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1.
Med Sci (Paris) ; 36(10): 859-865, 2020 Oct.
Artigo em Francês | MEDLINE | ID: mdl-33026327

RESUMO

Obesity is a complex, multifactorial disorder. About 5% of obese patients actually present with a monogenic form of obesity where only one mutation is sufficient to cause the disease. So far, the genes that have been found to be mutated in these monogenic forms play a key role in the leptin/melanocortin pathway which is mainly active in the hypothalamus and which regulates food intake and energy expenditure. Our laboratory has recently reported a novel monogenic form of obesity due to MRAP2 deficiency where, contrary to previously described monogenic forms of obesity, the carriers presented with hyperglycemia and hypertension in addition to obesity, suggesting that MRAP2 might play a pleiotropic role in metabolic tissues, in addition to its role in brain control of food intake and energy expenditure.


Assuntos
Regulação do Apetite/genética , Obesidade/genética , Animais , Predisposição Genética para Doença , Humanos , Leptina/genética , Leptina/metabolismo , Mutação/fisiologia , Obesidade/patologia , Obesidade/terapia , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
2.
PLoS Comput Biol ; 16(9): e1008185, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32925942

RESUMO

Cells adjust their metabolism in response to mutations, but how this reprogramming depends on the genetic context is not well known. Specifically, the absence of individual enzymes can affect reprogramming, and thus the impact of mutations in cell growth. Here, we examine this issue with an in silico model of Saccharomyces cerevisiae's metabolism. By quantifying the variability in the growth rate of 10000 different mutant metabolisms that accumulated changes in their reaction fluxes, in the presence, or absence, of a specific enzyme, we distinguish a subset of modifier genes serving as buffers or potentiators of variability. We notice that the most potent modifiers refer to the glycolysis pathway and that, more broadly, they show strong pleiotropy and epistasis. Moreover, the evidence that this subset depends on the specific growing condition strengthens its systemic underpinning, a feature only observed before in a toy model of a gene-regulatory network. Some of these enzymes also modulate the effect that biochemical noise and environmental fluctuations produce in growth. Thus, the reorganization of metabolism induced by mutations has not only direct physiological implications but also transforms the influence that other mutations have on growth. This is a general result with implications in the development of cancer therapies based on metabolic inhibitors.


Assuntos
Redes Reguladoras de Genes/genética , Redes e Vias Metabólicas , Mutação , Redes e Vias Metabólicas/genética , Redes e Vias Metabólicas/fisiologia , Mutação/genética , Mutação/fisiologia , Fenótipo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Biologia de Sistemas
3.
Proc Natl Acad Sci U S A ; 117(37): 23033-23043, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32873651

RESUMO

Numerous rhodopsin mutations have been implicated in night blindness and retinal degeneration, often with unclear etiology. D190N-rhodopsin (D190N-Rho) is a well-known inherited human mutation causing retinitis pigmentosa. Both higher-than-normal spontaneous-isomerization activity and misfolding/mistargeting of the mutant protein have been proposed as causes of the disease, but neither explanation has been thoroughly examined. We replaced wild-type rhodopsin (WT-Rho) in Rho D190N/WT mouse rods with a largely "functionally silenced" rhodopsin mutant to isolate electrical responses triggered by D190N-Rho activity, and found that D190N-Rho at the single-molecule level indeed isomerizes more frequently than WT-Rho by over an order of magnitude. Importantly, however, this higher molecular dark activity does not translate into an overall higher cellular dark noise, owing to diminished D190N-Rho content in the rod outer segment. Separately, we found that much of the degeneration and shortened outer-segment length of Rho D190N/WT mouse rods was not averted by ablating rod transducin in phototransduction-also consistent with D190N-Rho's higher isomerization activity not being the primary cause of disease. Instead, the low pigment content, shortened outer-segment length, and a moderate unfolded protein response implicate protein misfolding as the major pathogenic problem. Finally, D190N-Rho also provided some insight into the mechanism of spontaneous pigment excitation.


