scholarly journals How many samples are needed to infer truly clonal mutations from heterogenous tumours?

2019 ◽  
Author(s):  
Luka Opasic ◽  
Da Zhou ◽  
Benjamin Werner ◽  
David Dingli ◽  
Arne Traulsen
Keyword(s):  
Treatment Strategies ◽  
Epigenetic Alterations ◽  
Sampling Protocols ◽  
Underlying Causes ◽  
Informed Treatment ◽  
Sampling Biases ◽  
Clonal Mutation ◽  
Larger Sample ◽  
Main Factor ◽  
The Ideal

AbstractBackgroundModern cancer treatment strategies aim to target tumour specific genetic (or epigenetic) alterations. Treatment response improves if these alterations are clonal, i.e. present in all cancer cells within tumours. However, the identification of truly clonal alterations is impaired by the tremendous intra-tumour genetic heterogeneity and unavoidable sampling biases.MethodsHere, we investigate the underlying causes of these spatial sampling biases and how the distribution and sizes of biopsies in sampling protocols can be optimized to minimize such biases.ResultsWe find that in the ideal case, less than a handful of samples can be enough to infer truly clonal mutations. The frequency of the largest sub-clone at diagnosis is the main factor determining the accuracy of truncal mutation estimation in structured tumours. If the first sub-clone is dominating the tumour, higher spatial dispersion of samples and larger sample size can increase the accuracy of the estimation. In such an improved sampling scheme, fewer samples will enable the detection of truly clonal alterations with the same probability.ConclusionsTaking spatial tumour structure into account will decrease the probability to misclassify a sub-clonal mutation as clonal and promises better informed treatment decisions.

scholarly journals Neuroblastoma and the epigenome

2021 ◽  
Author(s):  
Irfete S. Fetahu ◽  
Sabine Taschner-Mandl
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Disease Diagnosis ◽  
Dna Methyltransferases ◽  
Epigenetic Alterations ◽  
Aberrant Expression ◽  
Tet Proteins ◽  
Relative Paucity ◽  
Underlying Causes ◽  
Aberrant Dna Methylation

AbstractNeuroblastoma (NB) is a pediatric cancer of the sympathetic nervous system and one of the most common solid tumors in infancy. Amplification of MYCN, copy number alterations, numerical and segmental chromosomal aberrations, mutations, and rearrangements on a handful of genes, such as ALK, ATRX, TP53, RAS/MAPK pathway genes, and TERT, are attributed as underlying causes that give rise to NB. However, the heterogeneous nature of the disease—along with the relative paucity of recurrent somatic mutations—reinforces the need to understand the interplay of genetic factors and epigenetic alterations in the context of NB. Epigenetic mechanisms tightly control gene expression, embryogenesis, imprinting, chromosomal stability, and tumorigenesis, thereby playing a pivotal role in physio- and pathological settings. The main epigenetic alterations include aberrant DNA methylation, disrupted patterns of posttranslational histone modifications, alterations in chromatin composition and/or architecture, and aberrant expression of non-coding RNAs. DNA methylation and demethylation are mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) proteins, respectively, while histone modifications are coordinated by histone acetyltransferases and deacetylases (HATs, HDACs), and histone methyltransferases and demethylases (HMTs, HDMs). This article focuses predominately on the crosstalk between the epigenome and NB, and the implications it has on disease diagnosis and treatment.

Formalization as a tool for environmental peacebuilding? Artisanal and small-scale mining in Liberia and Sierra Leone

2021 ◽  
Vol 97 (1) ◽  
pp. 35-55
Author(s):  
Christina Ankenbrand ◽  
Abrina Welter ◽  
Nina Engwicht
Keyword(s):  
Sierra Leone ◽  
Well Being ◽  
Small Scale ◽  
Transformative Change ◽  
Community Based ◽  
Community Benefits ◽  
Sustainable Peace ◽  
Underlying Causes ◽  
Ethical Sourcing ◽  
The Ideal

