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1.
EBioMedicine ; 39: 272-279, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30587460

RESUMO

This study aimed to develop and validate a prognostic nomogram for recurrence-free survival (RFS) after surgery in the absence of adjuvant therapy to guide the selection for adjuvant imatinib therapy based on Residual Neural Network (ResNet). The ResNet model was developed based on contrast-enhanced computed tomography (CE-CT) in a training cohort consisted of 80 patients pathologically diagnosed gastrointestinal sromal tumors (GISTs) and validated in internal and external validation cohort respectively. Independent clinicopathologic factors were integrated with the ResNet model to construct the individualized nomogram. The performance of the nomogram was evaluated in regard to discrimination, calibration, and clinical usefulness. The ResNet model was significantly associated with RFS. Integrable predictors in the individualized ResNet nomogram included the tumor site, size, and mitotic count. Compared with modified NIH, AFIP, and clinicopathologic nomogram, both ResNet nomogram and ResNet model showed a better discrimination capability with AUCs of 0·947(95%CI, 0·910-0·984) for 3-year-RFS, 0·918(0·852-0·984) for 5-year-RFS, and AUCs of 0·912 (0·851-0·973) for 3-year-RFS, 0·887(0·816-0·960) for 5-year-RFS, respectively. Calibration curve shows the good calibration of the nomogram in terms of the agreement between the estimated and the observed 3- and 5- year outcomes. Decision curve analysis showed that the ResNet nomogram had a higher overall net benefit. In conclusion, we presented a deep learning-based prognostic nomogram to predict RFS after resection of localized primary GISTs with excellent performance and could be a potential tool to select patients for adjuvant imatinib therapy.


Assuntos
Neoplasias Gastrointestinais/cirurgia , Tumores do Estroma Gastrointestinal/cirurgia , Nomogramas , Adulto , Idoso , Aprendizado Profundo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
2.
Eur Radiol ; 2018 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-30302589

RESUMO

OBJECTIVE: Accurate detection and segmentation of organs at risks (OARs) in CT image is the key step for efficient planning of radiation therapy for nasopharyngeal carcinoma (NPC) treatment. We develop a fully automated deep-learning-based method (termed organs-at-risk detection and segmentation network (ODS net)) on CT images and investigate ODS net performance in automated detection and segmentation of OARs. METHODS: The ODS net consists of two convolutional neural networks (CNNs). The first CNN proposes organ bounding boxes along with their scores, and then a second CNN utilizes the proposed bounding boxes to predict segmentation masks for each organ. A total of 185 subjects were included in this study for statistical comparison. Sensitivity and specificity were performed to determine the performance of the detection and the Dice coefficient was used to quantitatively measure the overlap between automated segmentation results and manual segmentation. Paired samples t tests and analysis of variance were employed for statistical analysis. RESULTS: ODS net provides an accurate detection result with a sensitivity of 0.997 to 1 for most organs and a specificity of 0.983 to 0.999. Furthermore, segmentation results from ODS net correlated strongly with manual segmentation with a Dice coefficient of more than 0.85 in most organs. A significantly higher Dice coefficient for all organs together (p = 0.0003 < 0.01) was obtained in ODS net (0.861 ± 0.07) than in fully convolutional neural network (FCN) (0.8 ± 0.07). The Dice coefficients of each OAR did not differ significantly between different T-staging patients. CONCLUSION: The ODS net yielded accurate automated detection and segmentation of OARs in CT images and thereby may improve and facilitate radiotherapy planning for NPC. KEY POINTS: • A fully automated deep-learning method (ODS net) is developed to detect and segment OARs in clinical CT images. • This deep-learning-based framework produces reliable detection and segmentation results and thus can be useful in delineating OARs in NPC radiotherapy planning. • This deep-learning-based framework delineating a single image requires approximately 30 s, which is suitable for clinical workflows.

3.
J Surg Res ; 196(1): 149-58, 2015 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-25801977

RESUMO

BACKGROUND: Vascular hyporesponsiveness is an important pathophysiological feature of some critical conditions such as hemorrhagic shock. Many proteins and molecules are involved in the regulation of the pathologic process, however the mechanism has still remained unclear. Our study was intended to look for the related protein markers involved in the regulation of vascular reactivity after hemorrhagic shock. METHODS: Differential in-gel electrophoresis and tandem mass spectrometry were applied to quantify the differences of protein expression in the superior mesenteric arteries from hemorrhagic shock and normal rats. RESULTS: A total of 2317 differentially expressed protein spots in the superior mesenteric arteries of rats before and after hemorrhagic shock were found, and 146 protein spots were selected for tandem mass spectrometry identification. Thirty-seven differentially expressed proteins were obtained, including 3 uncharacterized proteins and 34 known proteins. Among them, heat shock protein beta-1 and calmodulin were the known proteins involved in the occurrence of vascular hyporesponsiveness. Bioinformatics analysis results showed that 18 proteins were related to vasoconstriction, 11 proteins may be involved in other vascular functions such as regulation of angiogenesis and endothelial cell proliferation. CONCLUSIONS: The changes of vascular responsiveness after hemorrhagic shock in rats may be associated with the upregulation or downregulation of previously mentioned protein expressions. These findings may provide the basis for understanding and further study of the mechanism and treatment targets of vascular hyporeactivity after shock.