Assuntos
Degeneração Retiniana/metabolismo , Rodopsina/metabolismo , Animais , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Humanos , Transdução de Sinal Luminoso/fisiologia , Camundongos , Mutação/fisiologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinite Pigmentosa/metabolismo , Segmento Externo da Célula Bastonete/metabolismo
4.
Biodemography Soc Biol ; 65(3): 245-256, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32727277

RESUMO

Hand grip strength (GS) is a valid and reliable predictor of future morbidity and mortality and is considered a useful indicator of aging. In this paper, we use results from the genetic analysis in animal studies to evaluate associations for GS, frailty, and subsequent mortality among humans. Specifically, we use data from the Health and Retirement Survey (HRS) to investigate the association between three polymorphisms in a candidate frailty gene (Tiam1) and GS. Results suggest that the A allele in rs724561 significantly reduces GS among older adults in the US (b = -0.340; p < .006) and is significantly associated with self-reported weakness (b = 0.221; p = .036). This same polymorphism was weakly associated (one-tailed) with an increased risk of mortality (b = 1.091; p < .093) and adjustments for GS rendered this association statistically non-significant (b = 1.048; p < .361). Overall, our results provide tentative evidence that the Tiam1 gene may be associated with frailty development, but we encourage further studies.


Assuntos
Força da Mão/fisiologia , Mutação/genética , Mutação/fisiologia , Estresse Psicológico/genética , Idoso , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mortalidade , Dinamômetro de Força Muscular , Modelos de Riscos Proporcionais , Estresse Psicológico/fisiopatologia
5.
Nat Rev Endocrinol ; 16(7): 378-393, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376986

RESUMO

The ATP-sensitive potassium channel (KATP channel) couples blood levels of glucose to insulin secretion from pancreatic ß-cells. KATP channel closure triggers a cascade of events that results in insulin release. Metabolically generated changes in the intracellular concentrations of adenosine nucleotides are integral to this regulation, with ATP and ADP closing the channel and MgATP and MgADP increasing channel activity. Activating mutations in the genes encoding either of the two types of KATP channel subunit (Kir6.2 and SUR1) result in neonatal diabetes mellitus, whereas loss-of-function mutations cause hyperinsulinaemic hypoglycaemia of infancy. Sulfonylurea and glinide drugs, which bind to SUR1, close the channel through a pathway independent of ATP and are now the primary therapy for neonatal diabetes mellitus caused by mutations in the genes encoding KATP channel subunits. Insight into the molecular details of drug and nucleotide regulation of channel activity has been illuminated by cryo-electron microscopy structures that reveal the atomic-level organization of the KATP channel complex. Here we review how these structures aid our understanding of how the various mutations in the genes encoding Kir6.2 (KCNJ11) and SUR1 (ABCC8) lead to a reduction in ATP inhibition and thereby neonatal diabetes mellitus. We also provide an update on known mutations and sulfonylurea therapy in neonatal diabetes mellitus.


Assuntos
Diabetes Mellitus/congênito , Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Canais KATP/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores Sulfonilureia/genética , Animais , Diabetes Mellitus/tratamento farmacológico , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Secreção de Insulina/genética , Mutação/fisiologia , Compostos de Sulfonilureia/uso terapêutico
6.
Nat Rev Cancer ; 20(8): 471-480, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32404993

RESUMO

The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2-p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.


