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1.
Nat Commun ; 11(1): 2768, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488016

RESUMO

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.


Assuntos
Contratura de Dupuytren/imunologia , Contratura de Dupuytren/metabolismo , Fibrose/imunologia , Fibrose/metabolismo , Células Estromais/metabolismo , Actinas/metabolismo , Biomarcadores/metabolismo , Quimiocinas CXC/metabolismo , Contratura de Dupuytren/patologia , Fibrose/patologia , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Medicina Molecular , Miofibroblastos/metabolismo , Tetraspaninas/metabolismo , Microambiente Tumoral/fisiologia
2.
Nat Commun ; 11(1): 1923, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317663

RESUMO

Drug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using 'evolutionary steering' to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108-109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Evolução Molecular , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Evolução Clonal , Biologia Computacional , Simulação por Computador , Gefitinibe/farmacologia , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Modelos Teóricos , Medicina Molecular , Piridonas/farmacologia , Pirimidinonas/farmacologia , Processos Estocásticos
3.
Nat Commun ; 11(1): 1733, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265441

RESUMO

Dysregulation of extracellular signal-regulated kinases (ERK1/2) is linked to several diseases including heart failure, genetic syndromes and cancer. Inhibition of ERK1/2, however, can cause severe cardiac side-effects, precluding its wide therapeutic application. ERKT188-autophosphorylation was identified to cause pathological cardiac hypertrophy. Here we report that interference with ERK-dimerization, a prerequisite for ERKT188-phosphorylation, minimizes cardiac hypertrophy without inducing cardiac adverse effects: an ERK-dimerization inhibitory peptide (EDI) prevents ERKT188-phosphorylation, nuclear ERK1/2-signaling and cardiomyocyte hypertrophy, protecting from pressure-overload-induced heart failure in mice whilst preserving ERK1/2-activity and cytosolic survival signaling. We also examine this alternative ERK1/2-targeting strategy in cancer: indeed, ERKT188-phosphorylation is strongly upregulated in cancer and EDI efficiently suppresses cancer cell proliferation without causing cardiotoxicity. This powerful cardio-safe strategy of interfering with ERK-dimerization thus combats pathological ERK1/2-signaling in heart and cancer, and may potentially expand therapeutic options for ERK1/2-related diseases, such as heart failure and genetic syndromes.


Assuntos
Cardiotoxicidade , Peptídeos Penetradores de Células/farmacologia , Dimerização , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Técnicas de Cultura de Células , Peptídeos Penetradores de Células/síntese química , Peptídeos Penetradores de Células/toxicidade , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Sistemas de Liberação de Medicamentos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Medicina Molecular , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
4.
Nat Rev Clin Oncol ; 17(1): 11-32, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31289352

RESUMO

The number of molecularly stratified treatment options available to patients with colorectal cancer (CRC) is increasing, with a parallel rise in the use of biomarkers to guide prognostication and treatment decision-making. The increase in both the number of biomarkers and their use has resulted in a progressively complex situation, evident both from the extensive interactions between biomarkers and from their sometimes complex associations with patient prognosis and treatment benefit. Current and emerging biomarkers also reflect the genomic complexity of CRC, and include a wide range of aberrations such as point mutations, amplifications, fusions and hypermutator phenotypes, in addition to global gene expression subtypes. In this Review, we provide an overview of current and emerging clinically relevant biomarkers and their role in the management of patients with CRC, illustrating the intricacies of biomarker interactions and the growing treatment opportunities created by the availability of comprehensive molecular profiling.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/terapia , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Humanos , Medicina Molecular/métodos , Prognóstico
6.
BMC Med Educ ; 19(1): 390, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31651301

