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Introducción: La diabetes mellitus tipo 2 es una de las principales causas de morbimortalidad en el mundo, su prevalencia es aún mayor en países de medianos y bajos ingresos. El automanejo es una estrategia que ha demostrado controlar las enfermedades crónicas. Objetivo: Determinar la factibilidad y eficacia preliminar de la intervención educativa AMAS + Vida enfocada en el automanejo de la salud dirigida a personas adultas con diabetes tipo 2 en una Institución de salud de primer nivel en Neiva, Colombia. Materiales y Métodos: Estudio de factibilidad, pre test post test con un solo grupo, para establecer la eficacia preliminar de la intervención. Muestra intencional de 36 adultos con diabetes tipo 2. Los instrumentos empleados fueron ficha de caracterización y escala Partners in Health para medir automanejo. Resultados: 31 adultos con diabetes completaron el seguimiento de 3 meses, mayoría eran mujeres, con bajo nivel socioeconómico y educativo, hubo buena factibilidad de la intervención. Los participantes mejoraron significativamente los conocimientos de la enfermedad (p < 0,001); además hábitos alimenticios (p = 0,001), comportamientos de automanejo de la salud (p < 0,001) y disminución del índice de masa corporal (p = 0,01). No hubo cambios significativos en la actividad física (p = 0,125). Discusión: Las intervenciones basadas en el automanejo estructuradas bajo la teoría de adaptación a las enfermedades crónicas logran cambios en la promoción de la salud en personas con diabetes. Conclusiones: La intervención tuvo eficacia preliminar en el grupo estudiado con buena factibilidad. Se recomienda continuar desarrollando estudios de tipo experimental.
Introduction: Type 2 diabetes mellitus is a leading cause of morbidity and mortality worldwide, and its prevalence is even higher in middle- and low-income countries. Self-management is a strategy that has been shown to control chronic diseases. Objective: To determine the feasibility and preliminary efficacy of the AMAS + Vida educational intervention focused on health self-management in adults with type 2 diabetes in a primary health care facility in Neiva, Colombia. Materials and Methods: Feasibility study using a one-group pretest-posttest design to determine the preliminary efficacy of the intervention. Purposive sample of 36 adults with type 2 diabetes. The instruments used were a characterization form and the Partners in Health scale to measure self-management. Results: Thirty-one adults with diabetes completed the 3-month follow-up, most of whom were women with low socioeconomic and educational levels. The feasibility of the intervention was good. Participants significantly improved disease knowledge (p < 0.001), eating habits (p = 0.001), health self-management behaviors (p < 0.001), and decreased body mass index (p = 0.01). There were no significant changes in physical activity (p = 0.125). Discussion: Self-management-based interventions, structured according to the theory of adaptation to chronic illness, achieve health-promoting changes in people with diabetes. Conclusions: The intervention showed preliminary efficacy in the study group with good feasibility. Further experimental studies are recommended.
Introdução: O diabetes mellitus tipo 2 é uma das principais causas de morbidade e mortalidade no mundo; sua prevalência é ainda maior em países de baixa e média renda. A autogestão é uma estratégia que comprovadamente controla doenças crônicas. Objetivo: Determinar a viabilidade e eficácia preliminar da intervenção educativa AMAS + Vida focada na autogestão da saúde dirigida a adultos com diabetes tipo 2 em uma instituição de saúde de primeiro nível em Neiva, Colômbia. Materiais e Métodos: Estudo de viabilidade, pré-teste pós-teste com grupo único, para estabelecer a eficácia preliminar da intervenção. Amostra intencional de 36 adultos com diabetes tipo 2. Os instrumentos utilizados foram uma ficha de caracterização e a escala Partners in Health para medir a autogestão. Resultados: 31 adultos com diabetes completaram o acompanhamento de 3 meses, a maioria eram mulheres, com baixo nível socioeconômico e educacional, houve boa viabilidade da intervenção. Os participantes melhoraram significativamente o conhecimento sobre a doença (p < 0,001); também hábitos alimentares (p = 0,001), comportamentos de autogestão da saúde (p < 0,001) e diminuição do índice de massa corporal (p = 0,01). Não houve alterações significativas na atividade física (p = 0,125). Discussão: Intervenções baseadas na autogestão estruturadas sob a teoria da adaptação às doenças crônicas alcançam mudanças na promoção da saúde das pessoas com diabetes. Conclusões: A intervenção teve eficácia preliminar no grupo estudado com boa viabilidade. Recomenda-se continuar desenvolvendo estudos experimentais.
