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1.
Nat Cancer ; 5(4): 673-690, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38347143

RESUMO

Molecular profiling guides precision treatment of breast cancer; however, Asian patients are underrepresented in publicly available large-scale studies. We established a comprehensive multiomics cohort of 773 Chinese patients with breast cancer and systematically analyzed their genomic, transcriptomic, proteomic, metabolomic, radiomic and digital pathology characteristics. Here we show that compared to breast cancers in white individuals, Asian individuals had more targetable AKT1 mutations. Integrated analysis revealed a higher proportion of HER2-enriched subtype and correspondingly more frequent ERBB2 amplification and higher HER2 protein abundance in the Chinese HR+HER2+ cohort, stressing anti-HER2 therapy for these individuals. Furthermore, comprehensive metabolomic and proteomic analyses revealed ferroptosis as a potential therapeutic target for basal-like tumors. The integration of clinical, transcriptomic, metabolomic, radiomic and pathological features allowed for efficient stratification of patients into groups with varying recurrence risks. Our study provides a public resource and new insights into the biology and ancestry specificity of breast cancer in the Asian population, offering potential for further precision treatment approaches.


Assuntos
Povo Asiático , Neoplasias da Mama , Receptor ErbB-2 , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Feminino , Povo Asiático/genética , Receptor ErbB-2/genética , Mutação , Proteômica/métodos , Perfilação da Expressão Gênica/métodos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Pessoa de Meia-Idade , China/epidemiologia , Ferroptose/genética , Adulto , Metabolômica/métodos , Transcriptoma , Biomarcadores Tumorais/genética , População do Leste Asiático
3.
Sci Adv ; 9(40): eadf0837, 2023 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-37801493

RESUMO

Intratumor heterogeneity (ITH) profoundly affects therapeutic responses and clinical outcomes. However, the widespread methods for assessing ITH based on genomic sequencing or pathological slides, which rely on limited tissue samples, may lead to inaccuracies due to potential sampling biases. Using a newly established multicenter breast cancer radio-multiomic dataset (n = 1474) encompassing radiomic features extracted from dynamic contrast-enhanced magnetic resonance images, we formulated a noninvasive radiomics methodology to effectively investigate ITH. Imaging ITH (IITH) was associated with genomic and pathological ITH, predicting poor prognosis independently in breast cancer. Through multiomic analysis, we identified activated oncogenic pathways and metabolic dysregulation in high-IITH tumors. Integrated metabolomic and transcriptomic analyses highlighted ferroptosis as a vulnerability and potential therapeutic target of high-IITH tumors. Collectively, this work emphasizes the superiority of radiomics in capturing ITH. Furthermore, we provide insights into the biological basis of IITH and propose therapeutic targets for breast cancers with elevated IITH.


Assuntos
Neoplasias da Mama , Multiômica , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Genômica , Perfilação da Expressão Gênica/métodos , Fenótipo
4.
J Thorac Dis ; 15(5): 2528-2543, 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37324098

RESUMO

Background: Breast cancer has the highest incidence and mortality rates among women worldwide. Hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer is the most common molecular subtype, accounting for 50-79% of breast cancers. Deep learning has been widely used in cancer image analysis, especially for predicting targets related to precise treatment and patient prognosis. However, studies focusing on therapeutic target and prognosis predicting in HR+/HER2- breast cancer are lacking. Methods: This study retrospectively collected hematoxylin and eosin (H&E)-stained slides of HR+/HER2- breast cancer patients between January 2013 and December 2014 at Fudan University Shanghai Cancer Center (FUSCC) and scanned to generate whole-slide images (WSIs). Then, we built a deep-learning-based workflow to train and validate model to predict clinicopathological features, multi-omics molecular features and prognosis; the area under the curve (AUC) of the receiver operating characteristic (ROC) and the concordance index (C-index) of the test set were used to assess model effectiveness. Results: A total of 421 HR+/HER2- breast cancer patients were included in our study. Regarding clinicopathological features, grade III could be predicted with an AUC of 0.90 [95% confidence interval (CI): 0.84-0.97]. Regarding somatic mutations, TP53 and GATA3 mutation could be predicted with AUCs of 0.68 (95% CI: 0.56-0.81) and 0.68 (95% CI: 0.47-0.89), respectively. Regarding gene set enrichment analysis (GSEA) pathways, the G2-M checkpoint pathway was predicted with an AUC of 0.79 (95% CI: 0.69-0.90). Regarding markers of immunotherapy response, intratumoral tumor-infiltrating lymphocytes (iTILs), stromal tumor-infiltrating lymphocytes (sTILs), CD8A, and PDCD1 were predicted with AUCs of 0.78 (95% CI: 0.55-1.00), 0.76 (95% CI: 0.65-0.87), 0.71 (95% CI: 0.60-0.82), and 0.74 (95% CI: 0.63-0.85), respectively. In addition, we found that the integration of clinical prognostic variables and deep features of images can improve the stratification of patient prognosis. Conclusions: Using a deep-learning-based workflow, we developed models to predict the clinicopathological features, multi-omics features and prognosis of patients with HR+/HER2- breast cancer using pathological WSIs. This work may contribute to efficient patient stratification to promote the personalized management of HR+/HER2- breast cancer.

