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1.
J Stroke Cerebrovasc Dis ; 26(12): 2954-2963, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28823492

RESUMO

INTRODUCTION: Stroke results in limited ability to produce voluntary muscle contraction and movement on one side of the body, leading to further muscle wasting and weakness. Neuromuscular electrical stimulation is often used to facilitate involuntary muscle contraction; however, the effect of neuromuscular electrical stimulation on muscle growth and strengthening processes in hemiparetic muscle is not clear. This study examined the skeletal muscle anabolic response of an acute bout of neuromuscular electrical stimulation in individuals with chronic stroke and healthy older adults. METHODS: Eleven individuals (59.8 ± 2.7 years old) were divided into a chronic stroke group (n = 5) and a healthy older adult control group (n = 6). Muscle biopsies were obtained before and after stimulation from the vastus lateralis of the hemiparetic leg for the stroke group and the right leg for the control group. The neuromuscular electrical stimulation protocol consisted of a 60-minute, intermittent stimulation train at 60 Hz. Phosphorylation of mammalian target of rapamycin and ribosomal protein S6 kinase beta-1 were analyzed by Western blot. FINDINGS: An acute bout of neuromuscular electrical stimulation increased phosphorylation of mammalian target of rapamycin (stroke: 56.0%; control: 51.4%; P = .002) and ribosomal protein S6 kinase beta-1 (stroke: 131.2%; control: 156.3%; P = .002) from resting levels to post-neuromuscular electrical stimulation treatment, respectively. Phosphorylated protein content was similar between stroke and control groups at both time points. CONCLUSION: Findings suggest that paretic muscles of patients with chronic stroke may maintain ability to stimulate protein synthesis machinery in response to neuromuscular electrical stimulation.


Assuntos
Terapia por Estimulação Elétrica , Contração Muscular , Junção Neuromuscular/fisiopatologia , Paresia/terapia , Músculo Quadríceps/inervação , Transdução de Sinais , Acidente Vascular Cerebral/terapia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Junção Neuromuscular/metabolismo , Paresia/diagnóstico , Paresia/metabolismo , Paresia/fisiopatologia , Fosforilação , Músculo Quadríceps/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento
2.
J Thorac Oncol ; 12(8): 1268-1279, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28483607

RESUMO

INTRODUCTION: Proinflammatory cytokine interleukin-17A (IL-17A) is overexpressed in a subset of patients with lung cancer. We hypothesized that IL-17A promotes a protumorigenic inflammatory phenotype and inhibits antitumor immune responses. METHODS: We generated bitransgenic mice expressing a conditional IL-17A allele along with conditional KrasG12D and performed immune phenotyping of mouse lungs, a survival analysis, and treatment studies with antibodies either blocking programmed cell death 1 (PD-1) or IL-6 or depleting neutrophils. To support the preclinical findings, we analyzed human gene expression data sets and immune profiled patient lung tumors. RESULTS: Tumors in IL-17:KrasG12D mice grew more rapidly, resulting in a significantly shorter survival as compared with that of KrasG12D mice. IL-6, granulocyte colony-stimulating factor (G-CSF), milk fat globule-EGF factor 8 protein, and C-X-C motif chemokine ligand 1 were increased in the lungs of IL17:Kras mice. Time course analysis revealed that levels of tumor-associated neutrophils were significantly increased, and lymphocyte recruitment was significantly reduced in IL17:KrasG12D mice as compared with in KrasG12D mice. In therapeutic studies PD-1 blockade was not effective in treating IL-17:KrasG12D tumors. In contrast, blocking IL-6 or depleting neutrophils with an anti-Ly-6G antibody in the IL17:KrasG12D tumors resulted in a clinical response associated with T-cell activation. In tumors from patients with lung cancer with KRAS mutation we found a correlation between higher levels of IL-17A and colony- stimulating factor 3 and a significant correlation among high neutrophil and lower T-cell numbers. CONCLUSIONS: Here we have shown that an increase in a single cytokine, IL-17A, without additional mutations can promote lung cancer growth by promoting inflammation, which contributes to resistance to PD-1 blockade and sensitizes tumors to cytokine and neutrophil depletion.


Assuntos
Interleucina-17/biossíntese , Neoplasias Pulmonares/imunologia , Neutrófilos/imunologia , Receptor de Morte Celular Programada 1/imunologia , Animais , Progressão da Doença , Expressão Gênica , Humanos , Interleucina-17/imunologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Mutação , Neutrófilos/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/imunologia
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