RESUMO

BACKGROUND: Genetic testing rapidly penetrates into all medical specialties and medical students must acquire skills in this area. However, many of them consider it difficult. Furthermore, many find these topics less appealing and not connected to their future specialization in different fields of clinical medicine. Student-centred strategies such as problem-based learning, gamification and the use of real data can increase the appeal of a difficult topic such as genetic testing, a field at the crossroads of genetics, molecular biology and bioinformatics. METHODS: We designed an electronic teaching application which students registered in the undergraduate Medical Biology course can access online. A study was carried out to assess the influence of implementation of the new method. We performed pretest/posttest evaluation and analyzed the results using the sign test with median values. We also collected students' personal comments. RESULTS: The newly developed interactive application simulates the process of molecular genetic diagnostics of a hereditary disorder in a family. Thirteen tasks guide students through clinical and laboratory steps needed to reach the final diagnosis. Genetics and genomics are fields strongly dependent on electronic databases and computer-based data analysis tools. The tasks employ publicly available internet bioinformatic resources used routinely in medical genetics departments worldwide. Authenticity is assured by the use of modified and de-identified clinical and laboratory data from real families analyzed in our previous research projects. Each task contains links to databases and data processing tools needed to solve the task, and an answer box. If the entered answer is correct, the system allows the user to proceed to the next task. The solving of consecutive tasks arranged into a single narrative resembles a computer game, making the concept appealing. There was a statistically significant improvement of knowledge and skills after the practical class, and most comments on the application were positive. A demo version is available at https://medbio.lf2.cuni.cz/demo_m/ . Full version is available on request from the authors. CONCLUSIONS: Our concept proved to be appealing to the students and effective in teaching medical molecular genetics. It can be modified for training in the use of electronic information resources in other medical specialties.


Assuntos
Instrução por Computador , Educação de Graduação em Medicina/métodos , Testes Genéticos , Genética Médica/educação , Biologia Computacional/educação , Doenças Genéticas Inatas/diagnóstico , Humanos , Medicina Molecular/educação , Aprendizagem Baseada em Problemas , Ensino , Interface Usuário-Computador , Jogos de Vídeo
8.
Semin Diagn Pathol ; 36(6): 389-394, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31395291

RESUMO

Cryptogenic cirrhosis (CC) is defined as cirrhosis of unknown etiology despite extensive clinical, laboratory and pathologic work-up, and constitutes approximately 5-10% of all cirrhosis cases. Histologic examination can provide important clues and help identify the potential etiology of CC. Most CC cases can still be classified into four histologic patterns: hepatitic, steatotic, biliary, and patternless (bland). The use of genetic testing has significantly improved diagnostic ability and treatment, especially in pediatric patients with acute and chronic liver diseases. More recently, whole exome sequencing has been used for identifying genetic alterations that lead to a diagnosis in adults with liver disease of unknown etiology. Recent advances in genomic analysis has allowed the unraveling of the underlying etiology in a subset of CC cases, and also helped identify new disorders. Providing a diagnosis for these patients has several important implications for treatment, possible genetic counseling, and transplant eligibility. However, detailed clinical and histologic characterization of the patients still remains an important part of the CC work-up, since clinicopathologic and genomic correlation is crucial in making a diagnosis, or in some cases, discovery of a new entity. This article summarizes the main histologic findings that can be observed in CC cases, potential causes of CC, and recent advances in the field.


Assuntos
Genômica , Cirrose Hepática/congênito , Medicina Molecular , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cirrose Hepática/genética , Sequenciamento Completo do Exoma
10.
Trends Biotechnol ; 37(3): 234-237, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30100229

RESUMO

Clustered regularly interspaced short palindromic repeats (CRISPR) technology has enabled genetic engineering feats previously considered impracticable, offering great hopes for solutions to problems facing society. We consider it timely to highlight how CRISPR can benefit public health, medicine, and agriculture in sub-Saharan Africa (SSA) and offer recommendations for successful implementation.


