RESUMO
Hepatocellular carcinoma (HCC) carries a poor prognosis with no effective treatment available other than liver transplantation for selected patients. Vascular invasion of HCC is one of the most important negative predictor of survival. As the regulation of invasion of HCC cells is not well understood, our aim was to study the mechanisms by which galectin 3, a ß-galactosidase-binding lectin mediates HCC cell migration. HCC was induced by N-diethylnitrosamine in wild-type and galectin 3(-/-) mice, and tumor formation, histology, and tumor cell invasion were assessed. The galectin 3(-/-) mice developed significantly smaller tumor burden with a less invasive phenotype than the wild-type animals. Galectin 3 was upregulated in the wild-type HCC tumor tissue, but not in the surrounding parenchyma. Galectin 3 expression in HCC was induced by NF-κB transactivation as determined by chromatin immunoprecipitation assays. In vitro studies assessed the pro-migratory effects of galectin 3. The migration of hepatoma cells was significantly decreased after transfection by the galectin 3 siRNA and also after using the Rho kinase inhibitor Y-27632. The reorganization of the actin cytoskeleton, RhoA GTPase activity and the phosphorylation of MLC2 (myosin light chain 2) were decreased in the galectin 3 siRNA-transfected cells. In addition, in vitro and in vivo evidence showed that galectin 3 deficiency reduced hepatoma cell proliferation and increased their apoptosis rate. In conclusion, galectin 3 is an important lectin that is induced in HCC cells, and promotes hepatoma cell motility and invasion by an autocrine pathway. Targeting galectin 3 therefore could be an important novel treatment strategy to halt disease progression.
Assuntos
Carcinoma Hepatocelular/metabolismo , Galectina 3/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Quinase de Cadeia Leve de Miosina/metabolismo , Proteínas de Neoplasias/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/metabolismo , Citoesqueleto de Actina/patologia , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Miosinas Cardíacas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Galectina 3/antagonistas & inibidores , Galectina 3/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cadeias Leves de Miosina/metabolismo , Quinase de Cadeia Leve de Miosina/antagonistas & inibidores , Quinase de Cadeia Leve de Miosina/química , Invasividade Neoplásica , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/agonistas , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/genéticaRESUMO
This study adapts an existing methodology in psychology to assess congruence relationships in entrepreneurship management. More specifically, it describes the application of a response surface method to examine the congruence effect of two predictor variables on an outcome variable. The study presents both visual and text presentations to serve as a guideline that can aid management researchers in adapting the method. The paper underscores three strengths of using the response surface method as a robust analytical approach to evaluating congruent and incongruent relationships.â¢The response surface method can be used to examine congruency and incongruency between variables in the field of management in general and entrepreneurship management in particular.â¢The results can be visualized as two- and three-dimensional graphs.â¢Compared with a traditional approach, the response surface method offers a clearer visual representation of a focal relationship.
RESUMO
BACKGROUND: Repeated practice to acquire expertise could result in the structural and functional changes in relevant brain circuits as a result of long-term potentiation, neurogenesis, glial genesis, and remodeling. PURPOSE: The goal of this study is to use surface-based morphology (SBM) to study cortical thickness differences in Chinese chess experts and novices, and to use regions of cortical thickness differences as seeds to guide a resting state connectivity analysis of the same population. METHODS: A raw public dataset from Huaxi MR Research Center consisting of 29 Chinese chess experts and 29 novices was used in this study, with both T1-weighted and resting state functional MRI. Surface based morphometry was performed on the T1 images with the Freesurfur pipeline, with a vertex significance threshold of p<0.05 and a cluster false discovery rate of α < 0.05. Regions with significant differences were used in a seed-based comparison of resting state functional connectivity carried out with Statistical Parameter Mapping (SPM) and the Connectivity Toolbox (CONN). Regions of connectivity differences within groups were computed with a voxel significance threshold of p<0.05 and a cluster false discovery rate of α < 0.01. RESULTS: Ten regions of the cortex of Chinese chess experts were found to be thinner than chess novices, including regions involved in visual processing, attention, working and episodic memory, and mental imagery, as well as several regions in the prefrontal cortex. There were no regions where experts' cortices were thicker than novices. Three of the thinner regions exhibited increased functional connectivity to distant brain regions in chess experts. CONCLUSIONS: Brain regions that are structurally affected by chess training are associated with processes that would likely have a high utility in chess expertise. Using a hierarchical control model, we hypothesize that the functional changes linked with some of these structural changes are related to the professionally trained chess players' ability to perceive and use contextual information, visuospatial perception, and outcome prediction in the domain of chess, all contributing to their exceptional performance.
