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BACKGROUND: Cognitive behavioral therapy for insomnia (CBTi) is the first-line therapy for chronic insomnia. Mobile app-based CBTi (MCBTi) can enhance the accessibility of CBTi treatment; however, few studies have evaluated the effectiveness of MCBTi using a multicenter, randomized controlled trial design. OBJECTIVE: We aimed to assess the efficacy of Somzz, an MCBTi that provides real-time and tailored feedback to users, through comparison with an active comparator app. METHODS: In our multicenter, single-blind randomized controlled trial study, participants were recruited from 3 university hospitals and randomized into a Somzz group and a sleep hygiene education (SHE) group at a 1:1 ratio. The intervention included 6 sessions for 6 weeks, with follow-up visits over a 4-month period. The Somzz group received audiovisual sleep education, guidance on relaxation therapy, and real-time feedback on sleep behavior. The primary outcome was the Insomnia Severity Index score, and secondary outcomes included sleep diary measures and mental health self-reports. We analyzed the outcomes based on the intention-to-treat principle. RESULTS: A total of 98 participants were randomized into the Somzz (n=49, 50%) and SHE (n=49, 50%) groups. Insomnia Severity Index scores for the Somzz group were significantly lower at the postintervention time point (9.0 vs 12.8; t95=3.85; F2,95=22.76; ηp2=0.13; P<.001) and at the 3-month follow-up visit (11.3 vs 14.7; t68=2.61; F2,68=5.85; ηp2=0.03; P=.01) compared to those of the SHE group. The Somzz group maintained their treatment effect at the postintervention time point and follow-ups, with a moderate to large effect size (Cohen d=-0.62 to -1.35; P<.01 in all cases). Furthermore, the Somzz group showed better sleep efficiency (t95=-3.32; F2,91=69.87; ηp2=0.41; P=.001), wake after sleep onset (t95=2.55; F2,91=51.81; ηp2=0.36; P=.01), satisfaction (t95=-2.05; F2,91=26.63; ηp2=0.20; P=.04) related to sleep, and mental health outcomes, including depression (t95=2.11; F2,94=29.64; ηp2=0.21; P=.04) and quality of life (t95=-3.13; F2,94=54.20; ηp2=0.33; P=.002), compared to the SHE group after the intervention. The attrition rate in the Somzz group was 12% (6/49). CONCLUSIONS: Somzz outperformed SHE in improving insomnia, mental health, and quality of life. The MCBTi can be a highly accessible, time-efficient, and effective treatment option for chronic insomnia, with high compliance. TRIAL REGISTRATION: Clinical Research Information Service (CRiS) KCT0007292; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=22214&search_page=L.
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Terapia Cognitivo-Comportamental , Aplicativos Móveis , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/terapia , Método Simples-Cego , Terapia Cognitivo-Comportamental/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Resultado do TratamentoRESUMO
Magnesium (Mg) has many unique properties suitable for applications in the fields of energy conversion and storage. These fields presently rely on noble metals for efficient performance. However, among other challenges, noble metals have low natural abundance, which undermines their sustainability. Mg has a high negative standard reduction potential and a unique crystal structure, and its low melting point at 650 °C makes it a good candidate to replace or supplement numerous other metals in various energy applications. These attractive features are particularly helpful for improving the properties and limits of materials in energy systems. However, knowledge of Mg and its practical uses is still limited, despite recent studies which have reported Mg's key roles in synthesizing new structures and modifying the chemical properties of materials. At present, information about Mg chemistry has been rather scattered without any organized report. The present review highlights the chemistry of Mg and its uses in energy applications such as electrocatalysis, photocatalysis, and secondary batteries, among others. Future perspectives on the development of Mg-based materials are further discussed to identify the challenges that need to be addressed.
