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1.
Comput Intell Neurosci ; 2019: 7529572, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049051

RESUMO

Feature extraction of motor imagery electroencephalogram (MI-EEG) has shown good application prospects in the field of medical health. Also, multivariate entropy-based feature extraction methods have been gradually applied to analyze complex multichannel biomedical signals, such as EEG and electromyography. Compared with traditional multivariate entropies, refined composite multivariate multiscale fuzzy entropy (RCmvMFE) overcomes the defect of unstable entropy values caused by the scale factor increase and is beneficial towards obtaining richer feature information. However, the coarse-grained process of RCmvMFE is mean filtered, which weakens Gaussian noise and is powerless against random impulse noise interference. This yields poor quality feature information and low accuracy classification. In this paper, RCmvMFE is improved (IRCmvMFE) by using composite filters in the coarse-grained procedure to enhance filter performance. Median filters are employed to remove the impulse noise interference from multichannel MI-EEG signals, and these filtered MI-EEGs are further smoothed by the mean filters. The multiscale IRCmvMFEs are calculated for all channels of composite filtered MI-EEGs, forming a feature vector, and a support vector machine is used for pattern classification. Based on two public datasets with different motor imagery tasks, the recognition results of 10 × 10-fold cross-validation achieved 99.43% and 99.86%, respectively, and the statistical analysis of experimental results was completed, showing the effectiveness of IRCmvMFE, as well. The proposed IRCmvMFE-based feature extraction method is superior compared to entropy-based and traditional methods.


Assuntos
Interfaces Cérebro-Computador , Eletroencefalografia , Entropia , Processamento de Sinais Assistido por Computador , Algoritmos , Eletroencefalografia/métodos , Humanos , Distribuição Normal , Máquina de Vetores de Suporte
2.
Leuk Res ; 79: 34-37, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831481

RESUMO

Hemorrhage is the typical manifestation of APL-related coagulopathy while thrombosis is infrequently reported. In a retrospective analysis with 33 patients with hyperleukocytic APL, we found 6 out of 33 hyperleukocytic APL patients presented with thrombosis rather than hemorrhage. A notable feature in these high-risk APL patients with thrombosis is that there were no significant abnormalities in fibrinogen (FIB), prothrombin time (PT) and activated partial thromboplastin time (APTT). Compared with the normal ranges, both the high-risk APL patients with thrombosis and the high-risk APL patients with hemorrhage had a significant increase in fibrinogen degradation product (FDP) and d-dimer levels. However, the group with hemorrhage had noticeably higher plasma levels of FDP and d-dimer than the group with thrombosis. To find a close relationship between coagulation markers and the onset of thrombotic events in patients with high-risk APL, the potential effects of FDP/FIB and d-dimer/FIB ratios as risk markers were investigated. We demonstrated that FDP/FIB and d-dimer/FIB ratios in the patients with high-risk APL with thrombosis showed higher ratios than the normal range but significantly lower ratios than the patients with high-risk APL-related hemorrhage. Our data demonstrated that the alteration in FDP/FIB and d-dimer/FIB ratios have more significant relevance than the levels of FIB, FDP or d-dimer as potential factors for predicting thrombosis and may help with designing more appropriately risk-adapted treatment protocols or personalized therapy.