Assuntos
Estudos de Viabilidade , Educação em Saúde , Enfermagem , Diabetes Mellitus Tipo 2 , AutogestãoRESUMO
BACKGROUND: NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. METHODS: This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. RESULTS: Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1-15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. CONCLUSIONS: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. TRIAL REGISTRATION: NCT03476681 . Registered 03/26/2018.
Assuntos
Anticorpos Monoclonais , Antineoplásicos , Neoplasias da Mama , Neoplasias Colorretais , Neoplasias Pancreáticas , Adulto , Feminino , Humanos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Progressão da Doença , Neutropenia Febril/induzido quimicamente , Neoplasias Pancreáticas/tratamento farmacológicoRESUMO
The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.
RESUMO
Objective. This work sought to describe the adaptation process by men to the nurse role. Methods.Secondary analysis of data from a collective case study that had as participants 12 male nurses working in the city of Medellín, with ages between 28 and 47 years and average time of professional experience of 11 years. Information collection was carried out through in-depth interviews. The analysis was conducted through Roy's Adaptation Model (RAM), reading of the interviews, identification of RAM's components, grouping of fragments, assignment of tags, construction of a matrix and classification. Results. The analysis performed accounts for the coping processes and adaptation by male nurses and the ineffective responses (control of emotions and emotional silencing) when practicing a role considered feminine. Conclusion.In this study, it was possible to establish that, to achieve adaptation within nursing, men use strategies related with changes in bodily appearance, management of physical strength, and management of emotions.
Objetivo. Describir el proceso de adaptación de los hombres al rol enfermero. Métodos. Análisis secundario de los datos de un estudio de casos colectivo que tuvo como participantes a 12 enfermeros que trabajan en la ciudad de Medellín, con edades entre los 28 y los 47 años y un tiempo de experiencia profesional promedio de 11 años. La recolección de la información se realizó mediante entrevistas en profundidad. El análisis se realizó a partir del Modelo de Adaptación de Roy (RAM), lectura de las entrevistas, identificación de los componentes del RAM, agrupación de fragmentos, asignación de etiquetas, construcción de una matriz y clasificación. Resultados. El análisis realizado da cuenta de los procesos de afrontamiento y adaptación de los enfermeros y las respuestas inefectivas (control de emociones y silenciamiento emocional) al ejercer un rol considerado femenino. Conclusión. En este estudio fue posible establecer que, para alcanzar una adaptación dentro de la enfermería, los hombres utilizan estrategias relacionadas con cambios en la apariencia corporal, el manejo de la fuerza física y el manejo de las emociones.
