VHL mosaicism: the added value of multi-tissue analysis.
Ontology highlight
ABSTRACT:
SUBMITTER: Oldfield LE
PROVIDER: S-EPMC8933488 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
Publications
VHL mosaicism: the added value of multi-tissue analysis.
Oldfield Leslie E LE Grzybowski Jessica J Grenier Sylvie S Chao Elizabeth E Downs Gregory S GS Farncombe Kirsten M KM Stockley Tracy L TL Mete Ozgur O Kim Raymond H RH
NPJ genomic medicine 20220318 1
Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95-100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, ...[more]
Similar Datasets
Project description:BackgroundThough germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management.MethodsParticipants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories.ResultsAmong 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001), comparing germline with PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed, paraffin imbedded tissues demonstrated low variance (SE, 3%; P = 0.993) for TP53 variant allele fraction, with no significant difference (P = 0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in seven, ACE for 25, and three were indeterminate. Additional CH variants were detected in six ACE and two germline cases.ConclusionsWe demonstrated an effective approach and tools for discerning germline TP53 status.ImpactDiscernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.
| S-EPMC9866580 | biostudies-literature
Project description:AimNurse practitioners' added value is often mentioned in publications, but there is no consensus on what value is being added, what value is being added to, and in comparison with what can be considered to be an added value. A concept analysis was conducted to clarify the attributes, antecedents and meaning and better understand the Nurse practitioners' added value.DesignRodgers' evolutionary concept analysis.MethodsWe selected 16 studies from CINAHL, PubMed, Embase and Medline to conduct a thematic analysis, considering the date, location and discipline of publications.ResultsNurse practitioners' added value include: skills and competencies, activities performed, positive outcomes, and positive role perceptions, and antecedents and consequences were also identified. Nurse practitioners' added value is context-dependent and is often understood by comparing it to a context prior to implementation or other professional roles.
| S-EPMC10006655 | biostudies-literature
Project description:ObjectivesThere are multiple nationally representative databases that support epidemiologic and outcomes research, and it is unknown whether an otolaryngology-specific resource would prove indispensable or superfluous. Therefore, our objective was to determine the feasibility of analyses in the National Ambulatory Medical Care Survey (NAMCS) and National Hospital Ambulatory Medical Care Survey (NHAMCS) databases as compared with the otolaryngology-specific Creating Healthcare Excellence through Education and Research (CHEER) database.Study designParallel analyses in 2 data sets.SettingAmbulatory visits in the United States.Subjects and methodsTo test a fixed hypothesis that could be directly compared between data sets, we focused on a condition with expected prevalence high enough to substantiate availability in both. This query also encompassed a broad span of diagnoses to sample the breadth of available information. Specifically, we compared an assessment of suspected risk factors for sensorineural hearing loss in subjects 0 to 21 years of age, according to a predetermined protocol. We also assessed the feasibility of 6 additional diagnostic queries among all age groups.ResultsIn the NAMCS/NHAMCS data set, the number of measured observations was not sufficient to support reliable numeric conclusions (percentage standard error among risk factors: 38.6-92.1). Analysis of the CHEER database demonstrated that age, sex, meningitis, and cytomegalovirus were statistically significant factors associated with pediatric sensorineural hearing loss (P < .01). Among the 6 additional diagnostic queries assessed, NAMCS/NHAMCS usage was also infeasible; the CHEER database contained 1585 to 212,521 more observations per annum.ConclusionAn otolaryngology-specific database has added utility when compared with already available national ambulatory databases.
