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1.
Artigo em Inglês | MEDLINE | ID: mdl-34437074

RESUMO

High-dimensional multilabel data have increasingly emerged in many application areas, suffering from two noteworthy issues: instances with high-dimensional features and large-scale labels. Multilabel feature selection methods are widely studied to address the issues. Previous multilabel feature selection methods focus on exploring label correlations to guide the feature selection process, ignoring the impact of latent feature structure on label correlations. In addition, one encouraging property regarding correlations between features and labels is that similar features intend to share similar labels. To this end, a latent structure shared (LSS) term is designed, which shares and preserves both latent feature structure and latent label structure. Furthermore, we employ the graph regularization technique to guarantee the consistency between original feature space and latent feature structure space. Finally, we derive the shared latent feature and label structure feature selection (SSFS) method based on the constrained LSS term, and then, an effective optimization scheme with provable convergence is proposed to solve the SSFS method. Better experimental results on benchmark datasets are achieved in terms of multiple evaluation criteria.

3.
Lancet Digit Health ; 3(8): e486-e495, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325853

RESUMO

BACKGROUND: Medical artificial intelligence (AI) has entered the clinical implementation phase, although real-world performance of deep-learning systems (DLSs) for screening fundus disease remains unsatisfactory. Our study aimed to train a clinically applicable DLS for fundus diseases using data derived from the real world, and externally test the model using fundus photographs collected prospectively from the settings in which the model would most likely be adopted. METHODS: In this national real-world evidence study, we trained a DLS, the Comprehensive AI Retinal Expert (CARE) system, to identify the 14 most common retinal abnormalities using 207 228 colour fundus photographs derived from 16 clinical settings with different disease distributions. CARE was internally validated using 21 867 photographs and externally tested using 18 136 photographs prospectively collected from 35 real-world settings across China where CARE might be adopted, including eight tertiary hospitals, six community hospitals, and 21 physical examination centres. The performance of CARE was further compared with that of 16 ophthalmologists and tested using datasets with non-Chinese ethnicities and previously unused camera types. This study was registered with ClinicalTrials.gov, NCT04213430, and is currently closed. FINDINGS: The area under the receiver operating characteristic curve (AUC) in the internal validation set was 0·955 (SD 0·046). AUC values in the external test set were 0·965 (0·035) in tertiary hospitals, 0·983 (0·031) in community hospitals, and 0·953 (0·042) in physical examination centres. The performance of CARE was similar to that of ophthalmologists. Large variations in sensitivity were observed among the ophthalmologists in different regions and with varying experience. The system retained strong identification performance when tested using the non-Chinese dataset (AUC 0·960, 95% CI 0·957-0·964 in referable diabetic retinopathy). INTERPRETATION: Our DLS (CARE) showed satisfactory performance for screening multiple retinal abnormalities in real-world settings using prospectively collected fundus photographs, and so could allow the system to be implemented and adopted for clinical care. FUNDING: This study was funded by the National Key R&D Programme of China, the Science and Technology Planning Projects of Guangdong Province, the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the Fundamental Research Funds for the Central Universities. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Assuntos
Aprendizado Profundo , Sistemas Especialistas , Processamento de Imagem Assistida por Computador/métodos , Programas de Rastreamento/métodos , Modelos Biológicos , Retina , Doenças Retinianas/diagnóstico , Área Sob a Curva , Inteligência Artificial , Tecnologia Biomédica , China , Retinopatia Diabética/diagnóstico , Fundo de Olho , Humanos , Oftalmologistas , Fotografação , Curva ROC
4.
Graefes Arch Clin Exp Ophthalmol ; 259(9): 2513-2519, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33675393

RESUMO

PURPOSE: To compare the outcomes of macular buckling (MB) surgery between myopic foveal detachment (FD) eyes with and without ellipsoid zone (EZ) disruption. METHODS: A retrospective, case-control study. Forty-four consecutive eyes from 44 patients received MB surgery for myopic FD between November 2017 and January 2019 were included. The eyes were divided into two groups according to the integrity of EZ on spectral-domain optical coherence tomography (SD-OCT): 28 eyes with disrupted EZ band and 16 eyes with intact EZ band. Main outcome measures were visual acuity and the duration of subfoveal fluid (SFF) after MB. RESULTS: The mean follow-up time was 17.64 ± 6.61 and 16.06 ± 5.78 months in the disrupted EZ and intact EZ group, respectively (P = 0.430). The logMAR best-corrected visual acuity (BCVA) improved significantly, from 1.13 ± 0.46 and 1.12 ± 0.39 at baseline to 0.85 ± 0.65 (P = 0.002) and 0.53 ± 0.33 (P = 0.000) for the disrupted EZ group and intact EZ group, respectively. The mean visual improvement was 15.00 ± 14.14 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for the disrupted EZ group and 26.88 ± 19.48 ETDRS letters for the intact EZ group. Significant difference was found on both final postoperative BCVA (P = 0.035) and visual improvement (P = 0.025). At 6 months, SFF remained in 53.57% (15/28) of the eyes in the disrupted EZ group and in only 12.50% (2/16) of the eyes in the intact EZ group (P = 0.018). CONCLUSION: The intact EZ group showed better functional and anatomical outcomes than the disrupted EZ group after MB surgery.