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Background and Objectives: The mechanisms involved in the development of brain metastasis (BM) remain elusive. Here, we investigated whether BM is associated with spine involvement in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: A consecutive 902 patients with metastatic NSCLC were included from the Inha Lung Cancer Cohort. Patients with BM at diagnosis or subsequent BM development were evaluated for both spine involvement in NSCLC and anatomic proximity of BM to the cerebrospinal fluid (CSF) space. Results: At diagnosis, BM was found in 238 patients (26.4%) and bone metastasis was found in 393 patients (43.6%). In patients with bone metastasis, spine involvement was present in 280 patients. BM subsequently developed in 82 (28.9%) of 284 patients without BM at diagnosis. The presence of spine metastasis was associated with BM at diagnosis and subsequent BM development (adjusted odd ratios and 95% confidence intervals = 2.42 and 1.74-3.37, p < 0.001; 1.94 and 1.19-3.18, p = 0.008, respectively). Most patients with spine metastasis, either with BM at diagnosis or subsequent BM, showed BM lesions located adjacent (within 5mm) to the CSF space (93.8% of BM at the diagnosis, 100% of subsequent BM). Conclusions: These findings suggest that the presence of spine involvement is a risk factor for BM development in NSCLC patients with bone metastasis.
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Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Razão de Chances , PacientesRESUMO
OBJECTIVES: Evidence suggests that emotion regulation difficulty may play an important role in the association between life stress, sleep disturbance and depressive symptoms. We proposed two models depicting the possible moderating roles of prefrontal cortex activation during emotion regulation in the associations among these variables and tested them. We hypothesized that (1) the association between stress and sleep disturbance would differ across prefrontal cortex activation during emotion regulation (moderation model) and (2) the indirect effects of stress on depressive symptoms through sleep disturbance would depend on prefrontal cortex activation during emotion regulation (moderated mediation model). METHODS: Forty-eight healthy adults without sleep disorders based on nocturnal polysomnography participated in this study. They received functional magnetic resonance imaging scans while performing an emotion regulation task. They also completed questionnaires assessing life stress, sleep disturbance and depressive symptoms. The proposed models were tested using the PROCESS macro for SPSS. RESULTS: As hypothesized, there was a significant moderating effect of prefrontal cortex activation during emotion regulation on the association between life stress and sleep disturbance. Furthermore, right lateral prefrontal cortex activation had a moderating role in the indirect effect of life stress on depressive symptoms through sleep disturbance. CONCLUSION: These findings highlight the important role of prefrontal cortex function during emotion regulation in the associations between stress, sleep disturbance and depressive symptoms. Increasing lateral prefrontal cortex recruitment when regulating the emotional response to negative life events may be critical for the prevention and intervention of depression as well as sleep problems.
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Regulação Emocional , Transtornos do Sono-Vigília , Adulto , Depressão/psicologia , Humanos , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/diagnóstico por imagem , Sono , Transtornos do Sono-Vigília/complicações , Estresse Psicológico/complicaçõesRESUMO
Osteoclasts (OCs) play important roles in bone remodelling and contribute to bone loss by increasing bone resorption activity. Excessively activated OCs cause diverse bone disorders including osteoporosis. Isovaleric acid (IVA), also known as 3-methylbutanoic acid is a 5-carbon branched-chain fatty acid (BCFA), which can be generated by bacterial fermentation of a leucine-rich diet. Here, we find that IVA suppresses differentiation of bone marrow-derived macrophages into OCs by RANKL. IVA inhibited the expression of OC-related genes. IVA-induced inhibitory effects on OC generation were attenuated by pertussis toxin but not by H89, suggesting a Gi -coupled receptor-dependent but protein kinase A-independent response. Moreover, IVA stimulates AMPK phosphorylation, and treatment with an AMPK inhibitor blocks IVA-induced inhibition of OC generation. In an ovariectomized mouse model, addition of IVA to the drinking water resulted in significant decrease of body weight gain and inhibited the expression of not only OC-related genes but also fusogenic genes in the bone tissue. IVA exposure also blocked bone destruction and OC generation in the bone tissue of ovariectomized mice. Collectively, the results demonstrate that IVA is a novel bioactive BCFA that inhibits OC differentiation, suggesting that IVA can be considered a useful material to control osteoclast-associated bone disorders, including osteoporosis.
