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1.
Psychiatry Res ; : 112669, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31740217

RESUMO

Persistent cognitive deficits are prevalent during all stages of bipolar disorder (BD). However, few studies have examined subjective cognitive complaints in patients with BD. This study aimed to investigate the prevalence and relevant factors of subjective cognitive functioning and its potential effects on predicting psychosocial functioning and suicidal ideation in BD. Ninety-two patients with BD type I (including 42 depressed patients and 50 euthymic patients) and 60 healthy individuals were recruited for this study. All participants were assessed with a battery of neuropsychological tests examining attention and processing speed, visual memory, working memory and executive functions, as well as the Cognitive Complaints in Bipolar Disorder Rating Assessment, the Global Assessment of Functioning scale and the Beck Scale for Suicide Ideation. Bipolar patients exhibited worse subjective cognitive dysfunction compared with healthy individuals, and depressed patients expressed more cognitive complaints than euthymic bipolar patients. In bipolar group, psychosocial functioning, suicidal ideation and occupational status were the main relevant factors of subjective cognitive functioning. Subjective cognitive functioning could also predict psychosocial functioning and suicidal ideation. Depressive symptoms moderated the associations between objective cognitive functioning and suicidal ideation, but could not moderate the correlations between cognitive functioning and psychosocial functioning. These findings suggest that subjective cognitive assessment should be further emphasized in clinical practice.

2.
Med Phys ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31663134

RESUMO

PURPOSE: To apply tracer kinetic models as temporal constraints during reconstruction of under-sampled brain tumor dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). METHODS: A library of concentration vs time profiles is simulated for a range of physiological kinetic parameters. The library is reduced to a dictionary of temporal bases, where each profile is approximated by a sparse linear combination of the bases. Image reconstruction is formulated as estimation of concentration profiles and sparse model coefficients with a fixed sparsity level. Simulations are performed to evaluate modeling error, and error statistics in kinetic parameter estimation in presence of noise. Retrospective under-sampling experiments are performed on a brain tumor DCE digital reference object (DRO), and 12 brain tumor in-vivo 3T datasets. The performances of the proposed under-sampled reconstruction scheme and an existing compressed sensing-based temporal finite-difference (tFD) under-sampled reconstruction were compared against the fully sampled inverse Fourier Transform-based reconstruction. RESULTS: Simulations demonstrate that sparsity levels of 2 and 3 model the library profiles from the Patlak and extended Tofts-Kety (ETK) models, respectively. Noise sensitivity analysis showed equivalent kinetic parameter estimation error statistics from noisy concentration profiles, and model approximated profiles. DRO-based experiments showed good fidelity in recovery of kinetic maps from 20-fold under-sampled data. In-vivo experiments demonstrated reduced bias and uncertainty in kinetic mapping with the proposed approach compared to tFD at under-sampled reduction factors >= 20. CONCLUSIONS: Tracer kinetic models can be applied as temporal constraints during brain tumor DCE-MRI reconstruction. The proposed under-sampled scheme resulted in model parameter estimates less biased with respect to conventional fully sampled DCE MRI reconstructions and parameter estimation. The approach is flexible, can use nonlinear kinetic models, and does not require tuning of regularization parameters.