Assuntos
Fóvea Central , Tomografia de Coerência Óptica , Estudos de Casos e Controles , Humanos , Estudos Retrospectivos , Acuidade Visual
5.
ACS Omega ; 6(10): 6547-6553, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33748566

RESUMO

In this review, we will summarize our recent progress in the design and application of novel organic sensors with emission in the near-infrared region (600-900 nm). By coupling different functional groups with excited-state intramolecular proton transfer (ESIPT) segments, new probes are developed to achieve a large Stokes shift, high sensitivity, and selectivity and to tune the emission toward the near-infrared region. The developed probes exhibit attractive optical properties for bioimaging and environmental science applications. In addition, we further discuss the photophysical properties of ESIPT dyes and how their fluorescence could be affected by structural/environmental factors, which should be considered during the development of robust ESIPT-based fluorescence probes. Their potential applications as imaging reagents are illustrated for intracellular membranes, mitochondria, lysosomes, and some biomolecules.

6.
Br J Ophthalmol ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33397654

RESUMO

AIM: To compare the efficacy of macular buckling (MB) and pars plana vitrectomy (PPV) for full-thickness macular holes (FTMH) and associated macular detachment (MD) in highly myopic eyes. METHODS: Prospective interventional case series of eyes undergoing PPV or MB for FTMH and MD. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at postoperative month 24. Other measured outcomes include the initial surgical success rate, macular hole closure rate and the progression of myopic maculopathy. RESULTS: A total of 53 eyes from 53 participants were included in this study (26 participants receiving MB and 27 participants receiving PPV), and finally 49 eyes from 49 participants (25 participants in the MB group and 24 participants in the PPV group) were analysed. At postoperative month 24, the BCVA had improved significantly in those that underwent either MB (p<0.001) or PPV (p=0.04). The difference between the groups was not significant (p=0.653). The surgical failure rate after the primary treatment was significantly higher in the PPV group than the MB group (25.00% vs 4.00%, respectively; p=0.04). The macular closure rate was higher in the MB group compared with the PPV group, but the difference was not statistically significant (64.00% vs 58.33%, respectively; p=0.45). Myopic maculopathy development may be more severe following PPV than following MB surgery. CONCLUSION: Patients with high myopia obtained anatomical and functional improvements from either MB or PPV. However, MB achieved a significantly higher success rate in retinal reattachment compared with PPV. TRIAL REGISTRATION NUMBER: NCT03433547.

7.
Curr Med Chem ; 28(2): 329-345, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-31965935

RESUMO

BACKGROUND: Artemisinin is a sesquiterpene lactone compound with a special peroxide bridge that is tightly linked to the cytotoxicity involved in fighting malaria and cancer. Artemisinin and its derivatives (ARTs) are considered to be potential anticancer drugs that promote cancer cell apoptosis, induce cell cycle arrest and autophagy, inhibit cancer cell invasion and migration. Additionally, ARTs significantly increase intracellular Reactive Oxygen Species (ROS) in cancer cells, which result in ferroptosis, a new form of cell death, depending on the ferritin concentration. Ferroptosis is regarded as a cancer suppressor and as well as considered a new mechanism for cancer therapy. METHODS: The anticancer activities of ARTs and reference molecules were compared by literature search and analysis. The latest research progress on ferroptosis was described, with a special focus on the molecular mechanism of artemisinin-induced ferroptosis. RESULTS: Artemisinin derivatives, artemisinin-derived dimers, hybrids and artemisinin-transferrin conjugates, could significantly improve anticancer activity, and their IC50 values are lower than those of reference molecules such as doxorubicin and paclitaxel. The biological activities of linkers in dimers and hybrids are important in the drug design processes. ARTs induce ferroptosis mainly by triggering intracellular ROS production, promoting the lysosomal degradation of ferritin and regulating the System Xc-/Gpx4 axis. Interestingly, ARTs also stimulate the feedback inhibition pathway. CONCLUSION: Artemisinin and its derivatives could be used in the future as cancer therapies with broader applications due to their induction of ferroptosis. Meanwhile, more attention should be paid to the development of novel artemisinin-related drugs based on the mechanism of artemisinininduced ferroptosis.