Assuntos
Evolução Molecular , Genes p53/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Animais , Evolução Biológica , Genes BRCA1/fisiologia , Genes p53/fisiologia , Genes ras/genética , Humanos , Síndrome de Li-Fraumeni/genética , Mutação/fisiologia , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Transdução de Sinais/fisiologia , Células-Tronco/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Vertebrados/genética , Vertebrados/metabolismo , Vertebrados/fisiologia
7.
Nat Rev Cancer ; 20(7): 365-382, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32415283

RESUMO

Haematopoiesis is governed by haematopoietic stem cells (HSCs) that produce all lineages of blood and immune cells. The maintenance of blood homeostasis requires a dynamic response of HSCs to stress, and dysregulation of these adaptive-response mechanisms underlies the development of myeloid leukaemia. Leukaemogenesis often occurs in a stepwise manner, with genetic and epigenetic changes accumulating in pre-leukaemic HSCs prior to the emergence of leukaemic stem cells (LSCs) and the development of acute myeloid leukaemia. Clinical data have revealed the existence of age-related clonal haematopoiesis, or the asymptomatic clonal expansion of mutated blood cells in the elderly, and this phenomenon is connected to susceptibility to leukaemic transformation. Here we describe how selection for specific mutations that increase HSC competitive fitness, in conjunction with additional endogenous and environmental changes, drives leukaemic transformation. We review the ways in which LSCs take advantage of normal HSC properties to promote survival and expansion, thus underlying disease recurrence and resistance to conventional therapies, and we detail our current understanding of leukaemic 'stemness' regulation. Overall, we link the cellular and molecular mechanisms regulating HSC behaviour with the functional dysregulation of these mechanisms in myeloid leukaemia and discuss opportunities for targeting LSC-specific mechanisms for the prevention or cure of malignant diseases.


Assuntos
Carcinogênese/genética , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mieloide Aguda/fisiopatologia , Antineoplásicos/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Interação Gene-Ambiente , Instabilidade Genômica/efeitos dos fármacos , Instabilidade Genômica/fisiologia , Hematopoese/genética , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação/efeitos dos fármacos , Mutação/genética , Mutação/fisiologia , Nicho de Células-Tronco/efeitos dos fármacos , Nicho de Células-Tronco/fisiologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
8.
PLoS Genet ; 16(3): e1008654, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32150542

RESUMO

Mistranslation is typically deleterious for cells, although specific mistranslated proteins can confer a short-term benefit in a particular environment. However, given its large overall cost, the prevalence of high global mistranslation rates remains puzzling. Altering basal mistranslation levels of Escherichia coli in several ways, we show that generalized mistranslation enhances early survival under DNA damage, by rapidly activating the SOS response. Mistranslating cells maintain larger populations after exposure to DNA damage, and thus have a higher probability of sampling critical beneficial mutations. Both basal and artificially increased mistranslation increase the number of cells that are phenotypically tolerant and genetically resistant under DNA damage; they also enhance survival at high temperature. In contrast, decreasing the normal basal mistranslation rate reduces cell survival. This wide-ranging stress resistance relies on Lon protease, which is revealed as a key effector that induces the SOS response in addition to alleviating proteotoxic stress. The new links between error-prone protein synthesis, DNA damage, and generalised stress resistance indicate surprising coordination between intracellular stress responses and suggest a novel hypothesis to explain high global mistranslation rates.


Assuntos
Sobrevivência Celular/genética , Biossíntese de Proteínas/genética , Resposta SOS em Genética/genética , Dano ao DNA/genética , Dano ao DNA/fisiologia , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Mutação/genética , Mutação/fisiologia , Protease La/genética , Protease La/metabolismo
9.
Curr Opin Cell Biol ; 63: 135-143, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32092639

RESUMO

Tumors arise through waves of genetic alterations and clonal expansion that allow tumor cells to acquire cancer hallmarks, such as genome instability and immune evasion. Recent genomic analyses showed that the vast majority of cancer driver genes are mutated in a tissue-dependent manner, that is, are altered in some cancers but not others. Often the tumor type also affects the likelihood of therapy response. What is the origin of tissue specificity in cancer? Recent studies suggest that both cell-intrinsic and cell-extrinsic factors play a role. On one hand, cell type-specific wiring of the cell signaling network determines the outcome of cancer driver gene mutations. On the other hand, the tumor cells' exposure to tissue-specific microenvironments (e.g. immune cells) also contributes to shape the tissue specificity of driver genes and of therapy response. In the future, a more complete understanding of tissue specificity in cancer may inform methods to better predict and improve therapeutic outcomes.


