RESUMO
Epidermolysis bullosa (EB) is an umbrella term for a group of rare inherited skin disorders characterised by mucocutaneous fragility. Patients suffer from blisters and chronic wounds that arise spontaneously or following minor mechanical trauma, often resulting in inflammation, scarring and fibrosis due to poor healing. The recessive form of dystrophic EB (RDEB) has a particularly severe phenotype and is caused by mutations in the COL7A1 gene, encoding the collagen VII protein, which is responsible for adhering the epidermis and dermis together. One of the most feared and devastating complications of RDEB is the development of an aggressive form of cutaneous squamous cell carcinoma (cSCC), which is the main cause of mortality in this patient group. However, pathological drivers behind the development and progression of RDEB-associated cSCC (RDEB-cSCC) remain somewhat of an enigma, and the evidence to date points towards a complex process. Currently, there is no cure for RDEB-cSCC, and treatments primarily focus on prevention, symptom management and support. Therefore, there is an urgent need for a comprehensive understanding of this cancer's pathogenesis, with the aim of facilitating the discovery of drug targets. This review explores the current knowledge of RDEB-cSCC, emphasising the important role of the immune system, genetics, fibrosis, and the tumour-promoting microenvironment, all ultimately intricately interconnected.
Assuntos
Carcinoma de Células Escamosas , Colágeno Tipo VII , Epidermólise Bolhosa Distrófica , Neoplasias Cutâneas , Humanos , Epidermólise Bolhosa Distrófica/genética , Epidermólise Bolhosa Distrófica/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/imunologia , Colágeno Tipo VII/genética , Mutação , Animais , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Fibrose , Genes RecessivosRESUMO
The evidence for a role of somatic mutations, including copy-number variants (CNVs), in neurodegeneration has increased in the last decade. However, the understanding of the types and origins of these mutations, and their exact contributions to disease onset and progression, is still in its infancy. The use of single-cell (or nuclear) whole-genome sequencing (scWGS) has emerged as a powerful tool to answer these questions. In the present chapter, we provide laboratory and bioinformatic protocols used successfully in our lab to detect megabase-scale CNVs in single cells from multiple system atrophy (MSA) human postmortem brains, using immunolabeling prior to selection of nuclei for whole-genome amplification (WGA). We also present an unpublished comparison of scWGS generated from the same control substantia nigra (SN) sample, using the latest versions of popular WGA chemistries, MDA and PicoPLEX. We have used this protocol to focus on brain cell types most relevant to synucleinopathies (dopaminergic [DA] neurons in Parkinson's disease [PD] and oligodendrocytes in MSA), but it can be applied to any tissue and/or cell type with appropriate markers.
Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , Humanos , Variações do Número de Cópias de DNA , Sequenciamento Completo do Genoma , Encéfalo/metabolismo , Atrofia de Múltiplos Sistemas/genética , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/metabolismoAssuntos
Infecções por Coronavirus/epidemiologia , Educação Médica/organização & administração , Inovação Organizacional , Pneumonia Viral/epidemiologia , Betacoronavirus , COVID-19 , Controle de Doenças Transmissíveis/métodos , Infecções por Coronavirus/transmissão , Humanos , Pandemias , Pneumonia Viral/transmissão , SARS-CoV-2 , Desenvolvimento de Pessoal/organização & administração , Ensino/organização & administração , Reino UnidoRESUMO
BACKGROUND: In the UK there is limited coverage of antimicrobial stewardship across postgraduate curricula and evidence that final year medical students have insufficient and inconsistent antimicrobial stewardship teaching. A national undergraduate curriculum for antimicrobial resistance and stewardship is required to standardize an adequate level of understanding for all future doctors. OBJECTIVES: To provide a UK national consensus on competencies for antimicrobial resistance and stewardship for undergraduate medical education. METHODS: Using the modified Delphi method over two online survey rounds, an expert panel comprising leads for infection teaching from 25 UK medical schools reviewed competency descriptors for antimicrobial resistance and stewardship education. RESULTS: There was a response rate of 100% with all 28 experts who agreed to take part completing both survey rounds. Following the first-round survey, of the initial 55 descriptors, 43 reached consensus (78%). The second-round survey included the 12 descriptors from the first round in which agreement had not been reached, four amended descriptors and 12 new descriptors following qualitative feedback from the panel members. Following the second-round survey, a total of 58 consensus-based competency descriptors within six overarching domains were identified. CONCLUSIONS: The consensus-based competency descriptors defined here can be used to inform standards, design curricula, develop assessment tools and direct UK undergraduate medical education.