Assuntos
Agricultura/métodos , Biotecnologia/métodos , Sistemas CRISPR-Cas , Edição de Genes/métodos , Medicina Molecular/métodos , África ao Sul do Saara , Agricultura/educação , Biotecnologia/educação , Medicina Molecular/educação
11.
Clin Transl Oncol ; 21(7): 954-959, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30565082

RESUMO

INTRODUCTION: Our aim is to find features that define prognosis in surgically resected ductal pancreatic adenocarcinoma readily accessible in everyday practice. MATERIALS AND METHODS: Longitudinal retrospective case series of pancreatic adenocarcinoma operated with a curative intent in a large tertiary hospital in Madrid between 2009 and 2015. RESULTS: 162 were enrolled. 40.8% survived less than 1 year. Multivariate Cox's regression model revealed that gender, presence of symptoms, T and N stage independently influenced progression-free survival, while overall survival was determined by gender, smoking, presence of symptoms and N stage. Logistic regression analysis revealed that only symptoms at diagnosis could predict death, while gender, symptoms, histopathological type, vessel invasion, T stage and necrosis could independently predict recurrence. DISCUSSION: Our series show that patients with symptomatic disease at the time of diagnosis and females showed a shorter progression-free and overall survival. We herein propose a regression model to predict outcome.


Assuntos
Adenocarcinoma/patologia , Carcinoma Ductal Pancreático/patologia , Medicina Molecular , Recidiva Local de Neoplasia/patologia , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/métodos , Adenocarcinoma/cirurgia , Idoso , Carcinoma Ductal Pancreático/cirurgia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Recidiva Local de Neoplasia/cirurgia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos
12.
Trends Biotechnol ; 37(1): 72-85, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30115375

RESUMO

In the past several years, single-molecule sequencing platforms, such as those by Pacific Biosciences and Oxford Nanopore Technologies, have become available to researchers and are currently being tested for clinical applications. They offer exceptionally long reads that permit direct sequencing through regions of the genome inaccessible or difficult to analyze by short-read platforms. This includes disease-causing long repetitive elements, extreme GC content regions, and complex gene loci. Similarly, these platforms enable structural variation characterization at previously unparalleled resolution and direct detection of epigenetic marks in native DNA. Here, we review how these technologies are opening up new clinical avenues that are being applied to pathogenic microorganisms and viruses, constitutional disorders, pharmacogenomics, cancer, and more.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Técnicas de Diagnóstico Molecular/métodos , Medicina Molecular/métodos , Análise de Sequência de DNA/métodos , Humanos , Técnicas de Diagnóstico Molecular/tendências , Medicina Molecular/tendências
13.
Brief Bioinform ; 20(2): 609-623, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-29684165

RESUMO

Large amounts of data emerging from experiments in molecular medicine are leading to the identification of molecular signatures associated with disease subtypes. The contextualization of these patterns is important for obtaining mechanistic insight into the aberrant processes associated with a disease, and this typically involves the integration of multiple heterogeneous types of data. In this review, we discuss knowledge representations that can be useful to explore the biological context of molecular signatures, in particular three main approaches, namely, pathway mapping approaches, molecular network centric approaches and approaches that represent biological statements as knowledge graphs. We discuss the utility of each of these paradigms, illustrate how they can be leveraged with selected practical examples and identify ongoing challenges for this field of research.


Assuntos
Biologia Computacional , Medicina Molecular , Humanos , Medicina de Precisão
14.
Mo Med ; 116(6): 497-502, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31911736

RESUMO

Gene therapy has long been a promise of molecular biology. So far, that promise has largely been unrealized. The advent of gene editing using technology adapted from bacteria may finally usher in the era of gene therapy.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/ética , Terapia Genética/ética , Humanos , Medicina Molecular/tendências
15.
Mol Biol (Mosk) ; 52(3): 394-410, 2018.
Artigo em Russo | MEDLINE | ID: mdl-29989573

RESUMO

A critical analysis of proteomes provides a basis for understanding the operation of complex biochemical systems. A personalized approach to therapy takes into account biological uniqueness of each patient at genome, transcriptome, and proteome levels, and is a priority area in molecular medicine. The identification of proteoforms, which have dramatic impact on the phenotype of a disease, is a fundamental task of personal molecular profiling. Considerable progress of proteomic approaches presented new avenues for accurate, specific, and high-performance protein analysis. Thus, the identification of new efficient bio-markers can be expected based on studies of aberrant proteoforms associated with various diseases.