Assuntos
Neoplasias/classificação , Neoplasias/genética , Neoplasias/patologia , Animais , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica/fisiologia , Humanos , Mutação/fisiologia , Neoplasias/metabolismo , Oncogenes/fisiologia , Especificidade de Órgãos/genética , Transdução de Sinais/genética , Microambiente Tumoral/genética
10.
Hum Reprod Update ; 26(2): 197-213, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32068234

RESUMO

BACKGROUND: Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes. OBJECTIVE AND RATIONALE: This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine. SEARCH METHODS: Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms 'multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction' were used in various combinations. OUTCOMES: A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders. WIDER IMPLICATIONS: Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.


Assuntos
Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/etiologia , Impressão Genômica/fisiologia , Resultado da Gravidez/genética , Reprodução/genética , Animais , Feminino , Doenças Genéticas Inatas/patologia , Humanos , Masculino , Mutação/fisiologia , Gravidez , Prognóstico
11.
BMC Evol Biol ; 20(1): 30, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32059645

RESUMO

BACKGROUND: Modularity is important for evolutionary innovation. The recombination of existing units to form larger complexes with new functionalities spares the need to create novel elements from scratch. In proteins, this principle can be observed at the level of protein domains, functional subunits which are regularly rearranged to acquire new functions. RESULTS: In this study we analyse the mechanisms leading to new domain arrangements in five major eukaryotic clades (vertebrates, insects, fungi, monocots and eudicots) at unprecedented depth and breadth. This allows, for the first time, to directly compare rates of rearrangements between different clades and identify both lineage specific and general patterns of evolution in the context of domain rearrangements. We analyse arrangement changes along phylogenetic trees by reconstructing ancestral domain content in combination with feasible single step events, such as fusion or fission. Using this approach we explain up to 70% of all rearrangements by tracing them back to their precursors. We find that rates in general and the ratio between these rates for a given clade in particular, are highly consistent across all clades. In agreement with previous studies, fusions are the most frequent event leading to new domain arrangements. A lineage specific pattern in fungi reveals exceptionally high loss rates compared to other clades, supporting recent studies highlighting the importance of loss for evolutionary innovation. Furthermore, our methodology allows us to link domain emergences at specific nodes in the phylogenetic tree to important functional developments, such as the origin of hair in mammals. CONCLUSIONS: Our results demonstrate that domain rearrangements are based on a canonical set of mutational events with rates which lie within a relatively narrow and consistent range. In addition, gained knowledge about these rates provides a basis for advanced domain-based methodologies for phylogenetics and homology analysis which complement current sequence-based methods.


Assuntos
Eucariotos , Evolução Molecular , Estrutura Terciária de Proteína/genética , Proteínas/química , Proteínas/genética , Animais , Abelhas/fisiologia , Resistência à Doença/genética , Eucariotos/genética , Eucariotos/metabolismo , Células Eucarióticas/metabolismo , Fungos/classificação , Fungos/genética , Ontologia Genética , Mutação/fisiologia , Filogenia , Doenças das Plantas/microbiologia , Comportamento Social , Vertebrados/classificação , Vertebrados/genética , Vertebrados/metabolismo
12.
Epilepsy Behav ; 104(Pt A): 106848, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028124

RESUMO

Epilepsy is a common neurological disease characterized by recurrent seizures. About 70 million people were affected by epilepsy or epileptic seizures. Epilepsy is a complicated complex or symptomatic syndromes induced by structural, functional, and genetic causes. Meanwhile, several comorbidities are accompanied by epileptic seizures. Cognitive dysfunction is a long-standing complication associated with epileptic seizures, which severely impairs quality of life. Although the definitive pathogenic mechanisms underlying epilepsy-related cognitive dysfunction remain unclear, accumulating evidence indicates that multiple risk factors are probably involved in the development and progression of cognitive dysfunction in patients with epilepsy. These factors include the underlying etiology, recurrent seizures or status epilepticus, structural damage that induced secondary epilepsy, genetic variants, and molecular alterations. In this review, we summarize several theories that may explain the genetic and molecular basis of epilepsy-related cognitive dysfunction.