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Reabsorção Óssea/prevenção & controle , Diferenciação Celular , Hemiterpenos/farmacologia , Osteoclastos/citologia , Osteoporose/prevenção & controle , Ovariectomia/efeitos adversos , Ácidos Pentanoicos/farmacologia , Animais , Remodelação Óssea , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Feminino , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoporose/patologia , Osteoporose/cirurgia , Transdução de SinaisRESUMO
Osteoporosis is a disease in which bone mineral density decreases due to abnormal activity of osteoclasts, and is commonly found in post-menopausal women who have decreased levels of female hormones. Sphingosylphosphorylcholine (SPC) is an important biological lipid that can be converted to sphingosine-1-phosphate (S1P) by autotaxin. S1P is known to be involved in osteoclast activation by stimulating osteoblasts, but bone regulation by SPC is not well understood. In this study, we found that SPC strongly inhibits RANKL-induced osteoclast differentiation. SPC-induced inhibitory effects on osteoclast differentiation were not affected by several antagonists of S1P receptors or pertussis toxin, suggesting cell surface receptor independency. However, SPC inhibited RANKL-induced calcineurin activation and subsequent NFATc1 activity, leading to decrease of the expression of Trap and Ctsk. Moreover, we found that bone loss in an experimental osteoporosis mouse model was recovered by SPC injection. SPC also blocked ovariectomy-induced body weight increase and Nfatc1 gene expression in mice. We also found that SPC inhibits RANKL-induced osteoclast differentiation in human macrophages. Since currently available treatments for osteoporosis, such as administration of female hormones or hormone receptor modulators, show serious side effects, SPC has potential as a new agent for osteoporosis treatment.
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Cálcio/metabolismo , Calmodulina/metabolismo , Osteoclastos/metabolismo , Osteoporose/metabolismo , Ovariectomia/efeitos adversos , Fosforilcolina/análogos & derivados , Esfingosina/análogos & derivados , Animais , Western Blotting , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Fosforilcolina/uso terapêutico , Reação em Cadeia da Polimerase em Tempo Real , Esfingosina/uso terapêutico , Microtomografia por Raio-XRESUMO
We have designed a method of harvesting electrical energy using plasmon-enhanced light pressure. A device was fabricated as a cut cone structure that optimizes light collection so that the weak incident light pressure can be sufficiently enhanced inside the cut cone to generate electrical energy. An increase in the device's current output is a strong indication that the pressure of incident light has been enhanced by the surface plasmons on a platinum layer inside the cut cone. The electrical energy harvested in a few minutes by irradiating pulsed laser light on a single micro device was possible to illuminate a blue LED.
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OBJECTIVE: We evaluated the prognostic impacts of body composition components measured by computed tomography (CT) in patients with liver cirrhosis. METHODS: A total of 160 cirrhotic patients who underwent CT and hepatic venous pressure gradient measurements were retrospectively enrolled. Cross-sectional areas of skeletal muscle, visceral and subcutaneous fat, and mean CT attenuation of trabecular bone of the fourth lumbar vertebral level (L4HU) were measured. RESULTS: Multivariate analysis showed model for end-stage liver disease score [hazard ratio (HR), 1.086; 95% confidence interval (CI), 1.020-1.156; P = 0.010], hepatic venous pressure gradient (HR, 1.076; 95% CI, 1.021-1.135; P = 0.006), sarcopenia (HR, 1.890; 95% CI, 1.032-3.462; P = 0.039), and L4HU (HR, 1.960 for L4HU <145 Hounsfield units; 95% CI, 1.094-3.512; P = 0.024) were independently associated with long-term mortality. In patients with decompensated cirrhosis, subcutaneous adipose tissue index was the only independent predictor (HR, 0.984; 95% CI, 0.969-0.999; P = 0.039). CONCLUSION: Body composition abnormalities determined by CT are associated with long-term prognosis in cirrhotic patients.