3.
Medicine (Baltimore) ; 98(8): e14454, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30813145

RESUMO

BACKGROUND: Our previous studies demonstrate that the major histocompatibility complex (MHC) is associated with the progression of esophageal squamous cell carcinoma (ESCC). HLA-DQA1, which belongs to the MHC Class II family, may be a potential biomarker in ESCC progression. However, the association between HLA-DQA1 and ESCC in high-incidence area of northern China has not been well characterized. The purpose of this study is to investigate the relationship of HLA-DQA1 expression with the progression and prognosis of ESCC. METHODS: We analyzed the expression profiles of HLA-DQA1 in esophageal cancer (EC) samples in the TCGA database and validated HLA-DQA1 expression by immunohistochemistry, western blotting, and quantitative reverse-transcription polymerase chain reaction in matched EC and normal tissues, respectively. The correlation between HLA-DQA1 expression and clinicopathologic characteristics of ESCC was further analyzed. RESULT: Immunohistochemical analysis indicated that the expression level of HLA-DQA1 in ESCC tissues was significantly higher than the matched normal tissues (P < .001). HLA-DQA1 mRNA and protein expression were significantly higher in ESCC tissues compared to the matched normal tissues. Patients with family history negative or with tumor sizes >4 cm were associated with higher HLA-DQA1 expression levels. A prognostic significance of HLA-DQA1 was also found by the Log-rank method, in which high expression of HLA-DQA1 was correlated with a shorter overall survival time. The receiver operating characteristic (ROC) curve analysis yielded the area under the ROC curve value of 0.693. Univariate and multivariate analyses also suggest that high expression of HLA-DQA1 is a potential indicator for poor prognosis of ESCC. CONCLUSIONS: Our results demonstrate that HLA-DQA1 plays an important role in ESCC progression and may be a biomarker for ESCC diagnosis and prognosis, as well as a potential target for the treatment of patients with ESCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas do Esôfago/metabolismo , Cadeias alfa de HLA-DQ/metabolismo , Idoso , Western Blotting , China , Bases de Dados Factuais , Progressão da Doença , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Taxa de Sobrevida
4.
Development ; 146(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30910827

RESUMO

Vascular pruning is crucial for normal development, but its underlying mechanisms are poorly understood. Here, we report that retinal vascular pruning is controlled by the oxygen-sensing mechanism in local astrocytes. Oxygen sensing is mediated by prolyl hydroxylase domain proteins (PHDs), which use O2 as a substrate to hydroxylate specific prolyl residues on hypoxia inducible factor (HIF)-α proteins, labeling them for polyubiquitylation and proteasomal degradation. In neonatal mice, astrocytic PHD2 deficiency led to elevated HIF-2α protein levels, expanded retinal astrocyte population and defective vascular pruning. Although astrocytic VEGF-A was also increased, anti-VEGF failed to rescue vascular pruning. However, stimulation of retinal astrocytic growth by intravitreal delivery of PDGF-A was sufficient to block retinal vascular pruning in wild-type mice. We propose that in normal development, oxygen from nascent retinal vasculature triggers PHD2-dependent HIF-2α degradation in nearby astrocytic precursors, thus limiting their further growth by driving them to differentiate into non-proliferative mature astrocytes. The physiological limit of retinal capillary density may be set by astrocytes available to support their survival, with excess capillaries destined for regression.This article has an associated 'The people behind the papers' interview.

5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 26(4): 1005-1010, 2018 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-30111398

RESUMO

OBJECTIVE: To investigate the clinical characteristics and clinical prognostic factors of patients with acute lymphoblastic leukemia (ALL). METHODS: Ninety-six ALL patients in our hospital from June 2012 to August 2014 were selected and their clinical data were collected. The related clinical data of patients were recorded, and the relation between clinical characteristics and therapeutic efficacy was analyzed. The COX analysis was used to reveal the risk factors affecting the patient's OS and DFS time. RESULTS: Among 96 ALL patients, 65 patients achieved complete remission (CR) after treatment. The age, immunophenotype, central nervous system leukemia (CNSL) and peripheral blood WBC count correlated with complete remission (P<0.05). The age, WBC count, platelet level, immune typing and consolidation therapy were the prognostic factors (P<0.05), the 2 year OS rate was influenced by age, WBC count, CD34 and consolidation therapy (P<0.05), the 2 year DFS rate was influenced by age, CD34 and consolidation therapy (P<0.05). CONCLUSION: Age, WBC counts, CD34 and consolidated treatment after remission are prognostic factors for ALL patients, which has guiding significance for clinical treatment of ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Nervoso Central , Humanos , Prognóstico , Indução de Remissão
6.
Sci Rep ; 7(1): 17608, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29242645