Objetivo. Descrever o processo de adaptação do homem à função de enfermagem. Métodos.Análise secundária de dados de um estudo de caso coletivo que teve como participantes 12 enfermeiros que atuam na cidade de Medellín, com idade entre 28 e 47 anos e tempo de experiência profissional média 11 anos. As informações foram coletadas por meio de entrevistas em profundidade. A análise foi realizada por meio do Modelo de Adaptação de Roy (RAM), leitura das entrevistas, identificação dos componentes do RAM, agrupamento de fragmentos, atribuição de rótulos, construção de matriz e classificação. Resultados. A análise realizada dá conta dos processos de enfrentamento e adaptação das enfermeiras e das respostas ineficazes (controle das emoções e silenciamento emocional) ao exercer um papel considerado feminino. Conclusão.Neste estudo foi possível constatar que, para conseguir uma adaptação dentro da enfermagem, os homens utilizam estratégias relacionadas a mudanças na aparência corporal, manejo da força física e manejo emocional
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Humanos , Masculino , Masculinidade , Identidade de Gênero , Homens , Enfermeiros , Prática Profissional , Educação em EnfermagemRESUMO
AIMS: Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. We investigated whether C202 regulates the opening of PTP. METHODS AND RESULTS: We developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Infarct size is reduced in CypD-C202S Langendorff perfused hearts compared to wild type (WT). Cardiac mitochondria from CypD-C202S mice also have higher calcium retention capacity compared to WT. Therefore, we hypothesized that oxidation of C202 might target CypD to the PTP. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component F1F0-ATP-synthase. We previously found C202 to be S-nitrosylated in ischaemic preconditioning. Cysteine residues can also undergo S-acylation, and C202 matched an S-acylation motif. S-acylation of CypD-C202 was assessed using a resin-assisted capture (Acyl-RAC). WT hearts are abundantly S-acylated on CypD C202 under baseline conditions indicating that S-acylation on C202 per se does not lead to PTP opening. CypD C202S knock-in hearts are protected from ischaemia/reperfusion injury suggesting further that lack of CypD S-acylation at C202 is not detrimental (when C is mutated to S) and does not induce PTP opening. However, we find that ischaemia leads to de-acylation of C202 and that calcium overload in isolated mitochondria promotes de-acylation of CypD. Furthermore, a high bolus of calcium in WT cardiac mitochondria displaces CypD from its physiological binding partners and possibly renders it available for interaction with the PTP. CONCLUSIONS: Taken together the data suggest that with ischaemia CypD is de-acylated at C202 allowing the free cysteine residue to undergo oxidation during the first minutes of reperfusion which in turn targets it to the PTP.
Assuntos
Mitocôndrias Cardíacas/metabolismo , Poro de Transição de Permeabilidade Mitocondrial/metabolismo , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/enzimologia , Peptidil-Prolil Isomerase F/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Animais , Cálcio/metabolismo , Peptidil-Prolil Isomerase F/genética , Cisteína , Modelos Animais de Doenças , Preparação de Coração Isolado , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Cardíacas/patologia , Mutação , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Oxirredução , Estresse OxidativoRESUMO
The primary function of APOE (apolipoprotein E) is to mediate the transport of cholesterol- and lipid-containing lipoprotein particles into cells by receptor-mediated endocytosis. APOE also has pro- and antiinflammatory effects, which are both context and concentration dependent. For example, Apoe-/- mice exhibit enhanced airway remodeling and hyperreactivity in experimental asthma, whereas increased APOE levels in lung epithelial lining fluid induce IL-1ß secretion from human asthmatic alveolar macrophages. However, APOE-mediated airway epithelial cell inflammatory responses and signaling pathways have not been defined. Here, RNA sequencing of human asthmatic bronchial brushing cells stimulated with APOE identified increased expression of mRNA transcripts encoding multiple proinflammatory genes, including CXCL5 (C-X-C motif chemokine ligand 5), an epithelial-derived chemokine that promotes neutrophil activation and chemotaxis. We subsequently characterized the APOE signaling pathway that induces CXCL5 secretion by human asthmatic small airway epithelial cells (SAECs). Neutralizing antibodies directed against TLR4 (Toll-like receptor 4), but not TLR2, attenuated APOE-mediated CXCL5 secretion by human asthmatic SAECs. Inhibition of TAK1 (transforming growth factor-ß-activated kinase 1), IκKß (inhibitor of nuclear factor κ B kinase subunit ß), TPL2 (tumor progression locus 2), and JNK (c-Jun N-terminal kinase), but not p38 MAPK (mitogen-activated protein kinase) or MEK1/2 (MAPK kinase 1/2), attenuated APOE-mediated CXCL5 secretion. The roles of TAK1, IκKß, TPL2, and JNK in APOE-mediated CXCL5 secretion were verified by RNA interference. Furthermore, RNA interference showed that after APOE stimulation, both NF-κB p65 and TPL2 were downstream of TAK1 and IκKß, whereas JNK was downstream of TPL2. In summary, elevated levels of APOE in the airway may activate a TLR4/TAK1/IκKß/NF-κB/TPL2/JNK signaling pathway that induces CXCL5 secretion by human asthmatic SAECs. These findings identify new roles for TLR4 and TPL2 in APOE-mediated proinflammatory responses in asthma.