3.
J Affect Disord ; 249: 73-81, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30763798

RESUMO

BACKGROUND: Patients may present cognitive deficits during all stages of bipolar disorder (BD). Few studies have examined self-reported cognitive difficulties and its relation to neurocognitive dysfunction during symptomatic periods of BD. This study aimed to compare subjective cognitive functioning and explore associations between subjective and objective cognitive functioning across different BD clinical states, and investigate the predicting and moderating roles of mood symptoms. METHODS: Subjective cognitive functioning (measured by Cognitive Complaints in Bipolar Disorder Rating Assessment, COBRA) and several domains of cognitive functioning (assessed by a neuropsychological battery), including executive functions, attention and processing speed, and visual memory, were examined in 48 hypomanic or manic patients, 42 depressed bipolar patients, 50 euthymic bipolar patients and 60 healthy comparisons. RESULTS: All patients exhibited subjective and objective cognitive deficits in relation to healthy comparisons. There was a significant association between subjective and objective cognitive functioning in euthymic group, but the association was not significant in acute symptomatic groups, which could be moderated by depressive or manic symptoms in depressive or manic group, respectively. Subjective cognitive functioning was significantly correlated with mood symptoms, and the best predictor of subjective cognitive functioning was depressive symptoms. LIMITATIONS: This was a cross-sectional study with a mixed sample of inpatients and outpatients. The medication effect was not adjusted. CONCLUSIONS: The associations between subjective and objective cognitive dysfunction varied in clinical states, and mood symptoms moderated the associations. A neuropsychological test battery is required to substantiate actual cognitive dysfunction in clinical settings, irrespective of subjective cognitive deficits.


Assuntos
Transtorno Bipolar/psicologia , Transtornos Cognitivos/psicologia , Transtorno Ciclotímico/psicologia , Transtorno Depressivo/psicologia , Transtorno Distímico/psicologia , Adulto , Grupo com Ancestrais do Continente Asiático/etnologia , Transtorno Bipolar/etnologia , China/epidemiologia , Transtornos Cognitivos/etnologia , Estudos Transversais , Transtorno Ciclotímico/etnologia , Transtorno Depressivo/etnologia , Transtorno Distímico/etnologia , Função Executiva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Pacientes Ambulatoriais , Inquéritos e Questionários
4.
Magn Reson Med ; 81(3): 1511-1520, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30390319

RESUMO

PURPOSE: To develop and evaluate a technique for 3D dynamic MRI of the full vocal tract at high temporal resolution during natural speech. METHODS: We demonstrate 2.4 × 2.4 × 5.8 mm3 spatial resolution, 61-ms temporal resolution, and a 200 × 200 × 70 mm3 FOV. The proposed method uses 3D gradient-echo imaging with a custom upper-airway coil, a minimum-phase slab excitation, stack-of-spirals readout, pseudo golden-angle view order in kx -ky , linear Cartesian order along kz , and spatiotemporal finite difference constrained reconstruction, with 13-fold acceleration. This technique is evaluated using in vivo vocal tract airway data from 2 healthy subjects acquired at 1.5T scanner, 1 with synchronized audio, with 2 tasks during production of natural speech, and via comparison with interleaved multislice 2D dynamic MRI. RESULTS: This technique captured known dynamics of vocal tract articulators during natural speech tasks including tongue gestures during the production of consonants "s" and "l" and of consonant-vowel syllables, and was additionally consistent with 2D dynamic MRI. Coordination of lingual (tongue) movements for consonants is demonstrated via volume-of-interest analysis. Vocal tract area function dynamics revealed critical lingual constriction events along the length of the vocal tract for consonants and vowels. CONCLUSION: We demonstrate feasibility of 3D dynamic MRI of the full vocal tract, with spatiotemporal resolution adequate to visualize lingual movements for consonants and vocal tact shaping during natural productions of consonant-vowel syllables, without requiring multiple repetitions.

5.
Nat Commun ; 9(1): 1595, 2018 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-29686231

RESUMO

Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.


Assuntos
Antineoplásicos Hormonais/farmacologia , Proteína BRCA1/metabolismo , Neoplasias da Mama/terapia , Tamoxifeno/farmacologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antineoplásicos Hormonais/uso terapêutico , Proteína BRCA1/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/efeitos da radiação , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/metabolismo , Tolerância a Radiação/efeitos dos fármacos , Tolerância a Radiação/genética , Transdução de Sinais/efeitos dos fármacos , Taxa de Sobrevida , Tamoxifeno/uso terapêutico , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Magn Reson Med ; 79(5): 2804-2815, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28905411