5.
Cell Rep Med ; 3(12): 100808, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36543098

RESUMO

In this Backstory, we illustrate how a recent work from our multidisciplinary collaborative group identifies molecular subtypes of triple-negative breast cancer with a noninvasive radiomic pipeline. These findings appeared in the July 2022 issue of Cell Reports Medicine (https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(22)00230-0).


Assuntos
Medicina , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/genética
6.
J Transl Med ; 20(1): 471, 2022 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-36243806

RESUMO

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have become a promising biomarker for assessing tumor immune microenvironment and predicting immunotherapy response. However, the assessment of TILs relies on invasive pathological slides. METHODS: We retrospectively extracted radiomics features from magnetic resonance imaging (MRI) to develop a radiomic cohort of triple-negative breast cancer (TNBC) (n = 139), among which 116 patients underwent transcriptomic sequencing. This radiomic cohort was randomly divided into the training cohort (n = 98) and validation cohort (n = 41) to develop radiomic signatures to predict the level of TILs through a non-invasive method. Pathologically evaluated TILs in the H&E sections were set as the gold standard. Elastic net and logistic regression were utilized to perform radiomics feature selection and model training, respectively. Transcriptomics was utilized to infer the detailed composition of the tumor microenvironment and to validate the radiomic signatures. RESULTS: We selected three radiomics features to develop a TILs-predicting radiomics model, which performed well in the validation cohort (AUC 0.790, 95% confidence interval (CI) 0.638-0.943). Further investigation with transcriptomics verified that tumors with high TILs predicted by radiomics (Rad-TILs) presented activated immune-related pathways, such as antigen processing and presentation, and immune checkpoints pathways. In addition, a hot immune microenvironment, including upregulated T cell infiltration gene signatures, cytokines, costimulators and major histocompatibility complexes (MHCs), as well as more CD8+ T cells, follicular helper T cells and memory B cells, was found in high Rad-TILs tumors. CONCLUSIONS: Our study demonstrated the feasibility of radiomics model in predicting TILs status and provided a method to make the features interpretable, which will pave the way toward precision medicine for TNBC.


Assuntos
Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Humanos , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/genética , Microambiente Tumoral
7.
Chemosphere ; 308(Pt 1): 136208, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36041527

RESUMO

Limited evidence was found in the associations of volatile organic compound (VOC) exposure with bone health indicators. This study aimed to explore the associations of individual and combined metabolites of VOCs (mVOCs) in urine, a representative of the internal exposure level of VOCs, with bone mineral density (BMD), osteoporosis (OP) and fracture, and potential mediators. Data of the National Health Examination and Nutrition Survey 2005-2006 and 2013-2014 was used. Multiple linear and logistic regression modeling were performed to analyze the associations of individual mVOC with bone health indicators. The least absolute shrinkage and selection operator (LASSO) regression was adopted to select mVOCs that were more relevant to bone health indicators for further weight quantile sum (WQS) analysis used for analyzing the associations between multiple VOC co-exposure and bone health indicators. Mediation analysis was used to identify potential mediators. Seventeen mVOC members with detection rate of >50% in urine of all 3478 participants aged ≥20 years (1829 females) were involved. Levels of most mVOCs were higher in women than men. Eight mVOCs were negatively associated with BMDs, and two and four mVOCs were positively associated with OP and fracture risks, respectively. WQS regression revealed decreased femoral neck BMD (ß = -0.010 g/cm2, 95% CI: -0.020, -0.0001) and total spine BMD (ß = -0.015 g/cm2, 95% CI: -0.028, -0.002) in response to increasing mVOC mixture levels. And alkaline phosphatase (ALP), body mass index (BMI), fasting insulin (FI) and high-density lipoprotein (HDL), were mediators in the associations with proportions of mediating effect ranging from 4.6% to 10.2%. Individual and combined VOC (co-)exposure were associated with reduced BMDs in American adults. ALP, BMI, FI and HDL were demonstrated to be mediators in the association of multiple VOC co-exposure with BMD.