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Composição Corporal , Densidade Óssea , Doença Hepática Terminal/diagnóstico por imagem , Cirrose Hepática/mortalidade , Sarcopenia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Tecido Adiposo/diagnóstico por imagem , Doença Hepática Terminal/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Valor Preditivo dos Testes , Prognóstico , República da Coreia/epidemiologia , Estudos Retrospectivos , Sarcopenia/mortalidade , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420-0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment.
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Biomarcadores Tumorais/análise , Cistadenocarcinoma Seroso/metabolismo , Imunofluorescência/métodos , Neoplasias Ovarianas/metabolismo , Coloração e Rotulagem/métodos , Adulto , Idoso , Antígeno B7-H1/análise , Antígenos CD8/análise , Cistadenocarcinoma Seroso/diagnóstico , Feminino , Fatores de Transcrição Forkhead/análise , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Neoplasias Ovarianas/diagnóstico , Prognóstico , Análise de SobrevidaRESUMO
Formyl peptide receptors (FPRs) are G protein-coupled receptors mainly expressed in inflammatory myeloid cells. Previous reports demonstrated that human neutrophils express only FPR1 and FPR2 but not FPR3. Here, we found that FPR3 is expressed in sepsis patient derived neutrophils and Fpr3 is expressed in the mouse neutrophils. To test the role of Fpr3 in neutrophil activity, we synthesized Fpr3 pepducins and successfully developed an agonistic pepducin that stimulates Fpr3, eliciting calcium increase and chemotactic migration of neutrophils. We also found that administration of an Fpr3 pepducin in an experimental mouse sepsis model significantly increased the survival rate. The pepducin markedly inhibited lung injury, splenocyte apoptosis, and inflammatory cytokine production. Bacterial counts were significantly decreased by the pepducin in septic mice. Based on these results, we suggest that FPR3 can be regarded as a new target to control sepsis, and the newly generated Fpr3-based pepducin can be used for the development of anti-septic agents.
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Membrana Celular/metabolismo , Lipopeptídeos/uso terapêutico , Receptores de Formil Peptídeo/metabolismo , Sepse/tratamento farmacológico , Animais , Ceco/patologia , Membrana Celular/efeitos dos fármacos , Citocinas/biossíntese , Células HEK293 , Humanos , Mediadores da Inflamação/metabolismo , Ligadura , Lipopeptídeos/administração & dosagem , Lipopeptídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Punções , Sepse/patologiaRESUMO
BACKGROUND: Although biocides at low concentrations have been used to control pests, they can be more harmful than industrial chemicals as humans are directly and frequently exposed to such biocides. Benzalkonium chloride (BAC or BKC) is a non-toxic substance used to control pests. Recently, BAC has been increasingly used as a component in humidifier disinfectants in Korea, raising a serious health concern. Moreover, it poses significant health hazards to workers handling the chemical because of direct exposure. In the present study, we aimed to evaluate the respiratory toxicity of BAC due to its inhalation at exposure concentrations of 0.8 (T1 group), 4 (T2 group) and 20 (T3 group) mg/m3. RESULTS: In our previous study on the acute inhalational toxicity of BAC, bleeding from the nasal cavity was observed in all the rats after exposure to 50 mg/m3 BAC. Therefore, in this study, 20 mg/m3 was set as the highest exposure concentration, followed by 4 and 0.8 mg/m3 as the medium and low concentrations for 6 h/day and 14 days, respectively. After exposure, recovery periods of 2 and 4 weeks were provided. Additionally, alveolar lavage fluid was analyzed in males of the BAC-exposed groups at the end of exposure and 2 weeks after exposure to evaluate oxidative damage. In the T3 group exposed to BAC, deep breathing, hoarseness, and nasal discharge were observed along with a decline in feed intake and body weight, and nasal discharge was also observed in the T1 and T2 groups. ROS/RNS, IL-1ß, IL-6, and MIP-2 levels decreased in a concentration-dependent manner in the bronchoalveolar lavage fluid. Histopathological examination showed cellular changes in the nasal cavity and the lungs of the TI, T2, and T3 groups. CONCLUSIONS: As a result, it was confirmed that the target organs in the respiratory system were the nasal cavity and the lungs. The adverse effects were evaluated as reversible responses to oxidative damage. Furthermore, the no observed adverse effect level was found to be less than 0.8 mg/m3 and the lowest benchmark dose was 0.0031 mg/m3. Accordingly, the derived no-effect level of BAC was calculated as 0.000062 mg/m3.