Assuntos
Apolipoproteínas E/metabolismo , Asma/metabolismo , Quimiocina CXCL5/metabolismo , Células Epiteliais/metabolismo , Sistema Respiratório/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Quimiocinas/metabolismo , Humanos , Inflamação/metabolismo , Neutrófilos/metabolismo , RNA Mensageiro/metabolismoRESUMO
Objective.To describe the meaning given by adolescents and young adults to the changes in their bodies and corporality after a spinal cord injury. Methods. Qualitative study based on symbolic interactionism in which 12 adolescents and young adults, who had suffered spinal cord injury 6 months or more before, participated. The information was recollected through a series of in-depth interviews and field journals. The guidelines proposed by Corbin and Strauss were followed for the process of codification and categorization of the data. Results. Four categories were identified that describe the meanings given by participants to the changes in their bodies and corporality: Transformation of self-image, living with contradictions in the relationships with others, withstanding the burden of a disability and adapting to the new conditions. Conclusion. The results allow for the comprehension of the meanings that are given by the people who have suffered a spinal cord lesion to their situation. This will in turn open the possibility of offering these people a better individual nursing care that focuses more on the particular needs, so that both they and their families can be helped on their way to adaptation to the new situation.
Objetivo.Describir los significados que otorgan los adolescentes y adultos jóvenes a los cambios en el cuerpo y la corporalidad luego de una lesión traumática de la medula espinal. Métodos. Estudio cualitativo basado en el interaccionismo simbólico, en el cual participaron 12 adolescentes y adultos jóvenes con trauma raquimedular con un tiempo mayor a seis meses desde el evento. La información se recolectó a través de entrevistas de profundidad y diarios de campo. En el proceso de codificación y categorización de los datos, se siguieron los lineamientos propuestos por Corbin y Strauss. Resultados. Se identificaron cuatro categorías que describen los significados que tienen para los participantes los cambios en el cuerpo y la corporalidad: Transformación de la imagen de sí mismo, vivir contradicciones en las relaciones con otros, soportar la carga de la discapacidad y adaptarse a la nueva condición. Conclusión. Los resultados permiten comprender los significados que otorgan las personas con lesión medular a su condición, para poder brindar un cuidado de enfermería individual enfocado en las necesidades particulares, para ayudarlos a ellos y a sus familias a adaptarse a la situación.
Objetivo.Descrever os significados que outorgam os adolescentes e adultos jovens às mudanças no corpo e a corporalidade após de uma lesão traumática da medula espinal. Métodos. Estudo qualitativo baseado no interacionismo simbólico, no qual participaram 12 adolescentes e adultos jovens com trauma raquimedular com um tempo maior a seis meses desde o acontecimento. A informação se recolheu através de entrevistas de profundidade e diários de campo. No processo de codificação e categorização dos dados, se seguiram os alinhamentos propostos por Corbin e Strauss. Resultados. Se identificaram quatro categorias que descrevem os significados que têm para os participantes as mudanças no corpo e a corporalidade: Transformação da imagem de si mesmo, viver contradições nas relações com outros, suportar a carga da deficiência e adaptar-se á nova condição. Conclusão. Os resultados permitem compreender os significados que outorgam as pessoas com lesão medular a sua condição, para poder brindar um cuidado de enfermagem individual enfocado nas necessidades particulares, para ajuda-los a eles e a suas famílias a adaptar-se à situação.