Assuntos
Insulinas , Compostos Orgânicos Voláteis , Absorciometria de Fóton , Adulto , Fosfatase Alcalina , Densidade Óssea/fisiologia , Feminino , Humanos , Lipoproteínas HDL , Masculino , Inquéritos Nutricionais , Compostos Orgânicos Voláteis/análise
8.
Cell Rep Med ; 3(7): 100694, 2022 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-35858585

RESUMO

Triple-negative breast cancer (TNBC) is a subset of breast cancer with an adverse prognosis and significant tumor heterogeneity. Here, we extract quantitative radiomic features from contrast-enhanced magnetic resonance images to construct a breast cancer radiomic dataset (n = 860) and a TNBC radiogenomic dataset (n = 202). We develop and validate radiomic signatures that can fairly differentiate TNBC from other breast cancer subtypes and distinguish molecular subtypes within TNBC. A radiomic feature that captures peritumoral heterogeneity is determined to be a prognostic factor for recurrence-free survival (p = 0.01) and overall survival (p = 0.004) in TNBC. Combined with the established matching TNBC transcriptomic and metabolomic data, we demonstrate that peritumoral heterogeneity is associated with immune suppression and upregulated fatty acid synthesis in tumor samples. Collectively, this multi-omic dataset serves as a useful public resource to promote precise subtyping of TNBC and helps to understand the biological significance of radiomics.


Assuntos
Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais/genética , Humanos , Imageamento por Ressonância Magnética/métodos , Prognóstico , Transcriptoma , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem
11.
Ann Surg Oncol ; 29(11): 7165-7175, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35711018

RESUMO

BACKGROUND: Homologous recombination (HR) is a key pathway in DNA double-strand damage repair. HR deficiency (HRD) occurs more commonly in triple-negative breast cancers (TNBCs) than in other breast cancer subtypes. Several clinical trials have demonstrated the value of HRD in stratifying breast cancer patients into distinct groups based on their responses to poly(ADP ribose) polymerase inhibitors and chemotherapy. METHODS: We retrospectively collected TNBC samples to establish a multiomics cohort (n = 343) and explored the biological and phenotypic mechanisms underlying the better prognosis of patients with high HRD scores. Gene set enrichment analysis was conducted to elucidate the underlying pathways in patients with low HRD scores, and a radiomics model was established to predict the HRD score via a noninvasive method. RESULTS: Multivariable Cox analysis revealed the independent prognostic value of a low HRD score (hazard ratio 2.20, 95% confidence interval 1.05-4.59; p = 0.04). Furthermore, amino acid and lipid metabolism pathways were highly enriched in tumors from patients with low HRD scores, which was also demonstrated by differential abundant metabolite analysis. A noninvasive radiomics method was developed to predict the HRD status and it performed well in the independent validation cohort (support vector machine model: area under the curve [AUC] 0.739, sensitivity 0.571, and specificity 0.824; logistic regression model: AUC 0.695, sensitivity 0.571, and specificity 0.882). CONCLUSIONS: We revealed the prognostic value of the HRD score, predicted the HRD status with noninvasive radiomics features, and preliminarily explored druggable targets for TNBC patients with low HRD scores.