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Poluentes Atmosféricos/toxicidade , Compostos de Benzalcônio/toxicidade , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Cavidade Nasal/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/imunologia , Relação Dose-Resposta a Droga , Exposição por Inalação/análise , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Cavidade Nasal/imunologia , Cavidade Nasal/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
This study was designed to analyze urinary proteins associated with ovarian cancer (OC) and investigate the potential urinary biomarker panel to predict malignancy in women with pelvic masses. We analyzed 23 biomarkers in urine samples obtained from 295 patients with pelvic masses scheduled for surgery. The concentration of urinary biomarkers was quantitatively assessed by the xMAP bead-based multiplexed immunoassay. To identify the performance of each biomarker in predicting cancer over benign tumors, we used a repeated leave-group-out cross-validation strategy. The prediction models using multimarkers were evaluated to develop a urinary ovarian cancer panel. After the exclusion of 12 borderline tumors, the urinary concentration of 17 biomarkers exhibited significant differences between 158 OCs and 125 benign tumors. Human epididymis protein 4 (HE4), vascular cell adhesion molecule (VCAM), and transthyretin (TTR) were the top three biomarkers representing a higher concentration in OC. HE4 demonstrated the highest performance in all samples withOC(mean area under the receiver operating characteristic curve (AUC) 0.822, 95% CI: 0.772-0.869), whereas TTR showed the highest efficacy in early-stage OC (AUC 0.789, 95% CI: 0.714-0.856). Overall, HE4 was the most informative biomarker, followed by creatinine, carcinoembryonic antigen (CEA), neural cell adhesion molecule (NCAM), and TTR using the least absolute shrinkage and selection operator (LASSO) regression models. A multimarker panel consisting of HE4, creatinine, CEA, and TTR presented the best performance with 93.7% sensitivity (SN) at 70.6% specificity (SP) to predict OC over the benign tumor. This panel performed well regardless of disease status and demonstrated an improved performance by including menopausal status. In conclusion, the urinary biomarker panel with HE4, creatinine, CEA, and TTR provided promising efficacy in predicting OC over benign tumors in women with pelvic masses. It was also a non-invasive and easily available diagnostic tool.
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Biomarcadores Tumorais/urina , Neoplasias Ovarianas/urina , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Modelos Estatísticos , Pré-Albumina/urina , Molécula 1 de Adesão de Célula Vascular/urina , Proteína 2 do Domínio Central WAP de Quatro Dissulfetos/análiseRESUMO
We found that formyl peptide receptor (FPR) 1 and FPR3 were expressed intracellularly and/or the nucleus of naïve CD4 T cell. Activation of naïve CD4 T cells with synthetic intracellular agonists dTAT-WKYMVm and CTP-WKYMVm for FPR members stimulated CD4 T cell migration via pertussis toxin-sensitive manner. Knockdown of FPR1, but not knockdown of FPR3, blocked dTAT-WKYMVm-induced naïve CD4 T cell migration. Stimulation of naïve CD4 T cells with dTAT-WKYMVm elicited the activation of ERK, p38â¯MAPK, and Akt. Activation of CD4 T cells with anti-CD3 and anti-CD28 antibodies caused surface expression of FPR1 and FPR3, but not FPR2. CD4 T cells isolated from sepsis patients expressed the three members of FPR family on their cell surface. Taken together, our results suggest that intracellular FPR in naïve CD4 T cells and surface FPRs in activated CD4 T cells might regulate immune responses by regulating CD4 T cell activity.