RESUMO

In mice, retinal vascular and astrocyte networks begin to develop at birth, expanding radially from the optic nerve head (ONH) towards the retinal periphery. The retinal vasculature grows towards the periphery ahead of differentiated astrocytes, but behind astrocytic progenitor cells (APCs) and immature astrocytes. Endothelial cell specific Vegfr-2 disruption in newborn mice not only blocked retinal vascular development but also suppressed astrocytic differentiation, reducing the abundance of differentiated astrocytes while causing the accumulation of precursors. By contrast, retinal astrocytic differentiation was accelerated by the exposure of wild-type newborn mice to hyperoxia for 24 hours, or by APC specific deficiency in hypoxia inducible factor (HIF)-2α, an oxygen labile transcription factor. These findings reveal a novel function of the retinal vasculature, and imply that in normal neonatal mice, oxygen from the retinal circulation may promote astrocytic differentiation, in part by triggering oxygen dependent HIF-2α degradation in astrocytic precursors.

7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(1): 147-150, 2017 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-28245392

RESUMO

OBJECTIVE: To explore the correlation of Th17 cell rate and IL-17 level with pathogenetis of multiple myeloma(MM). METHODS: Forty-five cases of MM were enrolled in MM group, while 45 healthy volunteers were selected in control group. The rate of Th17 cells, levels of IL-17 and ß2-microglobulin(ß2-MG) in patients subgrouping according to ISS staging and treatment were detected by using flow cytometer and IL-17 assay kit. The correlation of Th17 cell rate and IL-17 level with MM was analyzed. RESULTS: The rate of Th17 cells and level of IL-17 in MM group were higher than those in control group(P<0.05), the rate of Th17 cells and level of IL-17 in ISS III stage patients were higher than those in ISS I and II stage patients(P<0.05); the rate of Th17 cells and level of IL-17 in ISS I and ISS II stage patients were not significant difference (P>0.05); the rate of Th17 cells and level of IL-17 in firstly treated, retreated/refractory patients were significantly higher than those in patients with effective treatment(P<0.05), while the rate of Th17 cells and level of IL-17 between firstly treated patients and retreated/refractory patients were not significant difference (P>0.05). The Th17 rate and IL-17 level in MM patients positively correlated with ß2-MG level (r=0.422, r=0.416, P<0.05). CONCLUSION: The obvious increase of Th17 rate, IL-17 and ß2-MG levels closely relates with pathogenesis of MM. The Th17 rate and IL-17 level may be used as important evidence for evaluation of ISS stage and therapeutic efficacy of MM.


Assuntos
Interleucina-17/análise , Mieloma Múltiplo/imunologia , Células Th17 , Citometria de Fluxo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 24(6): 1776-1781, 2016 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-28024493

RESUMO

OBJECTIVE: To study the clinical features of of patients with primary central nervous system lymphoma(PCNSL) and their influence on prognosis. METHODS: Forty-two cases of PCNSL hospitallized in our hospital from January 2012 to December 2015 were selected, and the laboratory analysis, imaging examination, bone marrow analysis and pathological examination all were performed, 26 cases were treated by lumbar puncture combined with intrathecal injection of drugs (Ara C, dexamethason and methotrexate), 8 cases were treated by methotrexate combined with rituximab, 8 cases voluntanly abandon treatment after being diagnosed as PCNSL. RESULTS: Headache accrued in 12 cases, diplopia in 2 cases, dizziness in 6 cases, limb weakness in 10 cases, amnesia in 2 cases, inhibited speech in 4 cases.Out of 42 patients 4 cases of peripheral T cell lymphoma, 38 cases of B cell lymphoma; 30 cases of multiple lesions, 12 cases of solitary lesions, 8 cases of corpus callosum, 8 cases of thalamus, 8 cases of frontal lobe, parietal lobe, temporal lobe, thalamus and other lesions, 2 cases of hydrocephalus, 2 cases of cerebral hemorrhage; and the patients HIV were negative. 8 cases erythrocyte sedimentation rate were faster, IgG, IgE and IgM levels increased to varying degrees in 42 cases, and the blood routine, liver function and blood coagulation examinations showed normal; There was no significant difference in the influence of the lumbar injection, methotrexate dose, radiation therapy, and hematopoietic stem cell transplantation on survival time(P>0.05); but there was significant difference in the influence of rituximab and number of lesions on survival time (P<0.05); there were significant differences in the effects of age and protein content in cerebrospinal fluid on therapeutic effecacy(P<0.05). CONCLUSION: There is no significant difference in the imaging examination and clinical manifestation between PCNSL and other intracranial tumors. The lumbar puncture is an effective way to identify, the age, cerebrospinal fluid protein and the number of lesions are the adverse factors influencing the prognosis.


Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Idoso , Citarabina , Humanos , Linfoma de Células B , Linfoma de Células T Periférico , Metotrexato , Prognóstico , Rituximab
9.
J Integr Neurosci ; 15(3): 321-335, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27774836

RESUMO

In this paper, a two-layer network is built to simulate the mechanism of visual selection and shifting based on the mapping dynamic model for instantaneous frequency. Unlike the differential equation model using limit cycle to simulate neuron oscillation, we build an instantaneous frequency mapping dynamic model to describe the change of the neuron frequency to avoid the difficulty of generating limit cycle. The activity of the neuron is rebuilt based on the instantaneous frequency and in this work, we use the first layer of neurons to implement image segmentation and the second layer of neurons to act as visual selector. The frequency of the second neuron (central neuron) is always changing, while central neuron resonates with the neurons corresponding to an object, the object is selected, then with the central neuron frequency changing, the selected object loses attention, the process goes on.


Assuntos
Atenção , Redes Neurais (Computação) , Percepção Visual , Atenção/fisiologia , Córtex Cerebral/fisiologia , Neurônios/fisiologia , Periodicidade , Retina/fisiologia , Percepção Visual/fisiologia
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 23(5): 1362-5, 2015 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-26524038

RESUMO

OBJECTIVE: To explore the values of detecting the serum levels of ß2-MG, TNF-α, CRP, IL-6 in the patients with multiple myeloma. METHODS: A total of 40 patents with multiple myeloma were included in the experiment group, and 40 healthy volunteers were selected as the control group. The levels of ß2-MG, TNF-α, CRP and IL-6 were detected and compared in 2 groups, the different durie-salmon (DS) stages of ß2-MG, TNF-α, CRP and IL-6 in the experiment group were analyzed. RESULTS: The levels of ß2-MG, CRP, IL-6 in the experiment group were higher than those in control group (P < 0.05); the level of TNF-α in the experiment group was lower than that in control group (P < 0.05); the levels of ß2-MG, CRP, IL-6 at stage I, II, III in the experiment group was higher than those in control group (P < 0.05); the level of TNF-α at stage I, II, III in the experiment group was lower than that in the control group (P < 0.05); the levels of ß2-MG, CRP, IL-6 at stage I, II, III in the experiment group displayed an increasing tendency, the levels of TNF-α at stage I, II, III in the experiment group displayed a declining trend (P < 0.05); the levels of ß2-MG, CRP, IL-6 in the experiment group after treatment for 8, 16 weeks were higher than those in control group (P < 0.05); the level of TNF-α in the experiment group after treatment for 8, 16 weeks was lower than that in control group (P < 0.05); the levels of ß2-MG, CRP and IL-6 in the experiment group after treatment for 16 weeks were lower than those for 8 weeks (P < 0.05); the levels of TNF-α in the experiment group after treatment for 16 weeks were higher than those for 8 weeks (P < 0.05). The levels of APE1 after treatment in the experiment group were lower than that before treatment. CONCLUSION: The serum levels of ß2-MG, TNF-α, CRP and IL-6 can be as index for diagnosis of multiple myeloma, can effectively evaluate the disease severity; their combination with APE1 expression level can evaluate the therapeutic efficacy; thus the detection of above-mentioned indexes is possessed of higher value for clinical applications.