Assuntos
Neoplasias de Mama Triplo Negativas , Aminoácidos/genética , Aminoácidos/uso terapêutico , Proteína BRCA1/genética , DNA , Recombinação Homóloga , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
12.
Signal Transduct Target Ther ; 6(1): 312, 2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417437

RESUMO

Immunotherapies play critical roles in cancer treatment. However, given that only a few patients respond to immune checkpoint blockades and other immunotherapeutic strategies, more novel technologies are needed to decipher the complicated interplay between tumor cells and the components of the tumor immune microenvironment (TIME). Tumor immunomics refers to the integrated study of the TIME using immunogenomics, immunoproteomics, immune-bioinformatics, and other multi-omics data reflecting the immune states of tumors, which has relied on the rapid development of next-generation sequencing. High-throughput genomic and transcriptomic data may be utilized for calculating the abundance of immune cells and predicting tumor antigens, referring to immunogenomics. However, as bulk sequencing represents the average characteristics of a heterogeneous cell population, it fails to distinguish distinct cell subtypes. Single-cell-based technologies enable better dissection of the TIME through precise immune cell subpopulation and spatial architecture investigations. In addition, radiomics and digital pathology-based deep learning models largely contribute to research on cancer immunity. These artificial intelligence technologies have performed well in predicting response to immunotherapy, with profound significance in cancer therapy. In this review, we briefly summarize conventional and state-of-the-art technologies in the field of immunogenomics, single-cell and artificial intelligence, and present prospects for future research.


Assuntos
Antígenos de Neoplasias/genética , Genoma Humano/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Inteligência Artificial , Biomarcadores Tumorais/imunologia , Linhagem da Célula , Humanos , Imunidade Inata/genética , Imunogenética/tendências , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , Proteoma/imunologia , Análise de Célula Única , Transcriptoma/imunologia
13.
Curr Med Sci ; 40(4): 654-661, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32862375

RESUMO

Ranolazine, a late sodium current inhibitor, has been demonstrated to be effective on heart failure. 18ß-glycyrrhetinic acid (18ß-GA) has the similar inhibitory effect on late sodium currents. However, its effect on diastolic function is still unknown. This study aimed to determine whether 18ß-GA can improve the diastolic function and to explore the underlying mechanisms. Eighty male Sprague Dawley (SD) rats of Langendorff model were randomly divided into the following groups: group A, normal cardiac perfusion group; group B, ischemia-reperfusion group; group C, ischemia-reperfusion with anemoniasulcata toxin II (ATX-II); group D, ranolazine group; and group E, 18ß-GA group with four different concentrations. Furthermore, a pressure-overloaded rat model induced by trans-aortic constriction (TAC) was established. Echocardiography and hemodynamics were used to evaluate diastolic function at 14th day after TAC. Changes of free intracellular calcium (Ca2+) concentration was indirectly detected by laser scanning confocal microscope to confirm the inhibition of late sodium currents. With the intervention of ATX-II on ischemia reperfusion injury group, 5 µmol/L ranolazine, and 5, 10, 20, 40 µmol/L 18ß-GA could improve ATX-II-induced cardiac diastolic dysfunction. 630 mg/kg glycyrrhizin tablets could improve cardiac diastolic function in the pressure-overloaded rats. 18ß-GA and ranolazine had similar effects on reducing the free calcium in cardiomyocytes. The study demonstrates that 18ß-GA and glycyrrhizin could improve diastolic dysfunction induced by ischemia-reperfusion injury in Langendorff-perfused rat hearts and pressure-overloaded rats. The mechanism may be attributed to the inhibition of enhanced late sodium currents.


Assuntos
Cálcio/metabolismo , Venenos de Cnidários/efeitos adversos , Diástole/efeitos dos fármacos , Ácido Glicirretínico/análogos & derivados , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Ranolazina/administração & dosagem , Animais , Modelos Animais de Doenças , Ecocardiografia , Ácido Glicirretínico/administração & dosagem , Ácido Glicirretínico/farmacologia , Hemodinâmica , Masculino , Microscopia Confocal , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Distribuição Aleatória , Ranolazina/farmacologia , Ratos , Comprimidos , Resultado do Tratamento
14.
J Zhejiang Univ Sci B ; 17(6): 425-36, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27256676

RESUMO

Blueberries are a rich source of anthocyanins, which are associated with health benefits contributing to a reduced risk for many diseases. The present study identified the functional Gardenblue blueberry (Vaccinium ashei Reade) anthocyanin extracts (GBBAEs) and evaluated their capacity and underlying mechanisms in protecting murine RAW 264.7 cells from lipopolysaccharide (LPS)-stimulated inflammation in vitro. Enzyme-linked immunosorbent assay (ELISA) kit results showed that GBBAEs significantly inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), IL-1ß, and interferon-γ (INF-γ). Real-time polymerase chain reaction (PCR) analysis indicated that the mRNA expression levels of IL-6, IL-1ß, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and cyclooxygenase 2 (COX-2) were suppressed in LPS-stimulated RAW 264.7 cells. Additionally, Western blot analysis was used to evaluate the relative protein expression levels of COX-2 and nuclear factor-κB p65 (NF-κBp65). All these results suggested the potential use of GBBAEs as a functional food for the treatment of inflammatory diseases.