RESUMO

PURPOSE: To develop and evaluate a model-based reconstruction framework for joint arterial input function (AIF) and kinetic parameter estimation from undersampled brain tumor dynamic contrast-enhanced MRI (DCE-MRI) data. METHODS: The proposed method poses the tracer-kinetic (TK) model as a model consistency constraint, enabling the flexible inclusion of different TK models and TK solvers, and the joint estimation of the AIF. The proposed method is evaluated using an anatomic realistic digital reference object (DRO), and nine retrospectively down-sampled brain tumor DCE-MRI datasets. We also demonstrate application to 30-fold prospectively undersampled brain tumor DCE-MRI. RESULTS: In DRO studies with up to 60-fold undersampling, the proposed method provided TK maps with low error that were comparable to fully sampled data and were demonstrated to be compatible with a third-party TK solver. In retrospective undersampling studies, this method provided patient-specific AIF with normalized root mean-squared-error (normalized by the 90th percentile value) less than 8% at up to 100-fold undersampling. In the 30-fold undersampled prospective study, the proposed method provided high-resolution whole-brain TK maps and patient-specific AIF. CONCLUSION: The proposed model-based DCE-MRI reconstruction enables the use of different TK solvers with a model consistency constraint and enables joint estimation of patient-specific AIF. TK maps and patient-specific AIF with high fidelity can be reconstructed at up to 100-fold undersampling in k,t-space. Magn Reson Med 79:2804-2815, 2018. © 2017 International Society for Magnetic Resonance in Medicine.


Assuntos
Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Idoso , Algoritmos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Meios de Contraste/química , Meios de Contraste/farmacocinética , Humanos , Cinética , Masculino
7.
Oncol Lett ; 13(4): 2805-2810, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28454470

RESUMO

Terrein is a bioactive fungal metabolite isolated from Aspergillus terreus. Besides being a melanogenesis inhibitor, previous studies have revealed that terrein has antiproliferative effects on a number of types of cancer tumors. In the present study, the inhibitory effect of terrein on esophageal cancer was evaluated and the possible underlying mechanisms were investigated. The results revealed that terrein inhibited the proliferation of Eca109 esophageal cancer cells in a dose- and time-dependent manner. Mechanistically, terrein treatment led to the G2/M phase arrest of Eca109 cells by indirectly regulating cyclin B1 and phosphorylating the cell division cycle protein 2 genes. Notably, terrein exhibited a synergistic effect on Eca109 cells when combined with cisplatin, which is a commonly used chemotherapeutic drug. Taken together, these findings indicate that terrein suppresses the proliferation of esophageal cancer cells, and may prove to be a novel therapeutic approach for the treatment of esophageal cancer via inhibiting the proliferation of cancer cells.

8.
Magn Reson Med ; 78(6): 2275-2282, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28185301

RESUMO

PURPOSE: To evaluate the feasibility of through-time spiral generalized autocalibrating partial parallel acquisition (GRAPPA) for low-latency accelerated real-time MRI of speech. METHODS: Through-time spiral GRAPPA (spiral GRAPPA), a fast linear reconstruction method, is applied to spiral (k-t) data acquired from an eight-channel custom upper-airway coil. Fully sampled data were retrospectively down-sampled to evaluate spiral GRAPPA at undersampling factors R = 2 to 6. Pseudo-golden-angle spiral acquisitions were used for prospective studies. Three subjects were imaged while performing a range of speech tasks that involved rapid articulator movements, including fluent speech and beat-boxing. Spiral GRAPPA was compared with view sharing, and a parallel imaging and compressed sensing (PI-CS) method. RESULTS: Spiral GRAPPA captured spatiotemporal dynamics of vocal tract articulators at undersampling factors ≤4. Spiral GRAPPA at 18 ms/frame and 2.4 mm2 /pixel outperformed view sharing in depicting rapidly moving articulators. Spiral GRAPPA and PI-CS provided equivalent temporal fidelity. Reconstruction latency per frame was 14 ms for view sharing and 116 ms for spiral GRAPPA, using a single processor. Spiral GRAPPA kept up with the MRI data rate of 18ms/frame with eight processors. PI-CS required 17 minutes to reconstruct 5 seconds of dynamic data. CONCLUSION: Spiral GRAPPA enabled 4-fold accelerated real-time MRI of speech with a low reconstruction latency. This approach is applicable to wide range of speech RT-MRI experiments that benefit from real-time feedback while visualizing rapid articulator movement. Magn Reson Med 78:2275-2282, 2017. © 2017 International Society for Magnetic Resonance in Medicine.