Assuntos
Proteína C-Reativa/metabolismo , Interleucina-6/sangue , Mieloma Múltiplo/sangue , Fator de Necrose Tumoral alfa/sangue , Microglobulina beta-2/sangue , Estudos de Casos e Controles , Humanos , Mieloma Múltiplo/diagnóstico
11.
Biomed Mater Eng ; 26 Suppl 1: S1019-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26405856

RESUMO

This paper aims to solve automated feature selection problem in brain computer interface (BCI). In order to automate feature selection process, we proposed a novel EEG feature selection method based on decision tree (DT). During the electroencephalogram (EEG) signal processing, a feature extraction method based on principle component analysis (PCA) was used, and the selection process based on decision tree was performed by searching the feature space and automatically selecting optimal features. Considering that EEG signals are a series of non-linear signals, a generalized linear classifier named support vector machine (SVM) was chosen. In order to test the validity of the proposed method, we applied the EEG feature selection method based on decision tree to BCI Competition II datasets Ia, and the experiment showed encouraging results.


Assuntos
Interfaces Cérebro-Computador , Árvores de Decisões , Eletroencefalografia/métodos , Algoritmos , Humanos , Análise de Componente Principal , Máquina de Vetores de Suporte
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 23(4): 994-8, 2015 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-26314432

RESUMO

OBJECTIVE: To explore the clinical value of arsenious acid (H3AsO3) for treating patients with acute promyelocytic leukemia (APL). METHODS: A total of 86 patients with APL were randomly divided into experimental group (43 cases) and control group (43 cases). The control group was treated by all trans retinoic acid combined with chemotherapy, the experimental group were treated by arsenous acid on the basis of the control group. RESULTS: The overall response rate (ORR) in experimental group (100.00%) was significantly higher than that in control group (88.37%) (P < 0.05). The time of returm to complete remission in experimental group (30.86 ± 4.34) was better than that in control group (42.42 ± 7.10) d (P < 0.05). The time of return to normal levels of peripheral WBC count (20.86 ± 9.28) × 109/L, hemoglobin count (68.62 ± 14.97) g/L and thrombocyte count in experimental group obviously less than that in control group (P < 0.05). The rates of high white blood syndrome (HWBS), disseminated intravascular coagulation (DIC) in experimental group were lower than that in control group (P < 0.05). The survival rates of 2 and 3 years in experimental group were higher than that in control group (P < 0.05). The recurrence rate after treatment in experimental group was lower than that in control group (P < 0.05). The application of arsenious acid was main factor for patients survival (P < 0.05). CONCLUSION: Arsenious acid can improve the clinical efficacy for the patients with acute promyelocytic leukemia, and reduce the complication, therefore it is worthy of application in clinic.


Assuntos
Leucemia Promielocítica Aguda , Arsenitos , Coagulação Intravascular Disseminada , Humanos , Contagem de Leucócitos , Contagem de Plaquetas , Recidiva , Indução de Remissão , Taxa de Sobrevida , Tretinoína
13.
Environ Sci Pollut Res Int ; 21(23): 13440-5, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25012204

RESUMO

To evaluate the effectiveness of human restoration in species conservation, in this study, we undertook a field survey of giant panda (Ailuropoda melanoleuca) habitat and man-made forest habitat in Wanglang Nature Reserve of China. Our results revealed that giant panda did not use the man-made forest in this area so far, and that there were significant differences between the giant panda habitat and the man-made forest habitat. Compared with giant panda habitat, the man-made forest habitat was characterized by lower shrub coverage, thinner trees and lower bamboo density. To improve the effectiveness of human restoration, the habitat requirement of giant panda should be fully consider in the whole process of habitat restoration.