Assuntos
Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Mirtilos Azuis (Planta) , Extratos Vegetais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/genética , Citocinas/genética , Lipopolissacarídeos/farmacologia , Camundongos , Óxido Nítrico/biossíntese , Fator de Transcrição RelA/genética
15.
Int J Cardiol ; 218: 305-311, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27240156

RESUMO

BACKGROUND: Relaxin is a peptide hormone which has been demonstrated to be safe and has a therapeutic effect on acute heart failure in clinic trials. However, its effect on diastolic function is still unknown. The aims of the study were to determine whether relaxin could improve the diastolic function in pressure-overloaded rat model and to analyze potential mechanisms. METHODS AND RESULTS: In the present study, a pressure-overloaded rat model induced by transaortic constriction (TAC) was established. Four weeks after TAC, echocardiography was performed and then all the rat models were randomly divided into 3 groups: models without intramyocardial injection (TAC), with intramyocardial injection of empty adenoviral vector (TAC+GFP) and adenoviral vector overexpression relaxin-2 gene (TAC+RLN2). A sham group was also included. Twelve days after intramyocardial injection, echocardiography and hemodynamics were carried out to evaluate diastolic function in sham, TAC, TAC+GFP and TAC+RLN2 groups. Then hearts were harvested for subsequent examinations. The results indicated that relaxin-2 had ameliorated diastolic function in the pressure-overloaded rats. Compared with the TAC and TAC+GFP groups, the relaxin-2 gene transfer increased phosphorylation of Akt at both the Ser473 and Thr308 sites. Meanwhile, it increased the Ser16 and Thr17- phosphorylation levels of phospholamban (PLB). Furthermore, SERCA2 activity was enhanced in the TAC+RLN2 group more than in the TAC and TAC+GFP groups. CONCLUSIONS: These results demonstrated that relaxin-2 gene therapy improved diastolic function in pressure-overloaded rats. The potential mechanism may be that relaxin-2 gene transfer enhances SERCA2 activity in hearts by increasing phospholamban phosphorylation through nuclear-targeted Akt phosphorylation.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cardiomegalia/terapia , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Relaxina/genética , Animais , Cardiomegalia/genética , Células Cultivadas , Dependovirus/genética , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos/administração & dosagem , Masculino , Miócitos Cardíacos/citologia , Distribuição Aleatória , Ratos , Relaxina/metabolismo , Resultado do Tratamento
16.
Food Funct ; 6(9): 3045-55, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26201407

RESUMO

This study was aimed at evaluating the hypouricemic effect of the anthocyanin-rich purple sweet potato extract (APSPE). In vitro, APSPE has been proved to significantly inhibit XO activity in a dose-dependent manner. In vivo, APSPE could not only inhibit the XO activity in mouse liver, but also reduce the serum uric acid level in hyperuricemic mice and affect the expression of mRNA levels of related renal transporters, such as mURAT1, mGLUT9, mOAT1 and mOCTN2. Moreover, APSPE could effectively regulate BUN and Cr levels to normal and decrease the inflammatory cellular influx in the tubule of the hyperuricemic mice. This study indicates the potential clinical utility of APSPE as a safe and effective anti-hyperuricemia bioactive agent or functional food.