Abstract Artisanal and small-scale mining (ASM) has long been a vital source of livelihoods for rural populations in the global South. Yet, it has also been linked to a host of social, political and environmental adversities, including violent conflict. As environmental peacebuilding increasingly stresses the importance of livelihood improvement as a means of fostering peace in conflict-affected extractive societies, ASM formalization has been identified as a solution to mitigate the sector's challenges, thereby addressing underlying causes of conflict. This article critically investigates the contribution of ASM formalization to sustainable peace by focusing on its impact on the livelihood dimension of peacebuilding. It analyses the livelihood impact of three formalization interventions in the diamond sectors of two countries: cooperatives in Liberia, and, in Sierra Leone, ethical sourcing schemes and a community-based natural resource management initiative. In line with calls for a paradigm shift from a narrow legalization-centred understanding of formalization to a broader approach that accounts for livelihood quality, the analysis presented here focuses on interventions that were informed by the ideal of improving the well-being of ASM workers and communities. We propose three pathways through which ASM formalization could potentially contribute to livelihood enhancement: income security, working conditions and community benefits. Based on fieldwork, this article highlights the challenges of generating livelihood improvements through formalization. Even when specifically designed to address the needs of ASM communities, during implementation, they risk prioritizing a narrow conceptualization of formalization and thus failing to become a conductor of transformative change.

scholarly journals The ideal mHealth-application for rheumatoid arthritis: qualitative findings from stakeholder focus groups

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Michaël Doumen ◽  
René Westhovens ◽  
Sofia Pazmino ◽  
Delphine Bertrand ◽  
Veerle Stouten ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Focus Groups ◽  
Patient Empowerment ◽  
Treatment Strategies ◽  
Systems Design ◽  
Ease Of Use ◽  
Task Support ◽  
Expected Benefits ◽  
Mhealth Apps ◽  
The Ideal

Abstract Background Shifts in treatment strategies for rheumatoid arthritis (RA) have made ambulatory care more labour-intensive. These developments have prompted innovative care models, including mobile health (mHealth) applications. This study aimed to explore the perceptions of mHealth-inexperienced stakeholders concerning these applications in RA care. Methods We performed a qualitative study by focus group interviews of stakeholders including RA patients, nurses specialised in RA care and rheumatologists. The qualitative analysis guide of Leuven (QUAGOL), which is based on grounded theory principles, was used to thematically analyse the data. In addition, the Persuasive Systems Design (PSD) model was used to structure recommended app-features. Results In total, 2 focus groups with nurses (total n = 16), 2 with patients (n = 17) and 2 with rheumatologists (n = 25) took place. Six overarching themes emerged from the analysis. Efficiency of care and enabling patient empowerment were the two themes considered as expected benefits of mHealth-use in practice by the stakeholders. In contrast, 4 themes emerged as possible barriers of mHealth-use: the burden of chronic app-use, motivational aspects, target group aspects, and legal and organisational requirements. Additionally, recommendations for an ideal mHealth-app could be structured into 4 domains (Primary Task Support, Dialogue Support, Social Support and System Credibility) according to the PSD-framework. Most recommended features were related to improving ease of use (Task Support) and System Credibility. Conclusions Although mHealth-apps were expected to improve care efficiency and stimulate patient empowerment, stakeholders were concerned that mHealth-app use could reinforce negative illness behaviour. For mHealth-apps to be successful in practice, challenges according to stakeholders were avoiding long-term poor compliance, finding the target audience and tailoring a legal and organisational framework. Finally, the ideal mHealth-application should above all be trustworthy and easy to use.

scholarly journals Genetic and Epigenetic Aspects of Atopic Dermatitis

2020 ◽  
Vol 21 (18) ◽  
pp. 6484 ◽  
Author(s):  
Bogusław Nedoszytko ◽  
Edyta Reszka ◽  
Danuta Gutowska-Owsiak ◽  
Magdalena Trzeciak ◽  
Magdalena Lange ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Treatment Strategies ◽  
Structural Proteins ◽  
Epigenetic Changes ◽  
Epigenetic Alterations ◽  
Adaptive Immune ◽  
Genes Encoding ◽  
Inflammatory Processes ◽  
Non Coding Rnas

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.