Assuntos
Disfunção Cognitiva/genética , Epigênese Genética/fisiologia , Epilepsia/genética , Estresse Oxidativo/fisiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Epilepsia/metabolismo , Epilepsia/psicologia , Humanos , Mutação/fisiologia , Qualidade de Vida/psicologia
13.
J Neurochem ; 153(4): 433-454, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31957016

RESUMO

Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019: Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.


Assuntos
Congressos como Assunto/tendências , Sinucleinopatias/diagnóstico , Sinucleinopatias/metabolismo , alfa-Sinucleína/metabolismo , Animais , Biomarcadores/metabolismo , Humanos , Corpos de Inclusão/genética , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Mutação/fisiologia , Portugal , Sinucleinopatias/genética
14.
Annu Rev Pathol ; 15: 149-177, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31977296

RESUMO

Chronic lymphocytic leukemia is a common disease in Western countries and has heterogeneous clinical behavior. The relevance of the genetic basis of the disease has come to the forefront recently, with genome-wide studies that have provided a comprehensive view of structural variants, somatic mutations, and different layers of epigenetic changes. The mutational landscape is characterized by relatively common copy number alterations, a few mutated genes occurring in 10-15% of cases, and a large number of genes mutated in a small number of cases. The epigenomic profile has revealed a marked reprogramming of regulatory regions in tumor cells compared with normal B cells. All of these alterations are differentially distributed in clinical and biological subsets of the disease, indicating that they may underlie the heterogeneous evolution of the disease. These global studies are revealing the molecular complexity of chronic lymphocytic leukemia and provide new perspectives that have helped to understand its pathogenic mechanisms and improve the clinical management of patients.


Assuntos
Epigênese Genética/fisiologia , Leucemia Linfocítica Crônica de Células B/genética , Mutação/fisiologia , Variações do Número de Cópias de DNA , Epigenômica , Genoma Humano/fisiologia , Genômica/métodos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia
15.
J Oncol Pharm Pract ; 26(4): 943-966, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31964218

RESUMO

Lymphomas are a diverse group of hematologic malignancies that arise from either T cell, B cell or the natural killer cell lineage. B cell lymphomas arise from gene mutations with critical functions during normal B cell development. Recent advances in the understanding of molecular pathogenesis demonstrate that many different recurrent genomic and molecular abnormalities and dysregulated oncogenic regulatory pathways exist for many subtypes of B cell lymphomas, both across and within histological subtypes. Pathogenetic processes such as (1) chromosomal aberrations, for example, t(14;18) in follicular lymphoma, t(11;14) in mantle cell lymphoma, t(8;14) in Burkitt lymphoma; dysregulations in signaling pathways of (2) nuclear factor- κB (NF-κB); (3) B cell receptor (BCR); (4) Janus kinase/signal transducers and transcription activators (JAK-STAT); (5) impaired apoptosis/cell cycle regulation due to mutated, rearranged or amplified MYC, BCL-2, BCL-6 proto-oncogenes; (6) epigenetic aberrations may contribute to pathogenesis. More studies are under way to elucidate the molecular heterogeneity underlying many types of lymphomas that account for variable responses to treatment, generation of subclones and treatment resistance. Although significant research is still needed, targeted therapy promises to provide new options for the treatment of patients with lymphomas. This article provides a non-exhaustive overview on the current understanding on the genetics of pathogenesis of B cell lymphomas and their therapeutic implications.