Assuntos
Antocianinas/administração & dosagem , Hiperuricemia/tratamento farmacológico , Ipomoea batatas/química , Extratos Vegetais/administração & dosagem , Ácido Úrico/sangue , Xantina Oxidase/sangue , Animais , Antocianinas/química , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Humanos , Hiperuricemia/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Camundongos , Proteína 1 Transportadora de Ânions Orgânicos/genética , Proteína 1 Transportadora de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Extratos Vegetais/química , Xantina Oxidase/genética
17.
Sheng Li Xue Bao ; 67(2): 201-6, 2015 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-25896051

RESUMO

This study was aimed to establish an experimental mouse model of combined transgenic inhibition of both multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and inward rectifier potassium current (Ik1), and to observe whether the specific inhibition of both CaMKII and Ik1 can bring about any effects on cardiac remodeling. Mice were divided into 4 groups: wild type (WT), CaMKII inhibited (AC3-I), Ik1 inhibited (Kir2.1-AAA) and combined inhibition of both CaMKII and Ik1 (AC3-I+Kir2.1-AAA). Mice in each group received electrocardiogram (ECG) and echocardiography examination. ECG in the condition of isoproterenol (ISO) injection was also checked. The whole cell patch clamp technique was used to measure Ik1 and the transient outward potassium current (Ito) from enzymatically isolated myocytes of left ventricle. In the condition of basal status, no significant changes of heart rate, PR interval and QRS interval were observed. No mouse showed ventricular arrhythmias in all of the 4 groups. After ISO injection, each group presented no significant ventricular arrhythmias either. The indexes measured by M-mode (motion-mode) and two-dimensional echocardiography had no significant differences among the four groups. Ik1 in AC3-I group was significantly higher than those in other three groups (P < 0.01) because of the results brought about by CaMKII inhibition. Among the latter three groups, both Kir2.1-AAA group and AC3-I+Kir2.1-AAA group had a significant reduced Ik1 compared with that of WT group, which was due to the Ik1 inhibition (P < 0.01). Ito in AC3-I group was higher than that of the other three groups (P < 0.01), but there were no significant differences in Ito among WT, Kir2.1-AAA and AC3-I+Kir2.1-AAA groups. Thus, combined transgenic myocardial CaMKII and Ik1 inhibition eliminated the up-regulation of Ik1 in CaMKII inhibited mice, and had no effects on cardiac remodeling including heart structure and function as well as arrhythmias at the basic and ISO conditions. The results of this study may provide a basis for the further investigation of combined inhibition of CaMKII and Ik1 in pathogenic cardiac remodeling.


Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Coração/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , Remodelação Ventricular , Animais , Arritmias Cardíacas , Síndrome de Brugada , Doença do Sistema de Condução Cardíaco , Modelos Animais de Doenças , Eletrocardiografia , Sistema de Condução Cardíaco/anormalidades , Ventrículos do Coração , Isoproterenol , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Regulação para Cima
18.
Int Heart J ; 55(5): 445-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25070116

RESUMO

This study aimed to assess the predictive effect of soluble ST2 (sST2) and depressive symptoms in patients with heart failure (HF) and to determine whether the prognosis of HF patients with preserved ejection fraction (HFpEF) differs from those with reduced ejection fraction (HFrEF). A cohort of 233 HF patients was followed for 1 year. Depressive symptoms were evaluated by the Hospital Anxiety and Depression Scale. The primary endpoint was all-cause mortality and HF-related hospitalization. For the analysis of survival, the left ventricular ejection fraction (LVEF) cut-offs for defining HFpEF were set at 50%, 45%, and 40%, respectively. With increasing LVEF, levels of sST2 were gradually decreased (45.2 ng/mL, 35.8 ng/mL, and 32.1 ng/mL in patients with LVEF ≤ 40%, 41% to 49%, and ≥ 50%, respectively, P for trend < 0.001), as well as the prevalence of depressive symptoms (35.4%, 33.3%, and 20.4%, respectively, P for trend = 0.022). After 1-year follow-up, 128 patients (54.9%) achieved the primary endpoint and 47 patients (20.2%) died. Depressive symptoms were independent risk factors of all-cause mortality and HF-related hospitalization. The combined presence of elevated sST2 (> 36.0 ng/mL) and depressive symptoms was associated with a 4.9-fold increased risk of the primary endpoint. Regardless of LVEF cut-offs, the associated risk of adverse outcomes in HFpEF was as high as in HFrEF after adjustment for significant risk factors including sST2 and N-terminal pro-brain natriuretic peptide. In conclusion, depressive symptoms provided additional prognostic information to that of sST2 in HF patients. The prognosis of HFpEF patients was similar to that of HFrEF patients.