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Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/fisiologia , Movimento Celular/fisiologia , Receptores de Formil Peptídeo/metabolismo , Células Cultivadas , HumanosRESUMO
A double left brachiocephalic vein is an uncommon anatomic variation. Among these, a accessory branch with preaortic course is extremely rare. In this case, both branches of the left brachiocephalic vein were anterior to the aortic arch. We describe the computed tomography findings with volume-rendering imaging of this rare anatomic variation.
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Variação Anatômica , Aorta Torácica/anatomia & histologia , Veias Braquiocefálicas/anatomia & histologia , Idoso , Aorta Torácica/diagnóstico por imagem , Veias Braquiocefálicas/diagnóstico por imagem , Feminino , Humanos , Tomografia Computadorizada por Raios XRESUMO
Formyl peptide receptors (FPRs) are a family of classical chemoattractant receptors. Although FPRs are mainly expressed in phagocytic innate immune cells including monocytes/macrophages and neutrophils, recent reports demonstrated that additional different cell types such as T-lymphocytes and several non-immune cells also express functional FPRs. FPRs were first reported as a specific receptor to detect bacteria-derived N-formyl peptides. However, accumulating evidence has shown that FPRs can recognize various ligands derived from pathogens, mitochondria, and host. This review summarizes studies on some interesting endogenous agonists for FPRs. Here, we discuss functional roles of FPRs and their ligands concerning the regulation of cellular differentiation focusing on myeloid lineage cells. Accumulating evidence also suggests that FPRs may contribute to the control of inflammatory diseases. Here, we briefly review the current understanding of the functional role of FPRs and their ligands in inflammatory disorders in some animal disease models. J. Cell. Biochem. 118: 1300-1307, 2017. © 2017 Wiley Periodicals, Inc.
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Inflamação/metabolismo , Células Mieloides/citologia , Receptores de Formil Peptídeo/metabolismo , Animais , Diferenciação Celular , Modelos Animais de Doenças , Humanos , Ligantes , Células Mieloides/metabolismo , Receptores de Formil Peptídeo/agonistasRESUMO
BACKGROUND: Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC. METHODS: This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used. RESULTS: The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events. CONCLUSIONS: Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society.
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Adenocarcinoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Adenoide Cístico/tratamento farmacológico , Carcinoma Mucoepidermoide/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias das Glândulas Salivares/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Carcinoma Adenoide Cístico/secundário , Carcinoma Mucoepidermoide/secundário , Término Precoce de Ensaios Clínicos , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Cuidados Paliativos , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/secundário , República da Coreia , Neoplasias das Glândulas Salivares/patologia , Falha de TratamentoRESUMO
In this study, we identified scolopendrasin X, a novel antimicrobial peptide (AMP), from centipede Scolopendra subspinipes mutilans. Scolopendrasin X strongly stimulated mouse neutrophils, resulting in intracellular calcium increase, chemotactic migration through pertussis toxin-sensitive G-protein and phospholipase C pathway, and increased superoxide anion production in neutrophils. Target receptor for scolopendrasin X, formyl peptide receptor (FPR)2 mediated scolopendrasin X-induced neutrophil activation. Moreover, scolopendrasin X significantly blocked inflammatory cytokine production induced by lipopolysaccharide in mouse neutrophils. Taken together, our results suggest that the novel AMP scolopendrasin X can be used as a material to regulate neutrophil activity through FPR2.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Receptores de Formil Peptídeo/genética , Sequência de Aminoácidos , Animais , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Artrópodes/química , Cálcio/metabolismo , Quimiotaxia/efeitos dos fármacos , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/citologia , Neutrófilos/imunologia , Cultura Primária de Células , Receptores de Formil Peptídeo/agonistas , Receptores de Formil Peptídeo/imunologia , Superóxidos/metabolismo , Fosfolipases Tipo C/genética , Fosfolipases Tipo C/imunologiaRESUMO
