
PubMed: 31891761
DOI: 10.1016/j.pupt.2019.101885