Assuntos
Neoplasias , Antimaláricos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Artemisininas/farmacologia , Artemisininas/uso terapêutico , Ferroptose , Humanos , Neoplasias/tratamento farmacológico
8.
Curr Eye Res ; 46(7): 1056-1060, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33249926

RESUMO

Purposes: To investigate the patterns of fundus autofluorescence (FAF) in patients with different grades of myopic atrophy maculopathy (MAM).Methods: Patients with MAM who visited Zhongshan Ophthalmic Center from January 2018 to December 2019 were screened. All patients received comprehensive ophthalmologic examinations as well as FAF imaging. The atrophic severity of each eye was identified based on the META-PM classification system, including no myopic retinal lesions (C0), tessellated fundus only (C1), diffuse chorioretinal atrophy (C2), patchy chorioretinal atrophy (C3), and macular atrophy (C4).Results: Eighty-nine consecutive patients with 137 affected eyes were included. Four different autofluorescence (AF) patterns were detected: unremarkable AF (48 eyes in C1 and 18 eyes in C2, 48.2%), compound AF (2 eyes in C1 and 12 eyes in C2, 10.2%), patchy AF defect (5 eyes in C2 and 34 eyes in C3, 28.5%), and macular AF defect (18 eyes in C4, 13.1%). Moreover, AF patterns were significantly correlated with age (r = 0.419, P < .001), best-corrected visual acuity (BCVA) (r = 0.592, P < .001), axial length (AL) (r = 0.529, P < .001), and subfovial choroidal thickness (SFCT) (r = -0.728, P < .001). In addition, with the help of FAF, 14.3% (5/35) of eyes initially categorized as C2 merely based on color fundus photographs (CFP) should be categorized as C3.Conclusions: The severity of FAF in eyes with MAM was significantly correlated with myopic characteristics. FAF might be beneficial for detecting unremarkable patchy chorioretinal atrophy on CFP of MAM.

9.
J Cataract Refract Surg ; 47(5): 593-598, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33278232

RESUMO

PURPOSE: To compare the performance of new-generation and traditional intraocular lens (IOL) calculation formulas in eyes undergoing combined silicone oil (SO) removal and cataract surgery and to evaluate the prediction accuracy of Wang-Koch (WK) adjustment in SO-filled long eyes. SETTING: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. DESIGN: Retrospective consecutive case-series study. METHODS: New-generation formulas (Barrett Universal II, Emmetropia Verifying Optical, Kane, and Ladas Super formulas) and traditional formulas (Haigis, Hoffer Q, Holladay 1, and SRK/T formulas) were compared. The performance of WK adjustment was assessed in eyes with axial length more than 26 mm. The median absolute error (MedAE) was the main parameter to evaluate the accuracy of formulas. RESULTS: A total of 211 participants (211 eyes) who underwent combined SO removal and phacoemulsification with IOL implantation were included. Four new-generation formulas displayed statistically significant lower MedAE (0.32 to 0.35 diopter [D]) and higher percentage of eyes within ±1.00 D of prediction error (85.31% to 87.20%) compared with those of the traditional formulas (MedAE: 0.39 to 0.50 D; ±1.00 D: 81.04% to 81.99%, P < .05). For SO-filled long eyes, all traditional formulas showed hyperopic bias (0.36 to 0.65 D, P < .05), except for Haigis formula (0.28 D, P = .083), and this bias could be corrected by WK adjustment (P > .05). EVO formula displayed the lowest MedAE both in total (0.32 D) and in long eyes (0.33 D). CONCLUSIONS: New-generation formulas and traditional formulas with WK adjustment showed satisfactory prediction accuracy in eyes undergoing combined SO removal and cataract surgery. EVO formula displayed the highest accuracy.