Assuntos
Proteínas Sanguíneas/análise , Músculo Liso Vascular/fisiopatologia , Choque Hemorrágico/fisiopatologia , Animais , Biomarcadores , Biologia Computacional , Proteômica , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem
4.
J Biol Chem ; 290(3): 1818-28, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25451924

RESUMO

MicroRNAs have been extensively studied as regulators of hematopoiesis and leukemogenesis. We identified miR-638 as a novel regulator in myeloid differentiation and proliferation of leukemic cells. We found that miR-638 was developmentally up-regulated in cells of myeloid but not lymphoid lineage. Furthermore, significant miR-638 down-regulation was observed in primary acute myeloid leukemia (AML) blasts, whereas miR-638 expression was dramatically up-regulated in primary AML blasts and leukemic cell lines undergoing forced myeloid differentiation. These observations suggest that miR-638 might play a role in myeloid differentiation, and its dysregulation may contribute to leukemogenesis. Indeed, ectopic expression of miR-638 promoted phorbol 12-myristate 13-acetate- or all-trans-retinoic acid-induced differentiation of leukemic cell lines and primary AML blasts, whereas miR-638 inhibition caused an opposite phenotype. Consistently, miR-638 overexpression induced G1 cell cycle arrest and reduced colony formation in soft agar. Cyclin-dependent kinase 2 (CDK2) was found to be a target gene of miR-638. CDK2 inhibition phenotypically mimicked the overexpression of miR-638. Moreover, forced expression of CDK2 restored the proliferation and the colony-forming ability inhibited by miR-638. Our data suggest that miR-638 regulates proliferation and myeloid differentiation by targeting CDK2 and may serve as a novel target for leukemia therapy or marker for AML diagnosis and prognosis.


Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/metabolismo , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Quinase 2 Dependente de Ciclina/genética , Células HEK293 , Células HL-60 , Hematopoese , Humanos , MicroRNAs/genética , Dados de Sequência Molecular , Oligonucleotídeos/genética , Fenótipo , Homologia de Sequência do Ácido Nucleico , Acetato de Tetradecanoilforbol , Regulação para Cima
5.
Am J Physiol Heart Circ Physiol ; 307(9): H1277-87, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25172895

RESUMO

Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1­15 µg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+ sensitivity, whereas it did not interfere with the intracellular Ca2+ concentration in hypoxia-treated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis.


Assuntos
Indutores da Angiogênese/farmacologia , Endotélio Vascular/metabolismo , Junções Comunicantes/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-sis/farmacologia , Choque Hemorrágico/tratamento farmacológico , Indutores da Angiogênese/uso terapêutico , Animais , Becaplermina , Sinalização do Cálcio , Conexina 43/genética , Conexina 43/metabolismo , Conexinas/genética , Conexinas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/fisiologia , Circulação Hepática , Artéria Mesentérica Superior/citologia , Artéria Mesentérica Superior/metabolismo , Artéria Mesentérica Superior/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-sis/uso terapêutico , Ratos , Ratos Wistar , Circulação Renal , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologia , Quinases Associadas a rho/metabolismo
6.
Ann Endocrinol (Paris) ; 73(6): 530-41, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23131471

RESUMO

AIM: To identify the changes of mitochondrial protein expression in diabetic renal parenchyma and to characterize their molecular functions and biological processes in diabetes. METHODS: Mitochondrial proteins extracted from renal parenchyma mitochondria of streptozotocin-induced diabetic rats and normal rats were separated by two-dimensional polyacrylamide gel electrophoresis and identified by matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry. RESULTS: Eleven proteins from 533 visualized protein spots displayed significant different expressions in mitochondria of diabetic kidneys compared with those in normal ones. Among these altered proteins, two proteins with the most obvious changes in protein expression were identified as alpha-2u globulin (mature protein, named A2) and its proteolytically modified form (named A2-fragment) respectively. These proteins were found in mitochondria of male rat renal parenchyma and were proved to be down-regulated in diabetic rats simultaneously. CONCLUSION: Our results suggest that down-regulation of alpha-2u globulin may be associated with an abnormal ß-oxidation of long-chain fatty acids during diabetes. The decreased expression of A2-fragment in renal mitochondria of diabetic nephropathy may reduce fatty acid ß-oxidation, which leads to a diminished energy supply from mitochondria to kidney tissue and the deposition of a large number of fatty acids in the kidney, ultimately causing and aggravating kidney damage. In conclusion, these findings may be helpful for understanding the molecular mechanism of diabetic nephropathy.