Assuntos
Comportamento Animal , Recuperação e Remediação Ambiental , Florestas , Ursidae , Animais , China , Conservação dos Recursos Naturais , Ecossistema , Humanos , Modelos Logísticos , Árvores
14.
Nurs Res ; 63(4): 278-88, 2014 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24977725

RESUMO

BACKGROUND: Experiencing a major natural disaster is a stressful event that challenges survival and sense of self. Adolescents are undergoing rapid developmental change in self-concept, and their sense of self is particularly susceptible to such stressful events. Although many studies have investigated adolescent self-concept, few have examined self-concept in relation to experiencing a natural disaster. OBJECTIVES: Following the Great Wenchuan Earthquake in Sichuan Province, China, in 2008, this study aimed to (a) describe disaster experiences; (b) describe social support, coping, and self-support; and (c) identify disaster experiences, social support, and coping factors associated with self-concept of adolescent survivors 3 months after the earthquake. METHODS: This was a large-scale cross-sectional study. A total of 1,976 adolescents living where the earthquake caused the most severe damage took part. The Tennessee Self-Concept Scale; Coping Styles Scale; and Internality, Powerful Others, and Chance Scales were used to assess self-concept, coping strategy, and locus of control, respectively. Sociodemographic characteristics, earthquake experiences, and social support were also obtained by self-report. RESULTS: Three months after the disaster, adolescent self-concept was generally positive. Locus of control centered on powerful others was the strongest predictor of total self-concept. The negative coping strategy, "abreacting," was a positive predictor of negative self-concept (self-criticism). DISCUSSION: Close attention to adolescents who use negative coping strategies and who tend to lack a sense of control is needed after major disaster events. Studies that examine long-term relationships between earthquake and other major disaster experiences and self-concept of adolescent survivors are needed.


Assuntos
Comportamento do Adolescente/psicologia , Desastres , Terremotos , Autoimagem , Transtornos de Estresse Pós-Traumáticos/psicologia , Sobreviventes/psicologia , Adaptação Psicológica , Adolescente , China , Estudos Transversais , Feminino , Humanos , Acontecimentos que Mudam a Vida , Masculino , Apoio Social , Fatores Socioeconômicos
15.
J Comput Neurosci ; 37(2): 281-91, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24756619

RESUMO

Voluntary motor performance is the result of cortical commands driving muscle actions. Corticomuscular coherence can be used to examine the functional coupling or communication between human brain and muscles. To investigate the effects of grip force level on corticomuscular coherence in an accessory muscle, this study proposed an expanded support vector regression (ESVR) algorithm to quantify the coherence between electroencephalogram (EEG) from sensorimotor cortex and surface electromyogram (EMG) from brachioradialis in upper limb. A measure called coherence proportion was introduced to compare the corticomuscular coherence in the alpha (7-15Hz), beta (15-30Hz) and gamma (30-45Hz) band at 25 % maximum grip force (MGF) and 75 % MGF. Results show that ESVR could reduce the influence of deflected signals and summarize the overall behavior of multiple coherence curves. Coherence proportion is more sensitive to grip force level than coherence area. The significantly higher corticomuscular coherence occurred in the alpha (p < 0.01) and beta band (p < 0.01) during 75 % MGF, but in the gamma band (p < 0.01) during 25 % MGF. The results suggest that sensorimotor cortex might control the activity of an accessory muscle for hand grip with increased grip intensity by changing functional corticomuscular coupling at certain frequency bands (alpha, beta and gamma bands).


Assuntos
Força da Mão/fisiologia , Modelos Neurológicos , Córtex Motor/fisiologia , Músculo Esquelético/fisiologia , Desempenho Psicomotor/fisiologia , Algoritmos , Eletroencefalografia , Eletromiografia , Humanos , Masculino , Máquina de Vetores de Suporte , Adulto Jovem
16.
Am J Pathol ; 184(4): 1240-1250, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24508125