Assuntos
Laringe/diagnóstico por imagem , Imagem por Ressonância Magnética , Fala , Algoritmos , Artefatos , Calibragem , Epiglote/diagnóstico por imagem , Humanos , Aumento da Imagem , Processamento de Imagem Assistida por Computador , Modelos Estatísticos , Faringe/diagnóstico por imagem , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade , Processamento de Sinais Assistido por Computador , Software
9.
Magn Reson Med ; 77(1): 112-125, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26778178

RESUMO

PURPOSE: The aim of this work was to develop and evaluate an MRI-based system for study of dynamic vocal tract shaping during speech production, which provides high spatial and temporal resolution. METHODS: The proposed system utilizes (a) custom eight-channel upper airway coils that have high sensitivity to upper airway regions of interest, (b) two-dimensional golden angle spiral gradient echo acquisition, (c) on-the-fly view-sharing reconstruction, and (d) off-line temporal finite difference constrained reconstruction. The system also provides simultaneous noise-cancelled and temporally aligned audio. The system is evaluated in 3 healthy volunteers, and 1 tongue cancer patient, with a broad range of speech tasks. RESULTS: We report spatiotemporal resolutions of 2.4 × 2.4 mm2 every 12 ms for single-slice imaging, and 2.4 × 2.4 mm2 every 36 ms for three-slice imaging, which reflects roughly 7-fold acceleration over Nyquist sampling. This system demonstrates improved temporal fidelity in capturing rapid vocal tract shaping for tasks, such as producing consonant clusters in speech, and beat-boxing sounds. Novel acoustic-articulatory analysis was also demonstrated. CONCLUSION: A synergistic combination of custom coils, spiral acquisitions, and constrained reconstruction enables visualization of rapid speech with high spatiotemporal resolution in multiple planes. Magn Reson Med 77:112-125, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Razão Sinal-Ruído , Espectrografia do Som/métodos , Fala/fisiologia , Prega Vocal/diagnóstico por imagem , Adulto , Algoritmos , Feminino , Humanos , Masculino , Processamento de Sinais Assistido por Computador , Neoplasias da Língua/diagnóstico por imagem
10.
Magn Reson Med ; 78(4): 1566-1578, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27859563

RESUMO

PURPOSE: The purpose of this work was to develop and evaluate a T1 -weighted dynamic contrast enhanced (DCE) MRI methodology where tracer-kinetic (TK) parameter maps are directly estimated from undersampled (k,t)-space data. THEORY AND METHODS: The proposed reconstruction involves solving a nonlinear least squares optimization problem that includes explicit use of a full forward model to convert parameter maps to (k,t)-space, utilizing the Patlak TK model. The proposed scheme is compared against an indirect method that creates intermediate images by parallel imaging and compressed sensing before to TK modeling. Thirteen fully sampled brain tumor DCE-MRI scans with 5-second temporal resolution are retrospectively undersampled at rates R = 20, 40, 60, 80, and 100 for each dynamic frame. TK maps are quantitatively compared based on root mean-squared-error (rMSE) and Bland-Altman analysis. The approach is also applied to four prospectively R = 30 undersampled whole-brain DCE-MRI data sets. RESULTS: In the retrospective study, the proposed method performed statistically better than indirect method at R ≥ 80 for all 13 cases. This approach provided restoration of TK parameter values with less errors in tumor regions of interest, an improvement compared to a state-of-the-art indirect method. Applied prospectively, the proposed method provided whole-brain, high-resolution TK maps with good image quality. CONCLUSION: Model-based direct estimation of TK maps from k,t-space DCE-MRI data is feasible and is compatible up to 100-fold undersampling. Magn Reson Med 78:1566-1578, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


Assuntos
Encéfalo/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imagem por Ressonância Magnética/métodos , Neoplasias Encefálicas/diagnóstico por imagem , Feminino , Humanos , Masculino , Imagens de Fantasmas , Estudos Retrospectivos
11.
Med Phys ; 43(5): 2013, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27147313