Assuntos
alfa-Globulinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Rim/metabolismo , Mitocôndrias/metabolismo , Proteômica , alfa-Globulinas/análise , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Regulação para Baixo , Eletroforese em Gel Bidimensional , Rim/patologia , Rim/ultraestrutura , Masculino , Mitocôndrias/química , Mitocôndrias/patologia , Proteínas Mitocondriais/análise , Proteínas Mitocondriais/metabolismo , Proteoma/análise , Proteoma/metabolismo , Proteômica/métodos , Ratos , Ratos Sprague-Dawley , Estreptozocina , Estudos de Validação como Assunto
7.
World J Gastroenterol ; 13(14): 2118-24, 2007 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-17465459

RESUMO

AIM: To compare and identify the differences in expression of retinal proteins between normal and diabetic rats, and to analyze the molecular pathogenetic mechanisms of retinal diseases caused by diabetes. METHODS: Changes in protein expression of retinal tissues from diabetic and normal rats were observed using 2-dimensional polyacrylamide gel electrophoresis (2-DE). Some protein spots exhibiting statistically significant variations (P<0.05) were selected randomly and identified by tandem mass spectrometry and analyzed by bioinformatics. RESULTS: 2-DE showed that the expression was up-regulated in 5 retinal proteins, down-regulated in 23 retinal proteins, and disappeared in 8 retinal proteins. Eight spots were identified from the 36 spots by tandem mass spectrometry (MS/MS) and analyzed by bioinformatics. Guanylate kinase 1, triosephosphate isomerase 1, ATP synthase subunit d, albumin and dimethylarginine dimethylaminohydrolase 2 played an important role in signal transduction. Triosephosphate isomerase 1, crystallin alpha B, ATP synthase subunit d and peroxiredoxin 6 were involved in energy metabolism of retinal tissues. Guanylate kinase 1 played an important role in photoexcitation of retinal rod photoreceptor cells. Whether crystallin beta A1 plays a role in diabetic retinas is unknown so far. CONCLUSION: There are differences in expression of retinal proteins between diabetic and normal rats. These proteins may be involved in the mechanisms and prognosis of retinal diseases caused by diabetes.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Retinopatia Diabética/etiologia , Proteínas do Olho/metabolismo , Aloxano , Animais , Diabetes Mellitus Experimental/genética , Retinopatia Diabética/genética , Modelos Animais de Doenças , Eletroforese em Gel de Poliacrilamida , Proteínas do Olho/genética , Feminino , Perfilação da Expressão Gênica , Focalização Isoelétrica , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
8.
Cell Mol Immunol ; 4(1): 65-70, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17349213

RESUMO

Diabetes mellitus (DM) is a chronic disease which is associated with numerous serious health complications such as diabetic retinopathy, and is the leading cause of new cases of blindness in adults at the age of 20-74 years old. The aim of the study was to establish and optimize a two-dimensional polyacrylamide gel electrophoresis (2-DE) technique for retina proteomics to improve the resolution and reproducibility, and to observe the proteomic changes of retinal tissues in diabetic and normal rats. Proteins were extracted from retinal tissues of normal and 8 weeks diabetic SD rats and used in two-dimensional electrophoresis. Various conditions of retina proteomic 2-DE were adjusted, optimized and protein spots of differential expression were obtained through analysis of 2-DE images with PDQuest software. By choosing appropriate sample amount, using pre-cast IPG dry strips (pH 5-8) and casting 12% equal gel, satisfactory 2-DE images of retina were obtained and a steady 2-DE technique was established. In this way, we found 36 spots in 2-DE gel of diabetic retinas that exhibited statistically significant variations, including up-regulation of 5 proteins in diabetic rat retinas, down-regulation of 23, and disappearance of 8, in comparison with normal tissues. The differences of protein expression were observed in retinas between diabetic and normal rats. Our established 2-DE technique of retina proteins could be effectively applied in proteomics of retina diseases.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Eletroforese em Gel Bidimensional/métodos , Proteínas/análise , Proteômica/métodos , Retina/química , Animais , Feminino , Ratos , Ratos Sprague-Dawley
9.
Genomics Proteomics Bioinformatics ; 4(3): 165-72, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17127214

RESUMO

Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS), incorporated with online database searching, were performed to investigate differential proteins of breast cancer and adjacent normal breast tissues. Considering that serum albumin is abundantly presented in normal control samples, 15 differential spots detected in 11 out of 12 (91.7%) breast cancer samples were identified by online SIENA-2DPAGE database searching and MALDI-TOF/TOF-MS analysis. The results indicate that pathological changes of breast cancer are concerned with augmentation of substance metabolism, promotion of proteolytic activity, decline of activity of some inhibitors of enzymes, and so on. Some important proteins involved in the pathological process of breast cancer with changed expression may be useful biomarkers, such as alpha-1-antitrypsin, EF-1-beta, cathepsin D, TCTP, SMT3A, RPS12, and PSMA1, among which SMT3A, RPS12, and PSMA1 were first reported for breast cancer in this study.


Assuntos
Neoplasias da Mama/metabolismo , Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteômica/métodos , Adulto , Biomarcadores Tumorais , Eletroforese em Gel Bidimensional , Feminino , Humanos , Espectrometria de Massas , Pessoa de Meia-Idade , Modelos Moleculares , Prognóstico , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
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