Assuntos
Medicina Molecular/métodos , Medicina de Precisão/métodos , Proteoma/metabolismo , Proteômica/métodos , Animais , Humanos , Proteoma/genética
17.
Curr Allergy Asthma Rep ; 18(7): 39, 2018 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-29886521

RESUMO

PURPOSE OF REVIEW: The aim of this article is to discuss how allergen-specific immunotherapy (AIT) can be improved through molecular approaches. We provide a summary of next-generation molecular AIT approaches and of their clinical evaluation. Furthermore, we discuss the potential of next generation molecular AIT forms for the treatment of severe manifestations of allergy and mention possible future molecular strategies for the secondary and primary prevention of allergy. RECENT FINDINGS: AIT has important advantages over symptomatic forms of allergy treatment but its further development is limited by the quality of the therapeutic antigen preparations which are derived from natural allergen sources. The field of allergy diagnosis is currently undergoing a dramatic improvement through the use of molecular testing with defined, mainly recombinant allergens which allows high-resolution diagnosis. Several studies demonstrate that molecular testing in early childhood can predict the development of symptomatic allergy later on in life. Clinical studies indicate that molecular AIT approaches have the potential to improve therapy of allergic diseases and may be used as allergen-specific forms of secondary and eventually primary prevention for allergy.


Assuntos
Alérgenos/imunologia , Dessensibilização Imunológica/métodos , Hipersensibilidade/prevenção & controle , Criança , Humanos , Hipersensibilidade/imunologia , Medicina Molecular , Prevenção Primária
18.
Curr Mol Med ; 18(1): 1-2, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29886829
20.
Proc Natl Acad Sci U S A ; 115(23): 5839-5848, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29802228

RESUMO

Oxygen-derived free radicals and related oxidants are ubiquitous and short-lived intermediates formed in aerobic organisms throughout life. These reactive species participate in redox reactions leading to oxidative modifications in biomolecules, among which proteins and lipids are preferential targets. Despite a broad array of enzymatic and nonenzymatic antioxidant systems in mammalian cells and microbes, excess oxidant formation causes accumulation of new products that may compromise cell function and structure leading to cell degeneration and death. Oxidative events are associated with pathological conditions and the process of normal aging. Notably, physiological levels of oxidants also modulate cellular functions via homeostatic redox-sensitive cell signaling cascades. On the other hand, nitric oxide (•NO), a free radical and weak oxidant, represents a master physiological regulator via reversible interactions with heme proteins. The bioavailability and actions of •NO are modulated by its fast reaction with superoxide radical ([Formula: see text]), which yields an unusual and reactive peroxide, peroxynitrite, representing the merging of the oxygen radicals and •NO pathways. In this Inaugural Article, I summarize early and remarkable developments in free radical biochemistry and the later evolution of the field toward molecular medicine; this transition includes our contributions disclosing the relationship of •NO with redox intermediates and metabolism. The biochemical characterization, identification, and quantitation of peroxynitrite and its role in disease processes have concentrated much of our attention. Being a mediator of protein oxidation and nitration, lipid peroxidation, mitochondrial dysfunction, and cell death, peroxynitrite represents both a pathophysiologically relevant endogenous cytotoxin and a cytotoxic effector against invading pathogens.


Assuntos
Radicais Livres/metabolismo , Medicina Molecular , Óxido Nítrico , Oxirredução , Ácido Peroxinitroso , Animais , Pesquisa Biomédica , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico/fisiologia , Ácido Peroxinitroso/metabolismo , Ácido Peroxinitroso/fisiologia , Proteínas/metabolismo , Superóxido Dismutase/metabolismo , Tirosina/metabolismo
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