RESUMO

PURPOSE: To clinically evaluate a highly accelerated T1-weighted dynamic contrast-enhanced (DCE) MRI technique that provides high spatial resolution and whole-brain coverage via undersampling and constrained reconstruction with multiple sparsity constraints. METHODS: Conventional (rate-2 SENSE) and experimental DCE-MRI (rate-30) scans were performed 20 minutes apart in 15 brain tumor patients. The conventional clinical DCE-MRI had voxel dimensions 0.9 × 1.3 × 7.0 mm(3), FOV 22 × 22 × 4.2 cm(3), and the experimental DCE-MRI had voxel dimensions 0.9 × 0.9 × 1.9 mm(3), and broader coverage 22 × 22 × 19 cm(3). Temporal resolution was 5 s for both protocols. Time-resolved images and blood-brain barrier permeability maps were qualitatively evaluated by two radiologists. RESULTS: The experimental DCE-MRI scans showed no loss of qualitative information in any of the cases, while achieving substantially higher spatial resolution and whole-brain spatial coverage. Average qualitative scores (from 0 to 3) were 2.1 for the experimental scans and 1.1 for the conventional clinical scans. CONCLUSIONS: The proposed DCE-MRI approach provides clinically superior image quality with higher spatial resolution and coverage than currently available approaches. These advantages may allow comprehensive permeability mapping in the brain, which is especially valuable in the setting of large lesions or multiple lesions spread throughout the brain.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
12.
Magn Reson Imaging ; 34(7): 940-50, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26707849

RESUMO

PURPOSE: To develop and evaluate a novel 3D Cartesian sampling scheme which is well suited for time-resolved 3D MRI using parallel imaging and compressed sensing. METHODS: The proposed sampling scheme, termed GOlden-angle CArtesian Randomized Time-resolved (GOCART) 3D MRI, is based on golden angle (GA) Cartesian sampling, with random sampling of the ky-kz phase encode locations along each Cartesian radial spoke. This method was evaluated in conjunction with constrained reconstruction of retrospectively and prospectively undersampled in-vivo dynamic contrast enhanced (DCE) MRI data and simulated phantom data. RESULTS: In in-vivo retrospective studies and phantom simulations, images reconstructed from phase encodes defined by GOCART were equal to or superior to those with Poisson disc or GA sampling schemes. Typical GOCART sampling tables were generated in <100ms. GOCART has also been successfully utilized prospectively to produce clinically valuable whole-brain DCE-MRI images. CONCLUSION: GOCART is a practical and efficient sampling scheme for time-resolved 3D MRI. It shows great potential for highly accelerated DCE-MRI and is well suited to modern reconstruction methods such as parallel imaging and compressed sensing.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imagem Tridimensional/métodos , Imagem por Ressonância Magnética/métodos , Algoritmos , Encéfalo/diagnóstico por imagem , Meios de Contraste , Humanos , Aumento da Imagem/métodos , Imagens de Fantasmas , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , Sensibilidade e Especificidade
13.
Oncotarget ; 6(34): 36370-82, 2015 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-26461473

RESUMO

Dysregulation of SOX10 was reported to be correlated with the progression of multiple cancer types, including melanocytic tumors and tumors of the nervous system. However, the mechanisms by which SOX10 is dysregulated in these tumors are poorly understood. In this study, we report that SOX10 is a direct substrate of Fbxw7α E3 ubiquitin ligase, a tumor suppressor in multiple cancers. Fbxw7α promotes SOX10 ubiquitination-mediated turnover through CPD domain of SOX10. Besides, GSK3ß phosphorylates SOX10 at CPD domain and facilitates Fbxw7α-mediated SOX10 degradation. Moreover, SOX10 protein levels were inversely correlated with Fbxw7α in melanoma cells, and modulation of Fbxw7α levels regulated the expression of SOX10 and its downstream gene MIA. More importantly, SOX10 reversed Fbxw7α-mediated suppression of melanoma cell migration. This study provides evidence that the tumor suppressor Fbxw7α is the E3 ubiquitin ligase responsible for the degradation of SOX10, and suggests that reduced Fbxw7α might contribute to the upregulation of SOX10 in melanoma cells.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Movimento Celular/fisiologia , Proteínas F-Box/metabolismo , Melanoma/metabolismo , Melanoma/patologia , Fatores de Transcrição SOXE/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Apoptose/fisiologia , Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Proteína 7 com Repetições F-Box-WD , Células HEK293 , Células HeLa , Humanos , Melanoma/genética , Fatores de Transcrição SOXE/genética , Transfecção , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
14.
Oncotarget ; 6(31): 31944-57, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26397135