| S-EPMC5072747 | biostudies-literature
Project description:ObjectivesTo determine the diagnostic ability of cervical mucosa radiomics signature of sagittal T2WI and T1 contrast-enhanced (CE) imaging in detecting early-stage cervical cancers with negative MRI.MethodsPreoperative images of postoperative pathology confirmed early-stage cervical cancer patients and normal cervix patients admitted to our hospital between January 2013 and December 2020 were retrospectively reviewed. Patients with cancer signals on T2WI, T1CE and DWI were deleted. Regions of interests (ROIs) were delineated on cervical mucosa (from cervical canal to cervical dome) with 5 mm width on sagittal T2WI and T1CE. The maximum-relevance and minimumredundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) methods were used for the calculation of radiomics signature scores. Diagnostic performance was assessed and compared between radiomics prediction models (model 1: T1CE; model 2: T2WI; model 3: model one combined with model 2). Differential diagnostic ability of radiomics signature in detecting lymphatic vascular space invasion (LVSI) was further explored.ResultsDiagnostic performance of model three was higher than model 1 and model 2 both in primary (model 3 0.874, model 1 0.857, model 2 0.816) and validation (model 3 0.853, model 1 0.847, model 2 0.634) cohorts. Model 3 showed statistical diagnostic difference compared with model 2 (primary p = 0.008, validation p = 0.000). However, the diagnostic improvement ability of model 3 showed no statistical difference compared with model 1 (primary p = 0.351, validation p = 0.739). Diagnostic efficiency of model 3 in detecting LVSI was not apparent (AUC 0.64).ConclusionsRadiomics analysis of cervical mucosa combining T1CE and T2WI is promising for predicting MRI invisible early-stage cervical cancers, however further ability in detecting LVSI was not apparent.Advances in knowledgeConventional MRI was originally defined as meaningless in very early-stage cervical cancers. However, whether MRI radiomics analysis of cervical mucosa can detecting tiny changes of invisible early stage cervical cancers has not been researched yet.
| S-EPMC10993977 | biostudies-literature
Project description:Over a decade ago, we introduced Anne O'Tate, a free, public web-based tool http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/AnneOTate.cgi to support user-driven summarization, drill-down and mining of search results from PubMed, the leading search engine for biomedical literature. A set of hotlinked buttons allows the user to sort and rank retrieved articles according to important words in titles and abstracts; topics; author names; affiliations; journal names; publication year; and clustered by topic. Any result can be further mined by choosing any other button, and small search results can be expanded to include related articles. It has been deployed continuously, serving a wide range of biomedical users and needs, and over time has also served as a platform to support the creation of new tools that address additional needs. Here we describe the current, greatly expanded implementation of Anne O'Tate, which has added additional buttons to provide new functionalities: We now allow users to sort and rank search results by important phrases contained in titles and abstracts; the number of authors listed on the article; and pairs of topics that co-occur significantly more than chance. We also display articles according to NLM-indexed publication types, as well as according to 50 different publication types and study designs as predicted by a novel machine learning-based model. Furthermore, users can import search results into two new tools: e) Mine the Gap!, which identifies pairs of topics that are under-represented within set of the search results, and f) Citation Cloud, which for any given article, allows users to visualize the set of articles that cite it; that are cited by it; that are co-cited with it; and that are bibliographically coupled to it. We invite the scientific community to explore how Anne O'Tate can assist in analyzing biomedical literature, in a variety of use cases.