Assuntos
Encéfalo/ultraestrutura , Cognição , Percepção , Adolescente , Adulto , Atenção , Mapeamento Encefálico , Jogos Recreativos/psicologia , Humanos , Rede Nervosa , Adulto JovemRESUMO
BACKGROUND: Repeated practice to acquire expertise could result in the structural and functional changes in relevant brain circuits as a result of long-term potentiation, neurogenesis, glial genesis, and remodeling. PURPOSE: The goal of this study is to use task fMRI to study the brain of expert radiologists performing a diagnosis task where a series of medical images were presented during fMRI acquisition for 12s and participants were asked to choose a diagnosis. Structural and diffusion-tensor MRI were also acquired. METHODS: Radiologists (N = 12, 11M, 38.2±10.3 years old) and non-radiologists (N = 17, 15M, 30.6±5.5 years old) were recruited with informed consent. Medical images were presented for 12 s and three multiple choices were displayed and the participants were asked to choose a diagnosis. fMRI, structural and diffusion-tensor MRI were acquired. fMRI analysis used FSL to determine differences in fMRI responses between groups. Voxel-wise analysis was performed to determine if subcortical volume, cortical thickness and fractional anisotropy differed between groups. Correction for multiple comparisons used false discovery rate. RESULTS: Radiologists showed overall lower task-related brain activation than non-radiologists. Radiologists showed significantly lower activation in the left lateral occipital cortex, left superior parietal lobule, occipital pole, right superior frontal and precentral gyri, lingual gyrus, and the left intraparietal sulcus (p<0.05). There were no significant differences between groups in cortical thickness, subcortical volume and fractional anisotropy (p>0.05). CONCLUSIONS: Radiologists and non-radiologists had no significant difference in structural metrics. However, in diagnosis tasks, radiologists showed markedly lower task-related brain activations overall as well as a number of high-order visual and non-visual brain regions than non-radiologists. Some brain circuits appear to be uniquely associated with differential-diagnosis paradigm expertise that are not involved in simpler object-recognition cases. Improved understanding of the brain circuitry involved in acquisition of expertise might be used to design optimal training paradigms.
Assuntos
Encéfalo/fisiologia , Imageamento por Ressonância Magnética , Adulto , Encéfalo/anatomia & histologia , Encéfalo/diagnóstico por imagem , Feminino , Lobo Frontal/anatomia & histologia , Lobo Frontal/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/anatomia & histologia , Lobo Occipital/fisiologia , Lobo Parietal/anatomia & histologia , Lobo Parietal/fisiologia , RadiologistasRESUMO
BACKGROUND AND PURPOSE: The purpose of this study was to assess the initial post-market experience of the device and how it is compared with the Penumbra Pivotal trial used to support the 510k application. METHODS: A retrospective case review of 157 consecutive patients treated with the Penumbra system at seven international centers was performed. Primary endpoints were revascularization of the target vessel (TIMI score of 2 or 3), good functional outcome as defined by a modified Rankin scale (mRS) score of ≤2 and incidence of procedural serious adverse events. Results were compared with those of the Penumbra pivotal trial. RESULTS: A total of 157 vessels were treated. Mean baseline values at enrollment were: age 65â years, NIHSS score 16. After use of the Penumbra system, 87% of the treated vessels were revascularized to TIMI 2 (54%) or 3 (33%) as compared with 82% reported in the Pivotal trial. Nine procedural serious adverse events were reported in 157 patients (5.7%). All-cause mortality was 20% (32/157), and 41% had a mRS of ≤2 at 90-day follow-up as compared with only 25% in the Pivotal trial. Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not. CONCLUSION: Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial. However, the proportion of patients who had good functional outcome was higher than expected.