RESUMO

About 50-70% of breast cancers are estrogen receptor α (ERα) positive and most of them are sensitive to endocrine therapy including tamoxifen. However, one third of these patients will eventually develop resistance and relapse. We found that the expression of miR-15a and miR-16 were significantly decreased in tamoxifen resistant ER positive breast cancer cell lines. Exogenous expression of miR-15a/16 mimics re-sensitized resistant cells to tamoxifen by inhibiting Cyclin E1 and B cell lymphoma-2 (Bcl-2) to induce cell growth arrest and apoptosis respectively. Further, we identified that a repressive member of E2F family, E2F7, was responsible for the suppression of miR-15a/16 cluster by competing with E2F1 for E2F binding site at the promoter of their host gene DLEU2. Moreover, high expression of E2F7 is correlated with high risk of relapse and poor prognosis in breast cancer patients receiving tamoxifen treatment. Together, our results suggest that overexpression of E2F7 represses miR-15a/16 and then increases Cyclin E1 and Bcl-2 that result in tamoxifen resistance. E2F7 may be a valuable prognostic marker and a therapeutic target of tamoxifen resistance in breast cancer.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F1/metabolismo , Fator de Transcrição E2F7/metabolismo , MicroRNAs/genética , Regiões Promotoras Genéticas/genética , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Apoptose , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Imunoprecipitação da Cromatina , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F7/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Células Tumorais Cultivadas
15.
Oncotarget ; 6(32): 32410-25, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26378045

RESUMO

Long noncoding RNA NBAT1 (neuroblastoma associated transcript 1) regulates cell proliferation and invasion by interacting with PRC2 (polycomb repressive complex 2) member EZH2 (enhancer of zeste 2). Decreased expression of NBAT1 is associated with poor clinical outcome in neuroblastomas. However, the roles of NBAT1 in other cancers remain unknown. Here, we report that NBAT1 is down-regulated in various types of cancer. Particularly, reduced NBAT1 in breast cancer is associated with tumor metastasis and poor patient prognosis. In vitro, ectopic NBAT1 inhibits migration and invasion of breast cancer cells. Mechanistic study shows that NBAT1 is associated with PRC2 member EZH2 and regulates global gene expression profile. Among them, DKK1 (dickkopf WNT signaling pathway inhibitor 1) is found to be regulated by NBAT1 in a PRC2 dependent manner, and is responsible for NBAT1's effects in inhibiting migration and invasion of breast cancer cells. Taken together, our study demonstrates that long noncoding RNA NBAT1 is a potential breast cancer prognostic marker, as well as a potential therapeutic target to inhibit breast cancer metastasis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/enzimologia , Movimento Celular , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Complexo Repressor Polycomb 2/metabolismo , RNA Longo não Codificante/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Proteína Potenciadora do Homólogo 2 de Zeste , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Estimativa de Kaplan-Meier , Células MCF-7 , Invasividade Neoplásica , Complexo Repressor Polycomb 2/genética , Prognóstico , Mapas de Interação de Proteínas , Interferência de RNA , RNA Longo não Codificante/genética , Transdução de Sinais , Fatores de Tempo , Transfecção
16.
Oncotarget ; 6(17): 14885-904, 2015 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-25912308