RESUMO

Prolyl hydroxylase domain (PHD) proteins catalyze oxygen-dependent prolyl hydroxylation of hypoxia-inducible factor 1α and 2α, tagging them for pVHL-dependent polyubiquitination and proteasomal degradation. In this study, albumin Cre (Alb(Cre))-mediated, hepatocyte-specific triple disruption of Phd1, Phd2, and Phd3 (Phd(1/2/3)hKO) promoted liver erythropoietin (EPO) expression 1246-fold, whereas renal EPO was down-regulated to 6.7% of normal levels. In Phd(1/2/3)hKO mice, hematocrit levels reached 82.4%, accompanied by severe vascular malformation and steatosis in the liver. In mice double-deficient for hepatic PHD2 and PHD3 (Phd(2/3)hKO), liver EPO increase and renal EPO loss both occurred but were much less dramatic than in Phd(1/2/3)hKO mice. Hematocrit levels, vascular organization, and liver lipid contents all appeared normal in Phd(2/3)hKO mice. In a chronic renal failure model, Phd(2/3)hKO mice maintained normal hematocrit levels throughout the 8-week time course, whereas floxed controls developed severe anemia. Maintenance of normal hematocrit levels in Phd(2/3)hKO mice was accomplished by sensitized induction of liver EPO expression. Consistent with such a mechanism, liver HIF-2α accumulated to higher levels in Phd(2/3)hKO mice in response to conditions causing modest systemic hypoxia. Besides promoting erythropoiesis, EPO is also known to modulate retinal vascular integrity and neovascularization. In Phd(1/2/3)hKO mice, however, neonatal retinas remained sensitive to oxygen-induced retinopathy, suggesting that local EPO may be more important than hepatic and/or renal EPO in mediating protective effects in the retina.


Assuntos
Anemia/metabolismo , Eritropoetina/metabolismo , Falência Renal Crônica/metabolismo , Fígado/enzimologia , Prolil Hidroxilases/deficiência , Doenças Retinianas/metabolismo , Anemia/patologia , Animais , Western Blotting , Modelos Animais de Doenças , Falência Renal Crônica/patologia , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Doenças Retinianas/patologia
17.
PLoS One ; 9(1): e84736, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24475033

RESUMO

Here we investigate the role of hypoxia inducible factor (HIF)-2α in coordinating the development of retinal astrocytic and vascular networks. Three Cre mouse lines were used to disrupt floxed Hif-2α, including Rosa26(CreERT2), Tie2(Cre), and GFAP(Cre). Global Hif-2α disruption by Rosa26(CreERT2) led to reduced astrocytic and vascular development in neonatal retinas, whereas endothelial disruption by Tie2(Cre) had no apparent effects. Hif-2α deletion in astrocyte progenitors by GFAP(Cre) significantly interfered with the development of astrocytic networks, which failed to reach the retinal periphery and were incapable of supporting vascular development. Perplexingly, the abundance of strongly GFAP(+) mature astrocytes transiently increased at P0 before they began to lag behind the normal controls by P3. Pax2(+) and PDGFRα(+) astrocytic progenitors and immature astrocytes were dramatically diminished at all stages examined. Despite decreased number of astrocyte progenitors, their proliferation index or apoptosis was not altered. The above data can be reconciled by proposing that HIF-2α is required for maintaining the supply of astrocyte progenitors by slowing down their differentiation into non-proliferative mature astrocytes. HIF-2α deficiency in astrocyte progenitors may accelerate their differentiation into astrocytes, a change which greatly interferes with the replenishment of astrocyte progenitors due to insufficient time for proliferation. Rapidly declining progenitor supply may lead to premature cessation of astrocyte development. Given that HIF-2α protein undergoes oxygen dependent degradation, an interesting possibility is that retinal blood vessels may regulate astrocyte differentiation through their oxygen delivery function. While our findings support the consensus that retinal astrocytic template guides vascular development, they also raise the possibility that astrocytic and vascular networks may mutually regulate each other's development, mediated at least in part by HIF-2α.