Assuntos
Depressão/etiologia , Insuficiência Cardíaca/mortalidade , Hospitalização/tendências , Receptores de Superfície Celular/sangue , Idoso , Causas de Morte/tendências , China/epidemiologia , Depressão/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Receptores de Interleucina-1 , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências
19.
PLoS One ; 9(4): e94551, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24728278

RESUMO

Fibrinogen-like protein 2 (fgl2) is highly expressed in microvascular endothelial cells in diseases associated with microcirculatory disturbances and plays a crucial role in microthrombosis. Previous studies have demonstrated that the Ser89 residue is a critical site for mouse fgl2 prothrombinase activity. The aim of this study was to investigate the prothrombinase inhibitory ability of antibodies against an hfgl2-derived peptide. The peptide was termed NPG-12 because it is located at the N-terminus of membrane-bound hfgl2, contains 12 amino acid residues (corresponding to residues 76 to 87), and is rich in Glu. This peptide was selected as an antigenic determinant to produce antibodies in immunized rabbits using the DNAStar and HomoloGene software program. Abundant hfgl2 expression was induced in human umbilical vein endothelial cells through treatment with TNF-α. The generated anti-NPG-12 antibodies specifically recognize fgl2, as determined by ELISA, Western Blot and immunostaining. Moreover, one-stage clotting and thrombin generation tests provide evidence that the antibodies can reduce the hfgl2 prothrombinase activity without affecting the platelet-poor plasma prothrombin time (PT) or the activated partial thromboplastin time (APTT). In addition, the antibodies exerted undetectable influence on the proliferation or activation of bulk T cell populations. In conclusion, the selected peptide sequence NPG-12 may be a critical domain for hfgl2 prothrombinase activity, and the development of inhibitors against this sequence may be promising for research or management of hfgl2-associated microcirculatory disturbances.


Assuntos
Anticorpos/farmacologia , Fibrinogênio/antagonistas & inibidores , Fibrinogênio/imunologia , Ácido Glutâmico/imunologia , Peptídeos/imunologia , Serina/metabolismo , Tromboplastina/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Especificidade de Anticorpos/efeitos dos fármacos , Especificidade de Anticorpos/imunologia , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fibrinogênio/química , Células Endoteliais da Veia Umbilical Humana , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Tempo de Tromboplastina Parcial , Peptídeos/química , Tempo de Protrombina , Coelhos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Tromboplastina/metabolismo
20.
J Huazhong Univ Sci Technolog Med Sci ; 33(4): 511-519, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23904370

RESUMO

Angiogenic gene therapy and cell-based therapy for peripheral arterial disease(PAD) have been studied intensively currently. This study aimed to investigate whether combining mesenchymal stem cells(MSCs) transplantation with ex vivo human hepatocyte growth factor(HGF) gene transfer was more therapeutically efficient than the MSCs therapy alone in a rat model of hindlimb ischemia. One week after establishing hindlimb ischemia models, Sprague-Dawley(SD) rats were randomized to receive HGF gene-modified MSCs transplantation(HGF-MSC group), untreated MSCs transplantation (MSC group), or PBS injection(PBS group), respectively. Three weeks after injection, angiogenesis was significantly induced by both MSCs and HGF-MSCs transplantation, and capillary density was the highest in the HGF-MSC group. The number of transplanted cell-derived endothelial cells was greater in HGF-MSC group than in MSC group after one week treatment. The expression of angiogenic cytokines such as HGF and VEGF in local ischemic muscles was more abundant in HGF-MSC group than in the other two groups. In vitro, the conditioned media obtained from HGF-MSCs cultures exerted proproliferative and promigratory effects on endothelial cells. It is concluded that HGF gene-modified MSCs transplantation therapy may induce more potent angiogenesis than the MSCs therapy alone. Engraftment of MSCs combined with angiogenic gene delivery may be a promising therapeutic strategy for the treatment of severe PAD.


Assuntos
Medula Óssea/metabolismo , Fator de Crescimento de Hepatócito/genética , Membro Posterior/patologia , Células-Tronco Mesenquimais/metabolismo , Neovascularização Fisiológica/genética , Animais , Medula Óssea/patologia , Transplante de Medula Óssea , Células Cultivadas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/patologia , Ratos
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