Assuntos
Humanos , Traumatismos da Medula Espinal , Teoria de Enfermagem , Adolescente , Pessoas com Deficiência , Adaptação a Desastres , Adulto JovemRESUMO
Alterations in mitophagy have been increasingly linked to aging and age-related diseases. There are, however, no convenient methods to analyze mitophagy in vivo. Here, we describe a transgenic mouse model in which we expressed a mitochondrial-targeted form of the fluorescent reporter Keima (mt-Keima). Keima is a coral-derived protein that exhibits both pH-dependent excitation and resistance to lysosomal proteases. Comparison of a wide range of primary cells and tissues generated from the mt-Keima mouse revealed significant variations in basal mitophagy. In addition, we have employed the mt-Keima mice to analyze how mitophagy is altered by conditions including diet, oxygen availability, Huntingtin transgene expression, the absence of macroautophagy (ATG5 or ATG7 expression), an increase in mitochondrial mutational load, the presence of metastatic tumors, and normal aging. The ability to assess mitophagy under a host of varying environmental and genetic perturbations suggests that the mt-Keima mouse should be a valuable resource.
Assuntos
Proteínas Luminescentes/metabolismo , Camundongos Transgênicos , Mitofagia , Envelhecimento/fisiologia , Animais , Proteínas Luminescentes/genética , Camundongos , Especificidade de Órgãos , Oxigênio/metabolismoRESUMO
Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-α activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-α. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-α-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction.
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Necrose/enzimologia , Sirtuína 2/genética , Sirtuína 2/metabolismo , Acetilação , Animais , Linhagem Celular , Feminino , Células HEK293 , Células HeLa , Humanos , Células Jurkat , Masculino , Camundongos , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Ligação Proteica , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
Withdrawal of nutrients triggers an exit from the cell division cycle, the induction of autophagy, and eventually the activation of cell death pathways. The relation, if any, among these events is not well characterized. We found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 to regulate the transcription of the gene encoding the cell cycle inhibitor p21(CDKN1A). With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 partially rescued postnatal lethality in Atg7(-/-) mice. Thus, when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways.
Assuntos
Proteínas Associadas aos Microtúbulos/metabolismo , Estresse Fisiológico , Proteína Supressora de Tumor p53/metabolismo , Enzimas Ativadoras de Ubiquitina/metabolismo , Animais , Apoptose , Autofagia , Proteína 7 Relacionada à Autofagia , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Células Cultivadas , Quinase do Ponto de Checagem 2 , Inibidor de Quinase Dependente de Ciclina p21/genética , Dano ao DNA , Regulação da Expressão Gênica , Humanos , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Multimerização Proteica , Proteínas Serina-Treonina Quinases/genética , Transcrição Gênica , Enzimas Ativadoras de Ubiquitina/genéticaRESUMO
Oncogene-induced senescence (OIS) is characterized by permanent growth arrest and the acquisition of a secretory, pro-inflammatory state. Increasingly, OIS is viewed as an important barrier to tumorgenesis. Surprisingly, relatively little is known about the metabolic changes that accompany and therefore may contribute to OIS. Here, we have performed a metabolomic and bioenergetic analysis of Ras-induced senescence. Profiling approximately 300 different intracellular metabolites reveals that cells that have undergone OIS develop a unique metabolic signature that differs markedly from cells undergoing replicative senescence. A number of lipid metabolites appear uniquely increased in OIS cells, including a marked increase in the level of certain intracellular long chain fatty acids. Functional studies reveal that this alteration in the metabolome reflects substantial changes in overall lipid metabolism. In particular, Ras-induced senescent cells manifest a decline in lipid synthesis and a significant increase in fatty acid oxidation. Increased fatty acid oxidation results in an unexpectedly high rate of basal oxygen consumption in cells that have undergone OIS. Pharmacological or genetic inhibition of carnitine palmitoyltransferase 1, the rate-limiting step in mitochondrial fatty acid oxidation, restores a pre-senescent metabolic rate and, surprisingly, selectively inhibits the secretory, pro-inflammatory state that accompanies OIS. Thus, Ras-induced senescent cells demonstrate profound alterations in their metabolic and bioenergetic profiles, particularly with regards to the levels, synthesis and oxidation of free fatty acids. Furthermore, the inflammatory phenotype that accompanies OIS appears to be related to these underlying changes in cellular metabolism.