Assuntos
Astrócitos/citologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Retina/citologia , Retina/embriologia , Células-Tronco/fisiologia , Animais , Astrócitos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Western Blotting , Diferenciação Celular/fisiologia , Primers do DNA/genética , Imunofluorescência , Genótipo , Camundongos , Camundongos Endogâmicos C57BL , Retina/metabolismo , Células-Tronco/metabolismo
18.
Am J Pathol ; 184(3): 686-96, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24440788

RESUMO

Deficiencies in prolyl hydroxylase domain proteins (PHDs) may lead to the accumulation of hypoxia-inducible factor-α proteins, the latter of which activate local angiogenic responses by paracrine mechanisms. Here, we investigate whether a keratinocyte-specific PHD deficiency may promote vascular survival and growth in a distantly located ischemic tissue by a remote signaling mechanism. We generated mice that carry a keratinocyte-specific Phd2 knockout (kPhd2KO) and performed femoral artery ligation. Relative to wild-type controls, kPhd2KO mice displayed improved vascular survival and arteriogenesis in ischemic hind limbs, leading to the accelerated recovery of hindlimb perfusion and superior muscle regeneration. Similar protective effects were also seen in type 1 and type 2 diabetic mice. Molecularly, both abundance of hypoxia-inducible factor-1α protein and expression of vascular endothelial growth factor-A were increased in epidermal tissues of kPhd2KO mice, accompanied by increased plasma concentration of vascular endothelial growth factor-A. Contrary to kPhd2KO mice, which are PHD2 deficient in all skin tissues, localized kPhd2KO in hindlimb skin tissues did not have similar effects, excluding paracrine signaling as a major mechanism. Confirming the existence of remote effects, hepatocyte-specific Phd2 knockout also protected hind limbs from ischemia injury. These data indicate that vascular survival and growth in ischemia-injured tissue may be stimulated by suppressing PHD2 in a remotely located tissue and may provide highly effective angiogenesis therapies without the need for directly accessing target tissues.


Assuntos
Diabetes Mellitus Experimental/fisiopatologia , Membro Posterior/irrigação sanguínea , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Isquemia/fisiopatologia , Transdução de Sinais , Animais , Modelos Animais de Doenças , Artéria Femoral/fisiopatologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Knockout , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Cancer Res ; 73(15): 4781-90, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23749643

RESUMO

Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate Kras(G12D) and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of ß-catenin and SMAD4. The relationship among HIF2α, ß-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced ß-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and ß-catenin.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Western Blotting , Carcinoma Ductal Pancreático/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Smad/metabolismo , beta Catenina/metabolismo
20.
Circulation ; 126(6): 741-52, 2012 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-22753193

RESUMO

BACKGROUND: Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1) is a potential therapeutic target for cardiovascular diseases, but its role in angiogenesis remains controversial. Whereas germline Vegfr-1(-/-) embryos die of abnormal vascular development in association with excessive endothelial differentiation, mice lacking only the kinase domain appear healthy. METHODS AND RESULTS: We performed Cre-loxP-mediated knockout to abrogate the expression of all known VEGFR-1 functional domains in neonatal and adult mice and analyzed developmental, pathophysiological, and molecular consequences. VEGFR-1 deficiency promoted tip cell formation and endothelial cell proliferation and facilitated angiogenesis of blood vessels that matured and perfused properly. Vascular permeability was normal at the basal level but elevated in response to high doses of exogenous VEGF-A. In the postinfarct ischemic cardiomyopathy model, VEGFR-1 deficiency supported robust angiogenesis and protected against myocardial infarction. VEGFR-1 knockout led to abundant accumulation of VEGFR-2 at the protein level, increased VEGFR-2 tyrosine phosphorylation transiently, and enhanced serine phosphorylation of Akt and ERK. Interestingly, increased angiogenesis, tip cell formation, vascular permeability, VEGFR-2 accumulation, and Akt phosphorylation could be partially rescued or suppressed by one or more of the following manipulations, including injection of the VEGFR-2 selective inhibitor SU1498, anti-VEGF-A, or introduction of Vegfr-2(+/-) heterozygosity into Vegfr-1 somatic knockout mice. CONCLUSIONS: Upregulation of VEGFR-2 abundance at the protein level contributes in part to increased angiogenesis in VEGFR-1-deficient mice.


Assuntos
Neovascularização Fisiológica/genética , Regulação para Cima , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/deficiência , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Regulação para Cima/genética , Regulação para Cima/fisiologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia
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