RESUMO

Cisplatin has been widely employed as a cornerstone chemotherapy treatment for a wide spectrum of solid neoplasms; increasing tumor responsiveness to cisplatin has been a topic of interest for the past 30 years. Strong evidence has indicated that mitochondrial fission participates in the regulation of apoptosis in many diseases; however, whether mitochondrial fission regulates cisplatin sensitivity remains poorly understood. Here, we show that MFF mediated mitochondrial fission and apoptosis in tongue squamous cell carcinoma (TSCC) cells after cisplatin treatment and that miR-593-5p was downregulated in this process. miR-593-5p attenuated mitochondrial fission and cisplatin sensitivity by targeting the 3' untranslated region sequence of MFF and inhibiting its translation. In exploring the underlying mechanism of miR-593-5p downregulation, we observed that BRCA1 transactivated miR-593-5p expression and attenuated cisplatin sensitivity in vitro. The BRCA1-miR-593-5p-MFF axis also affected cisplatin sensitivity in vivo. Importantly, in a retrospective analysis of multiple centers, we further found that the BRCA1-miR-593-5p-MFF axis was significantly associated with cisplatin sensitivity and the survival of patients with TSCC. Together, our data reveal a model for mitochondrial fission regulation at the transcriptional and post-transcriptional levels; we also reveal a new pathway for BRCA1 in determining cisplatin sensitivity through the mitochondrial fission program.


Assuntos
Proteína BRCA1/genética , Cisplatino/uso terapêutico , Proteínas de Membrana/genética , MicroRNAs/genética , Dinâmica Mitocondrial/genética , Proteínas Mitocondriais/genética , Neoplasias da Língua/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteína BRCA1/metabolismo , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Immunoblotting , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Confocal , Pessoa de Meia-Idade , Proteínas Mitocondriais/metabolismo , Análise Multivariada , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Neoplasias da Língua/genética , Neoplasias da Língua/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Acoust Soc Am ; 136(3): 1307, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25190403

RESUMO

USC-TIMIT is an extensive database of multimodal speech production data, developed to complement existing resources available to the speech research community and with the intention of being continuously refined and augmented. The database currently includes real-time magnetic resonance imaging data from five male and five female speakers of American English. Electromagnetic articulography data have also been presently collected from four of these speakers. The two modalities were recorded in two independent sessions while the subjects produced the same 460 sentence corpus used previously in the MOCHA-TIMIT database. In both cases the audio signal was recorded and synchronized with the articulatory data. The database and companion software are freely available to the research community.


Assuntos
Acústica , Pesquisa Biomédica , Bases de Dados Factuais , Fenômenos Eletromagnéticos , Imagem por Ressonância Magnética , Faringe/fisiologia , Acústica da Fala , Medida da Produção da Fala , Qualidade da Voz , Acústica/instrumentação , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Faringe/anatomia & histologia , Processamento de Sinais Assistido por Computador , Software , Medida da Produção da Fala/instrumentação , Fatores de Tempo , Transdutores
18.
IEEE Trans Med Imaging ; 32(5): 838-48, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23204279

RESUMO

Noninvasive imaging is widely used in speech research as a means to investigate the shaping and dynamics of the vocal tract during speech production. 3-D dynamic MRI would be a major advance, as it would provide 3-D dynamic visualization of the entire vocal tract. We present a novel method for the creation of 3-D dynamic movies of vocal tract shaping based on the acquisition of 2-D dynamic data from parallel slices and temporal alignment of the image sequences using audio information. Multiple sagittal 2-D real-time movies with synchronized audio recordings are acquired for English vowel-consonant-vowel stimuli /ala/, /a.ιa/, /asa/, and /a∫a/. Audio data are aligned using mel-frequency cepstral coefficients (MFCC) extracted from windowed intervals of the speech signal. Sagittal image sequences acquired from all slices are then aligned using dynamic time warping (DTW). The aligned image sequences enable dynamic 3-D visualization by creating synthesized movies of the moving airway in the coronal planes, visualizing desired tissue surfaces and tube-shaped vocal tract airway after manual segmentation of targeted articulators and smoothing. The resulting volumes allow for dynamic 3-D visualization of salient aspects of lingual articulation, including the formation of tongue grooves and sublingual cavities, with a temporal resolution of 78 ms.