| S-EPMC7939269 | biostudies-literature
Project description:BackgroundMedical schools are reported to be less accessible to students with non-traditional backgrounds. These students face barriers when applying for and transitioning to medical school, which may be reduced by offering free preparatory activities. By equalizing access to resources, these activities are expected to reduce disparities in selection outcomes and early academic performance. In the present study, four free institutionally-provided preparatory activities were evaluated by comparing the demographic composition of participating and non-participating applicants. Additionally, the association between participation and selection outcomes and early academic performance was investigated for subgroups (based on sex, migration background and parental education).MethodsParticipants were applicants to a Dutch medical school in 2016-2019 (N = 3592). Free preparatory activities included Summer School (N = 595), Coaching Day (N = 1794), Pre-Academic Program (N = 217), and Junior Med School (N = 81), supplemented with data on participation in commercial coaching (N = 65). Demographic compositions of participants and non-participants were compared using chi-squared tests. Regression analyses were performed to compare selection outcomes (curriculum vitae [CV], selection test score, probability of enrolment) and early academic performance (first-course grade) between participants and non-participants of demographic subgroups, controlling for pre-university grades and participation in other activities.ResultsGenerally, no differences in sociodemographic compositions of participants and non-participants were found, but males participated less often in Summer School and Coaching Day. Applicants with a non-Western background participated less often in commercial coaching, but the overall participation rate was low and participation had negligible effects on selection outcomes. Participation in Summer School and Coaching Day were stronger related with selection outcomes. In some cases, this association was even stronger for males and candidates with a migration background. After controlling for pre-university grades, none of the preparatory activities were positively associated with early academic performance.ConclusionsFree institutionally-provided preparatory activities may contribute to student diversity in medical education, because usage was similar across sociodemographic subgroups, and participation was positively associated with selection outcomes of underrepresented and non-traditional students. However, since participation was not associated with early academic performance, adjustments to activities and/or curricula are needed to ensure inclusion and retention after selection.
| S-EPMC10053372 | biostudies-literature
Project description:The multi-dimensional benefits offered by the manufacturing sector in economic growth and development make academicians and policymakers to consider this sector still as an engine of growth. The unique qualities of this sector occupy a predominant place in the development policies around the world. Against these insights gained from economic literature, the study empirically investigates the role of energy, human capital, finance and technology in influencing manufacturing value-added in an endogenous growth framework by assessing short-run and long-run relation through ARDL bounds test approach followed by VECM causality test. The results testify the existence of energy-led, finance-led (supply leading), technology-led, and human capital-led growth hypotheses. These results give important insights and directions to have long term well-framed policy perspectives to develop financial institutions, the uninterrupted energy flow to the manufacturing sector, a blend of education and skill intensive programs and, an import strategy specially designed to obtain the spillover benefit of foreign technology.
| S-EPMC7350157 | biostudies-literature
Project description:Understanding causal relationships between genotypes and phenotypes is a long-standing aim in genetics. In addition to high-throughput technologies that allow the measurement of many DNA variants it is possible to measure gene expression in specific tissues using array technology. "Systems genetics" is an emerging discipline that combines dense data on genotypes, gene expression, and outcome phenotypes to answer fundamental questions about causal pathways from genotype to phenotype. A recent paper by Chen et al. [Mol. Syst. Biol. 5, 310 (2009)] addressed the question of whether relative levels of mRNA expression help to elucidate causal paths from genotype to phenotype, using drug resistance in yeast as a model. The authors show that data on genetic markers and on gene expression, measured in a drug-free environment, can be combined to predict the growth of a yeast strain in the presence of a drug. They argue that their prediction can be used to identify causal pathways and for a subset of the genes used in prediction, the authors demonstrate that these genes cause an effect on drug sensitivity by deleting the gene or overexpressing it or swapping alleles between strains of yeast. This approach can also be applied to other species, including humans, and may become a tool in the study of personalized medicine.