Assuntos
Biomarcadores Tumorais/genética , Linfoma de Células B/genética , Linfoma de Células B/terapia , Medicina de Precisão/métodos , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Marcação de Genes/métodos , Marcação de Genes/tendências , Humanos , Linfoma de Células B/metabolismo , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/terapia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/metabolismo , Linfoma não Hodgkin/terapia , Mutação/efeitos dos fármacos , Mutação/fisiologia , Medicina de Precisão/tendências , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
16.
PLoS Comput Biol ; 16(1): e1007494, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31951609

RESUMO

The fixation probability of a single mutant invading a population of residents is among the most widely-studied quantities in evolutionary dynamics. Amplifiers of natural selection are population structures that increase the fixation probability of advantageous mutants, compared to well-mixed populations. Extensive studies have shown that many amplifiers exist for the Birth-death Moran process, some of them substantially increasing the fixation probability or even guaranteeing fixation in the limit of large population size. On the other hand, no amplifiers are known for the death-Birth Moran process, and computer-assisted exhaustive searches have failed to discover amplification. In this work we resolve this disparity, by showing that any amplification under death-Birth updating is necessarily bounded and transient. Our boundedness result states that even if a population structure does amplify selection, the resulting fixation probability is close to that of the well-mixed population. Our transience result states that for any population structure there exists a threshold r⋆ such that the population structure ceases to amplify selection if the mutant fitness advantage r is larger than r⋆. Finally, we also extend the above results to δ-death-Birth updating, which is a combination of Birth-death and death-Birth updating. On the positive side, we identify population structures that maintain amplification for a wide range of values r and δ. These results demonstrate that amplification of natural selection depends on the specific mechanisms of the evolutionary process.


Assuntos
Modelos Biológicos , Dinâmica Populacional/estatística & dados numéricos , Seleção Genética/fisiologia , Biologia Computacional , Mutação/fisiologia , Densidade Demográfica , Processos Estocásticos
17.
Ann N Y Acad Sci ; 1466(1): 17-23, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30767234

RESUMO

The hematopoietic niche is composed of endothelial cells, mesenchymal stromal cells of several types, and megakaryocytes, and functions to support the survival, proliferation, and differentiation of normal hematopoietic stem cells (HSCs). An abundance of evidence from a range of hematological malignancies supports the concept that the niche also participates in the pathogenesis of malignant hematopoiesis, differentially supporting malignant stem or progenitor cells over that of normal blood cell development. In 2005, patients with myeloproliferative neoplasms were reported to harbor an acquired, activating, missense V617F mutation of the cytokine-signaling Janus kinase (JAK)-2, JAK2V617F , present in virtually all patients with polycythemia vera and half of patients with essential thrombocythemia and primary myelofibrosis. Using both in vitro and in vivo methods, several investigators have shown that in addition to driving cytokine-independent proliferation in HSCs, JAK2V617F contributes to these neoplasms by altering the hematopoietic niche. The role of both endothelial cells and megakaryocytes bearing JAK2V617F will be presented, which involves altering cytokine production within the niche, resulting in their differential support of mutant kinase-bearing stem cells over their normal counterparts, and imparting relative radiation resistance to stem cells. The clinical correlates of these findings will be discussed, as will their therapeutic implications.


Assuntos
Medula Óssea/patologia , Medula Óssea/fisiologia , Neoplasias Hematológicas/patologia , Nicho de Células-Tronco/fisiologia , Animais , Microambiente Celular/fisiologia , Hematopoese/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/patologia , Humanos , Janus Quinase 2/genética , Mutação/fisiologia , Microambiente Tumoral/fisiologia
18.
Annu Rev Pathol ; 15: 419-438, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31689371

RESUMO

Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.


Assuntos
Envelhecimento/fisiologia , Doenças Cardiovasculares/etiologia , Evolução Clonal/fisiologia , Hematopoese/fisiologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doenças Cardiovasculares/epidemiologia , Células Cultivadas , Hematopoese/genética , Humanos , Incidência , Mutação/fisiologia , Fatores de Risco
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