scholarly journals Multifocal Assessment Reveals Anemia-related Program Gaps and Implementation Challenges in Ghana (P10-088-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Brenda Abu ◽  
Rachel Stefanic ◽  
Olivia Garror ◽  
Nicole Buttner ◽  
Kingsley Pereko ◽  
...  
Keyword(s):  
Human Resources ◽  
Dietary Intake ◽  
Treatment Strategies ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Financial Investment ◽  
Prevention And Treatment ◽  
Childhood Anemia ◽  
Underlying Causes ◽  
Inadequate Dietary Intake

Abstract Objectives Despite existing program efforts in Ghana, incidence of childhood anemia remain high. This study describes existing childhood anemia prevention and treatment strategies and assessed implementation gaps. Methods A cross-sectional study using purposive sampling/snowballing technique identified organizations implementing childhood anemia prevention and treatment programs. Interview guides constructed around UNICEF's conceptual framework of malnutrition identified programs addressing each cause of anemia. Interviews were administered via in-person and phone in August 2018. Interviews were audio-recorded, transcribed, and coded/analyzed using Dedoose software version 8.1.8. Results Twenty-five officials from Universities (n = 2), local non-governmental (n = 4), government departments (n = 6) and international (n = 2) agencies completed interviews. Reported contextual immediate causes of anemia were malaria, diarrhea, worm infestation and inadequate dietary intake. All organizations implemented programs addressing ≥1 of the immediate causes, with many overlapping programs from different organizations addressing inadequate dietary intake in the same district. Government-assisted programs and Universities reported national scope; non-governmental/private organizations had regional/district focus. The contextual underlying causes reported were inadequate nutrition knowledge, food safety and environmental hygiene, food insecurity and health services. All organizations were implementing programs addressing ≥1 of these underlying causes. Few programs addressed the reported basic causes namely, inadequate human resources (n = 5) and housing/water/toilet facilities (n = 3) and poverty/financial resources (n = 2). Reported program gaps included inadequate human resources and scarce funding for projects. The main observed gap was insufficient communication and integration between programs implementer. Conclusions Multiple programs, sometimes with overlapping focus in the same region were addressing anemia. Re-designing programs to prioritize communication between current program may result in efficient use of limited funding and human resources. New programs may focus on improving financial investment in programs and more personnel. Funding Sources RIT Miller Chair Grant for Global Experiential Research.

scholarly journals Advances in CpG Island Methylator Phenotype Colorectal Cancer Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaofei Zhang ◽  
Wenjun Zhang ◽  
Pingan Cao
Keyword(s):  
Colorectal Cancer ◽  
Cpg Island ◽  
Treatment Strategies ◽  
Cancer Therapies ◽  
Chemotherapeutic Drugs ◽  
Epigenetic Alterations ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Molecular Phenotypes ◽  
Colorectal Cancer Patients

With the aging of the population, the incidence of colorectal cancer in China is increasing. One of the epigenetic alterations: CpG island methylator phenotype (CIMP) plays an important role in the incidence of colorectal cancer. Recent studies have shown that CIMP is closely related to some specific clinicopathological phenotypes and multiple molecular phenotypes in colorectal cancer. In this paper, the newest progress of CIMP colorectal cancer in chemotherapeutic drugs, targeted agents and small molecular methylation inhibitors are going to be introduced. We hope to provide potential clinical treatment strategies for personalized and precise treatment of colorectal cancer patients.

scholarly journals The Needle in the Haystack—Searching for Genetic and Epigenetic Differences in Monozygotic Twins Discordant for Tetralogy of Fallot

2020 ◽  
Vol 7 (4) ◽  
pp. 55
Author(s):  
Marcel Grunert ◽  
Sandra Appelt ◽  
Paul Grossfeld ◽  
Silke R. Sperling
Keyword(s):  
Tetralogy Of Fallot ◽  
High Throughput Sequencing ◽  
Heart Defects ◽  
Monozygotic Twins ◽  
Disease Status ◽  
Epigenetic Alterations ◽  
Structural Genomic ◽  
Genome Wide ◽  
Underlying Causes ◽  
The Impact