Assuntos
Imagem Tridimensional/métodos , Imagem por Ressonância Magnética/métodos , Medida da Produção da Fala/métodos , Prega Vocal/anatomia & histologia , Prega Vocal/fisiologia , Adulto , Humanos , Masculino , Processamento de Sinais Assistido por Computador
19.
J Biol Chem ; 287(1): 465-73, 2012 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-22074923

RESUMO

Tumor-initiating cells (T-ICs), a subpopulation of cancer cells with stem cell-like properties, are related to tumor relapse and metastasis. Our previous studies identified a distinct profile of microRNA (miRNA) expression in breast T-ICs (BT-ICs), and the dysregulated miRNAs contribute to the self-renewal and tumorigenesis of these cells. However, the underlying mechanisms for miRNA dysregulation in BT-ICs remain obscure. In the present study, we demonstrated that the expression and function of miR-34c were reduced in the BT-ICs of MCF-7 and SK-3rd cells, a breast cancer cell line enriched for BT-ICs. Ectopic expression of miR-34c reduced the self-renewal of BT-ICs, inhibited epithelial-mesenchymal transition, and suppressed migration of the tumor cells via silencing target gene Notch4. Furthermore, we identified a single hypermethylated CpG site in the promoter region of miR-34c gene that contributed to transcriptional repression of miR-34c in BT-ICs by reducing DNA binding activities of Sp1. Therefore, miR-34c reduction in BT-ICs induced by a single hypermethylated CpG site in the promoter region promotes self-renewal and epithelial-mesenchymal transition of BT-ICs.


Assuntos
Neoplasias da Mama/patologia , Metilação de DNA/genética , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Neoplasias da Mama/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Ilhas de CpG/genética , Humanos , Células-Tronco Neoplásicas/metabolismo , Regiões Promotoras Genéticas/genética , Proteínas Proto-Oncogênicas/genética , Receptor Notch4 , Receptores Notch/genética , Fator de Transcrição Sp1/metabolismo
20.
Clin Cancer Res ; 17(22): 7105-15, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21953503

RESUMO

PURPOSE: Tumor-initiating cells are resistant to chemotherapy, but how microRNAs play a role in regulating drug resistance of breast tumor-initiating cells (BT-IC) needs to be clarified. EXPERIMENTAL DESIGN: Lentivirus-mediated miR-128 transduction was done in BT-ICs, enriched by mammosphere cultures or CD44(+)CD24(-) fluorescence-activated cell sorting. Apoptosis and DNA damage were determined upon treatment with doxorubicin. Expression of miR-128 in breast cancer tissues was examined by in situ hybridization and correlated with breast tumor response to neoadjuvant chemotherapy and patient survival. RESULTS: MiR-128 was significantly reduced in chemoresistant BT-ICs enriched from breast cancer cell lines and primary breast tumors (P < 0.01), accompanied by an overexpression of Bmi-1 and ABCC5, which were identified as targets of miR-128. Ectopic expression of miR-128 reduced the protein levels of Bmi-1 and ABCC5 in BT-ICs, along with decreased cell viability (P < 0.001) and increased apoptosis (P < 0.001) and DNA damage (P < 0.001) in the presence of doxorubicin. Reduced miR-128 expression in breast tumor tissues was associated with chemotherapeutic resistance (P < 0.001) and poor survival of breast cancer patients (P < 0.05; n = 57). CONCLUSIONS: Reduction in miR-128 leading to Bmi-1 and ABCC5 overexpression is a stem cell-like feature of BT-ICs, which contributes to chemotherapeutic resistance in breast cancers. Ectopic expression of miR-128 sensitizes BT-ICs to the proapoptotic and DNA-damaging effects of doxorubicin, indicating therapeutic potential.


Assuntos
Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/fisiologia , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Proteínas Repressoras/fisiologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/uso terapêutico , Marcação de Genes , Humanos , Complexo Repressor Polycomb 1
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