Assuntos
Senescência Celular/genética , Metabolismo Energético/genética , Metabolismo dos Lipídeos/genética , Oncogenes , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Citocinas/biossíntese , Perfilação da Expressão Gênica , Humanos , Inflamação/genética , Metabolômica/métodos , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Consumo de OxigênioRESUMO
Las lesiones de la médula espinal constituyen una experiencia devastadora para las personas, debido a las secuelas súbitas y permanentes que ocasionan a nivel motor, sensitivo y autónomo. Objetivo: describir los significados que tienen para las personas con paraplejia, secundaria a una lesión traumática de la médula espinal, los cambios en el cuerpo y la corporalidad. Método: el artículo es una parte de un estudio cualitativo de teoría fundamentada, guiado por los lineamientos de Corbin y Strauss (2008). La información se recolectó a través de 22 entrevistas de profundidad, con participantes vinculados a una institución hospitalaria mediante la estrategia de bola de nieve. Las entrevistas fueron grabadas y transcritas en su totalidad, y el proceso de recolección y análisis de los datos fue paralelo. Resultados: el estudio describe nueve categorías que reflejan el impacto de los cambios en el cuerpo y en la corporalidad en las personas con paraplejia. El análisis de los datos muestra que, con el tiempo, las personas adquieren consciencia de las secuelas, aprenden a reconocer los nuevos patrones de expresión de su cuerpo, desarrollan nuevas habilidades. Se amoldan al uso de equipos y aditamentos y descubren una nueva normalidad, cuando asimilan los cambios en el ser y se aceptan a sí mismas con la discapacidad. Los resultados guían a los profesionales de la salud en general y a los de enfermería en particular, para el cuidado encaminado a reconocer el nuevo cuerpo y reconstruir una nueva corporalidad.
Spinal cord injuries are a devastating experience for people due to sudden and permanent sequels caused in terms of movility, sensitivity and independence. Purpose: describe the meaning of changes in the body and embodiment for paraplegic persons. Method: the paper is part of a qualitative study of grounded theory, oriented by the guidelines of Corbin e Strauss (2008). Information was gathered through 22 in-depth interviews, with participants linked to a hospital institution through the snowball strategy. Interviews were recorded and typed in full, and the process of gathering and analyzing data was performed in parallel. Results: the study describes nine categories that reflect the impact of changes in the body and corporality of paraplegic persons. The analysis of data shows that, with the passing of time, people are more aware of the sequels, they learn to recognize new patterns of corporal expression, develop new skills, adapt themselves to the use of equipment and fittings and discover a new kind of normality when they embrace the changes and accept their physical handicap. The results guide health-care professionals, in general, and nurses, in particular, towards a practice of care aimed at recognizing the new body and reconstructing a new corporality.
As lesões da medula espinal são uma experiência devastadora para as pessoas, por causa das sequelas súbitas e permanentes que causam ao nível motor, sensitivo e autônomo. Objetivo: descrever o significado que as mudanças no corpo e na corporalidade tem para pessoas paraplégicas. Método: o trabalho faz parte de um estudo qualitativo de teoria fundamentada, orientado pelas orientações de Corbin e Strauss (2008). A informação foi compilada através de 22 entrevistas em profundidade, com participantes vinculados a uma instituição hospitalar mediante a estratégia da bola de neve. As entrevistas foram gravadas e transcritas totalmente, e o processo de compilação e análise de dados foi paralelo. Resultados: o estudo descreve nove categorias que refletem o impacto das mudanças no corpo e na corporalidade nas pessoas paraplégicas. A análise dos dados demonstra que, com o passo do tempo, as pessoas são mais cientes das seque-las, apreendem a reconhecer os novos padrões de expressão do corpo, desenvolvem novas habilidades, adaptam-se ao uso de equipamentos e acessórios e descobrem uma nova normalidade quando assimilam os câmbios e aceitam sua deficiência física. Os resultados orientam os professionais da saúde em geral e da enfermagem em particular para um cuidado voltado ao reconhecimento do novo corpo e à reconstrução duma nova corporalidade.