Assuntos
Isquemia Encefálica/cirurgia , Revascularização Cerebral/métodos , Transtornos Cerebrovasculares/cirurgia , Vigilância de Produtos Comercializados/normas , Acidente Vascular Cerebral/cirurgia , Dispositivos de Acesso Vascular/normas , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , Revascularização Cerebral/instrumentação , Revascularização Cerebral/tendências , Transtornos Cerebrovasculares/diagnóstico por imagem , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados/tendências , Estudos Retrospectivos , Acidente Vascular Cerebral/diagnóstico por imagem , Trombectomia/instrumentação , Trombectomia/métodos , Trombectomia/tendências , Estados Unidos/epidemiologia , Dispositivos de Acesso Vascular/tendênciasRESUMO
BACKGROUND: Patients with diabetes have increased incidence and severity of periodontal disease not accounted for by differences in the subgingival microbial infection. Poor glycemic control has been consistently associated with periodontal disease severity. Also, recent evidence suggests that hyperglycemia may induce inflammatory cytokine production. Few studies, however, have examined local biochemical measures of periodontal inflammation in patients with type 2 diabetes. The aim of this study was to determine whether glycemic control was related to gingival crevicular fluid (GCF) levels of interleukin-1beta (IL-1beta). METHODS: GCF samples were collected from 45 patients with type 2 diabetes and untreated chronic periodontitis. Plaque index (PI), bleeding on probing (BOP), probing depth (PD), and attachment level (AL) were recorded at six sites per tooth. IL-1beta levels were determined from individual GCF samples by enzyme-linked immunoabsorbent assay (ELISA). Individual site and mean patient values were calculated. Glycated hemoglobin (HbA1c) levels were measured from anticoagulated whole blood using an automated affinity chromatography system. Serum glucose was also determined. RESULTS: Clinical periodontal measures (PD, AL, BOP) and measures of glycemic control (HbA1c, random glucose) were significantly correlated with GCF IL-1beta. Patients with greater than 8% HbA1c had significantly higher mean GCF IL-1beta levels than patients with less than 8% HbA1c. In a multivariate model adjusting for age, gender, PD, AL, BOP, and PI, HbA1c and random glucose were independent predictors of high GCF IL-1beta. CONCLUSIONS: Poor glycemic control is associated with elevated GCF IL-1beta. These data are consistent with the hypothesis that hyperglycemia contributes to an heightened inflammatory response, and suggests a mechanism to account for the association between poor glycemic control and periodontal destruction.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Líquido do Sulco Gengival/imunologia , Interleucina-1/análise , Periodontite/imunologia , Adulto , Fatores Etários , Idoso , Doença Crônica , Índice de Placa Dentária , Diabetes Mellitus Tipo 2/prevenção & controle , Feminino , Líquido do Sulco Gengival/química , Hemorragia Gengival/classificação , Hemoglobinas Glicadas/análise , Humanos , Hiperglicemia/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Perda da Inserção Periodontal/classificação , Bolsa Periodontal/classificação , Fatores SexuaisRESUMO
Galectin-3 (Gal 3) is a glycan-binding protein that can be secreted by activated macrophages and mast cells at inflammation sites and plays an important role in inflammatory diseases caused by Bacteria and their products, such as lipopolysaccharides (LPS). Although it is well established that Gal 3 can interact with LPS, the pathophysiological importance of LPS/Gal 3 interactions is not fully understood. Data presented herein demonstrate for the first time that the interaction of Gal 3, either via its carbohydrate binding C-terminal domain or via its N-terminal part, with LPS from different bacterial strains, enhances the LPS-mediated neutrophil activation in vitro. Gal 3 allowed low LPS concentrations (1 µg/mL without serum, 1 ng/mL with serum) to upregulate CD11b expression and reactive oxygen species (ROS) generation on human neutrophils in vitro and drastically enhanced the binding efficiency of LPS to the neutrophil surface. These effects required LPS preincubation with Gal 3, before neutrophil stimulation and involved specific Gal 3/LPS interaction. A C-terminal Gal-3 fragment, which retains the lectin domain but lacks the N-terminal part, was still able to bind both to Escherichia coli LPS and to neutrophils, but had lost the ability to enhance neutrophil response to LPS. This result emphasizes the importance of an N-terminus-mediated Gal 3 oligomerization induced by its interaction with LPS. Finally we demonstrated that Balb/C mice were more susceptible to LPS-mediated shock when LPS was pretreated with Gal 3. Altogether, these results suggest that multimeric interactions between Gal 3 oligomers and LPS potentiate its pro-inflammatory effects on neutrophils.
Assuntos
Galectina 3/metabolismo , Lipopolissacarídeos/toxicidade , Ativação de Neutrófilo/efeitos dos fármacos , Animais , Antígeno CD11b/metabolismo , Células Cultivadas , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Multimerização Proteica/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND AND PURPOSE: The purpose of this study was to assess the initial post-market experience of the device and how it is compared with the Penumbra Pivotal trial used to support the 510k application. METHODS: A retrospective case review of 157 consecutive patients treated with the Penumbra system at seven international centers was performed. Primary endpoints were revascularization of the target vessel (TIMI score of 2 or 3), good functional outcome as defined by a modified Rankin scale (mRS) score of ≤2 and incidence of procedural serious adverse events. Results were compared with those of the Penumbra pivotal trial. RESULTS: A total of 157 vessels were treated. Mean baseline values at enrollment were: age 65 years, NIHSS score 16. After use of the Penumbra system, 87% of the treated vessels were revascularized to TIMI 2 (54%) or 3 (33%) as compared with 82% reported in the Pivotal trial. Nine procedural serious adverse events were reported in 157 patients (5.7%). All-cause mortality was 20% (32/157), and 41% had a mRS of ≤2 at 90-day follow-up as compared with only 25% in the Pivotal trial. Patients who were successfully revascularized by the Penumbra system had significantly better outcomes than those who were not. CONCLUSION: Initial post-market experience of the Penumbra system revealed that the revascularization rate and safety profile of the device are comparable to those reported in the Pivotal trial. However, the proportion of patients who had good functional outcome was higher than expected.