Foreign body giant cell (FBGC) formation is associated with the inflammatory response following material implantation. However, the intracellular signaling events that regulate the process remain unclear. Here, we investigated the potential role of phospholipase C (PLC)γ1, a crucial enzyme required for growth factor-induced signaling, on FBGC formation. Knock-down of PLCγ1 using shRNA induced FBGC formation accompanied by increased expression of cathepsin K, DC-STAMP and CD36. Re-addition of PLCγ1 decreased FBGC formation. PLCγ1-deficiency caused a decrease in RUNX1 and subsequent PU.1 upregulation while subsequent rescue of RUNX1 in sh-PLCγ1-transfected cells strongly inhibited FBGC formation. FBGC generated by knock-down of PLCγ1 using shRNA resulted in strongly increased TNF-α production, with augmented activation of ERK, p38 MAPK and JNK, and subsequently NF-κB. Taken together, we suggest that PLCγ1 plays a role in the foreign body response by regulating the RUNX1/PU.1/DC-STAMP axis in macrophages.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Células Gigantes de Corpo Estranho/citologia , Macrófagos/citologia , Fosfolipase C gama/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Catepsina K/genética , Catepsina K/metabolismo , Fusão Celular , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Regulação para Baixo , Técnicas de Silenciamento de Genes , Células Gigantes de Corpo Estranho/metabolismo , Células HEK293 , Humanos , Macrófagos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Fosfolipase C gama/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Células RAW 264.7 , Transativadores/genética , Transativadores/metabolismo , Regulação para CimaRESUMO
OBJECTIVES: The purpose of this study was to compare the sonographic findings of angio lipomas with those of superficial lipomas. METHODS: Preoperative sonograms of 26 angiolipomas from 18 patients and 47 superficial lipomas from 43 patients that were confirmed by biopsy were reviewed retrospectively. The echo texture, echogenicity, internal echogenic stranding, vascularity, visualization of lateral and superficial-deep tumor capsules, shape, and tumor length, width, and length-to-width ratio were evaluated and compared between angiolipomas and superficial lipomas. RESULTS: Angiolipomas frequently appeared as heterogeneous (19 of 26 [73.1%]), hyperechoic (23 of 26 [88.5%]), and ovoid (17 of 26 [65.4%]) masses with lesser visualized lateral tumor capsules (6 of 26 [23.1%]), whereas superficial lipomas appeared as homogeneous (36 of 47 [76.6%]), isoechoic (35 of 47 [74.5%]), and spindle-shaped (23 of 47 [48.9%]) masses with well-visualized lateral capsules (33 of 47 [70.2%]), and the differences were statistically significant (P < .001). Vascularity was seen in 4 angiolipomas (16.7%) and in no superficial lipomas (0%). The mean length and width ± SD of angiolipomas (2.2 ± 1.02 and 0.6 ± 0.27 cm, respectively) were smaller than those of superficial lipomas (4.2 ± 1.52 and 1.1 ± 0.51 cm), with statistical significance (P< .001). The other sonographic findings did not reveal statistically significant differences between the tumor types. CONCLUSIONS: Sonography might help differentiate angiolipomas from superficial lipomas.
Assuntos
Angiolipoma/diagnóstico por imagem , Lipoma/diagnóstico por imagem , Ultrassonografia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
Sepsis is a serious, life-threatening, infectious disease. In this study, we demonstrate that sucrose methyl 3-formyl-4-methylpentanoate (SMFM), a novel natural compound isolated from garlic (Allium sativum L.), markedly enhances survival rates by inhibiting lung inflammation in a cecal ligation and puncture (CLP) experimental polymicrobial sepsis model. SMFM strongly reduced bacterial colony units from peritoneal fluid in CLP mice by stimulating the generation of reactive oxygen species. Lymphocyte apoptosis in spleens from CLP mice was also markedly decreased by SMFM administration. SMFM also significantly inhibited the production of proinflammatory cytokines, such as TNF-α, interleukin-1ß (IL-1ß) and IL-6, in CLP mice. Lipopolysaccharide-stimulated production of TNF-α and IL-6 were also strongly inhibited by SMFM in mouse bone marrow-derived macrophages. Taken together, our results indicate that SMFM has therapeutic effects against polymicrobial sepsis that are mediated by enhanced microbial killing and blockage of cytokine storm.