Congenital heart defects (CHDs) are the most common birth defect in human with an incidence of almost 1% of all live births. Most cases have a multifactorial origin with both genetics and the environment playing a role in its development and progression. Adding an epigenetic component to this aspect is exemplified by monozygotic twins which share the same genetic background but have a different disease status. As a result, the interplay between the genetic, epigenetic and the environmental conditions might contribute to the etiology and phenotype. To date, the underlying causes of the majority of CHDs remain poorly understood. In this study, we performed genome-wide high-throughput sequencing to examine the genetic, structural genomic and epigenetic differences of two identical twin pairs discordant for Tetralogy of Fallot (TOF), representing the most common cyanotic form of CHDs. Our results show the almost identical genetic and structural genomic identity of the twins. In contrast, several epigenetic alterations could be observed given by DNA methylation changes in regulatory regions of known cardiac-relevant genes. Overall, this study provides first insights into the impact of genetic and especially epigenetic factors underlying monozygotic twins discordant for CHD like TOF.

scholarly journals Transformation of fibroblast‐like synoviocytes in rheumatoid arthritis; from a friend to foe

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Mohammad Javad Mousavi ◽  
Jafar Karami ◽  
Saeed Aslani ◽  
Mohammad Naghi Tahmasebi ◽  
Arash Sharafat Vaziri ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Treatment Strategies ◽  
Oxygen Metabolism ◽  
Systemic Autoimmune Disease ◽  
Epigenetic Alterations ◽  
Pannus Formation ◽  
Type B ◽  
Comprehensive Understanding ◽  
Genetic Abnormalities ◽  
Fibroblast Like Synoviocytes

AbstractSwelling and the progressive destruction of articular cartilage are major characteristics of rheumatoid arthritis (RA), a systemic autoimmune disease that directly affects the synovial joints and often causes severe disability in the affected positions. Recent studies have shown that type B synoviocytes, which are also called fibroblast-like synoviocytes (FLSs), as the most commonly and chiefly resident cells, play a crucial role in early-onset and disease progression by producing various mediators. During the pathogenesis of RA, the FLSs’ phenotype is altered, and represent invasive behavior similar to that observed in tumor conditions. Modified and stressful microenvironment by FLSs leads to the recruitment of other immune cells and, eventually, pannus formation. The origins of this cancerous phenotype stem fundamentally from the significant metabolic changes in glucose, lipids, and oxygen metabolism pathways. Moreover, the genetic abnormalities and epigenetic alterations have recently been implicated in cancer-like behaviors of RA FLSs. In this review, we will focus on the mechanisms underlying the transformation of FLSs to a cancer-like phenotype during RA. A comprehensive understanding of these mechanisms may lead to devising more effective and targeted treatment strategies.

scholarly journals En plaget ungdomsgenerasjon?

2021 ◽  
pp. 207-229
Author(s):  
Ole Jacob Madsen ◽  
Tilmann von Soest
Keyword(s):  
Mental Health ◽  
Social Media ◽  
Psychological Distress ◽  
Life Skills ◽  
Mental Health Problems ◽  
Media Use ◽  
Gradual Increase ◽  
Anxiety And Depression ◽  
Underlying Causes ◽  
The Ideal

In this chapter we present an overview of the prevalence of and trends in psychological distress among Norwegian adolescents, including self-reported symptoms of anxiety and depression. We specifically highlight Ungdata surveys from 2010 to 2020, which show a gradual increase in mental health problems for both genders and particularly alarming measurements from 2015 onwards. We discuss different explanations for this increase, in particular social media use, school stress and social and economic inequality. Moreover, because psychological distress is assessed primarily via young people’s self-reporting, we inquire – in line with the ideal of reflexivity – whether an increased focus on young people’s mental health can become a self-fulfilling prophecy. Finally, we ask what should be done, and we discuss whether the introduction of the interdisciplinary topic health and life skills in Norwegian schools is in fact helpful. Our conclusion is that this measure may fail to properly address the most likely underlying causes for youths’ increased report of psychological distress, and effective measures will most likely have to involve political and economic resolutions.

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