| S-EPMC2880025 | biostudies-other
Project description:BackgroundSubclinical atherosclerosis may result in fatal cardiovascular (CV) events, but the underlying mechanisms and molecular players leading to disease are not entirely understood. Thus, novel approaches capable of identifying the factors involved in pathological progression and providing a better understanding of the subjacent mechanisms are needed. Extracellular vesicles (EVs) have been shown to have numerous biological functions, and their metabolome has recently generated interest as a source of novel biomarkers. The metabolic content of the exosomes has been so far unexplored in cardiovascular disease (CVD), and here, we developed an analytical strategy aimed at probing urinary exosomal metabolite content and its association to CV risk.ResultsDirect analysis of the exosomes without metabolite extraction was evaluated by high-resolution magic angle spinning (1H HR-MAS). Other two methodologies for the analysis of exosomal metabolites by 1H NMR were set up, based on methanol or organic solvents sequential extraction. The three methods were compared in terms of the number of detected signals and signal to noise ratio (S/N). The methanol method was applied to identify altered metabolites in the urinary exosomes of subjects with programmed coronary artery by-pass grafting (CABG) versus a control group. Target mass spectrometry (MS) was also performed for differential analysis. The clinical performance of exosomal metabolites of interest in CVD was investigated, and the added value of the exosomes compared to urine analysis was evaluated. Based on S/N ratio, simplicity, reproducibility, and quality of the spectrum, the methanol method was chosen for the study in CVD. A cardiometabolic signature composed by 4-aminohippuric acid, N-1-methylnicotinamide, and citric acid was identified in urinary exosomes. Directly in urine, 4-aminohippuric acid and citric acid do not show variation between groups and changes in N-1-methylnicotinamide are less pronounced, proving the added value of exosomes.ConclusionsWe set up a novel methodology to analyze metabolic alterations in urinary exosomes and identified a cardiometabolic signature in these microvesicles. This study constitutes the first evidence of a role for the exosomal metabolism in CVD and demonstrates the possibility to evaluate the urinary exosomal metabolic content by NMR and MS.
| S-EPMC7737341 | biostudies-literature
Project description:Background & objectives: Despite the wide interest surrounding drug repurposing, no common terminology has been yet agreed for these products and their full potential value is not always recognised and rewarded, creating a disincentive for further development. The objectives of the present study were to assess from a wide perspective which value drug repurposing might bring to society, but also to identify key obstacles for adoption of these medicines and to discuss policy recommendations. Methods: A preliminary comprehensive search was conducted to assess how the concept of drug repurposing was described in the literature. Following completion of the literature review, a primary research was conducted to get perspective of various stakeholders across EU member states on drug repurposing (healthcare professionals, regulatory authorities and Health Technology Assessment (HTA) bodies/payers, patients, and representatives of the pharmaceutical industry developing medicines in this field). Ad hoc literature review was performed to illustrate, when appropriate, statements of the various stakeholders. Results: Various nomenclatures have been used to describe the concept of drug repurposing in the literature, with more or less broad definitions either based on outcomes, processes, or being a mix of both. In this context, Medicines for Europe (http://www.medicinesforeurope.com/value-added-medicines/) established one single terminology for these medicines, known as value added medicines, defined as 'medicines based on known molecules that address healthcare needs and deliver relevant improvements for patients, healthcare professionals and/or payers'. Stakeholder interviews highlighted three main potential benefits for value added medicines: (1) to address a number of medicine-related healthcare inefficiencies related to irrational use of medicines, non-availability of appropriate treatment options, shortage of mature products, geographical inequity in medicine access; (2) to improve healthcare system efficiency; and (3) to contribute to sustainability of healthcare systems through economic advantages. Current HTA framework, generic stigma, and pricing rules, such as internal reference pricing or tendering processes in place in some countries, were reported as the current key hurdles preventing the full recognition of value added medicines' benefits, discouraging manufacturers from bringing such products to the market. Discussion & conclusions: There is currently a gap between increasing regulatory authority interest in capturing value added medicines' benefits and the resistance of HTA bodies/payers, who tend to ignore this important segment of the pharmaceutical field. This situation calls for policy changes to foster appropriate incentives to enhance value recognition of value added medicines and deliver the expected benefit to society. Policy changes from HTA perspective should include: absence of any legislative barriers preventing companies from pursuing HTA; HTA requirements proportionate to potential reward; HTA decision-making framework taking into account the specific characteristics of value added medicines; eligibility for early HTA dialogues; Policy changes from pricing perspective should encompass: tenders/procurement policies allowing differentiation from generic medicines; eligibility for early entry agreement; non-systematic implementation of external and internal reference pricing policies; recognition of indication-specific pricing. At the same time, the pharmaceutical industry should engage all the stakeholders (patients, healthcare providers, HTA bodies/payers) in early dialogues to identify their expectations and to ensure the developed value added medicines address their needs.
| S-EPMC5328340 | biostudies-literature