Assuntos
Catarata , Lentes Intraoculares , Comprimento Axial do Olho , Biometria , China , Humanos , Implante de Lente Intraocular , Óptica e Fotônica , Refração Ocular , Estudos Retrospectivos , Óleos de Silicone
10.
Retina ; 41(7): 1496-1501, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33239543

RESUMO

PURPOSE: To analyze clinical characteristics in eyes with myopic traction maculopathy (MTM). METHODS: Nine hundred and ninety-one patients (1,334 eyes) with MTM, who visited Zhongshan Ophthalmic Center from January 2014 to December 2019, were involved. Myopic traction maculopathy was classified into six grades according to the new classification system: no macular schisis (T0), inner or outer foveoschisis (FS) (T1); inner and outer FS (T2), foveal detachment (T3), full-thickness macular hole (T4), and macular hole retinal detachment (T5). RESULTS: Seven hundred and seventy-eight (58.32%) eyes were in T0, 157 (11.77%) in T1, 177 (13.27%) in T2, 129 (9.67%) in T3, 45 (3.37%) in T4, and 48 (3.67%) in T5. With the severity of MTM, age increased and the best-corrected visual acuity became worse (P < 0.001). However, no significant differences were found on spherical equivalent refraction or axial length among different grades of MTM (P > 0.05). Moreover, significant differences on best-corrected visual acuity, spherical equivalent refraction, axial length, and staphyloma rate existed between eyes with inner FS and eyes with outer FS (P < 0.01), but not between eyes with outer FS and eyes with both inner FS and outer FS (P > 0.05). Besides, significant differences were found on spherical equivalent refraction, axial length, and staphyloma rate between full-thickness macular hole with and without macular schisis (P < 0.001). CONCLUSION: Spherical equivalent refraction and axial length were not correlated with the severity of MTM in this cohort. It might be preferable to categorize eyes with outer FS and eyes with both inner FS and outer FS as a same grade. Potential difference in the pathogenesis between full-thickness macular hole with and without macular schisis might exist.

11.
Entropy (Basel) ; 22(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-33286568

RESUMO

Multi-label data often involve features with high dimensionality and complicated label correlations, resulting in a great challenge for multi-label learning. Feature selection plays an important role in multi-label learning to address multi-label data. Exploring label correlations is crucial for multi-label feature selection. Previous information-theoretical-based methods employ the strategy of cumulative summation approximation to evaluate candidate features, which merely considers low-order label correlations. In fact, there exist high-order label correlations in label set, labels naturally cluster into several groups, similar labels intend to cluster into the same group, different labels belong to different groups. However, the strategy of cumulative summation approximation tends to select the features related to the groups containing more labels while ignoring the classification information of groups containing less labels. Therefore, many features related to similar labels are selected, which leads to poor classification performance. To this end, Max-Correlation term considering high-order label correlations is proposed. Additionally, we combine the Max-Correlation term with feature redundancy term to ensure that selected features are relevant to different label groups. Finally, a new method named Multi-label Feature Selection considering Max-Correlation (MCMFS) is proposed. Experimental results demonstrate the classification superiority of MCMFS in comparison to eight state-of-the-art multi-label feature selection methods.

12.
Br J Ophthalmol ; 2020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33355150

RESUMO

BACKGROUND/AIMS: To apply deep learning technology to develop an artificial intelligence (AI) system that can identify vision-threatening conditions in high myopia patients based on optical coherence tomography (OCT) macular images. METHODS: In this cross-sectional, prospective study, a total of 5505 qualified OCT macular images obtained from 1048 high myopia patients admitted to Zhongshan Ophthalmic Centre (ZOC) from 2012 to 2017 were selected for the development of the AI system. The independent test dataset included 412 images obtained from 91 high myopia patients recruited at ZOC from January 2019 to May 2019. We adopted the InceptionResnetV2 architecture to train four independent convolutional neural network (CNN) models to identify the following four vision-threatening conditions in high myopia: retinoschisis, macular hole, retinal detachment and pathological myopic choroidal neovascularisation. Focal Loss was used to address class imbalance, and optimal operating thresholds were determined according to the Youden Index. RESULTS: In the independent test dataset, the areas under the receiver operating characteristic curves were high for all conditions (0.961 to 0.999). Our AI system achieved sensitivities equal to or even better than those of retina specialists as well as high specificities (greater than 90%). Moreover, our AI system provided a transparent and interpretable diagnosis with heatmaps. CONCLUSIONS: We used OCT macular images for the development of CNN models to identify vision-threatening conditions in high myopia patients. Our models achieved reliable sensitivities and high specificities, comparable to those of retina specialists and may be applied for large-scale high myopia screening and patient follow-up.

13.
Mol Ther Nucleic Acids ; 22: 557-571, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33230457

RESUMO

Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation in vitro and in vivo. Mechanism analysis indicated that miR-4721 directly targetes GSK3ß and reduces its expression, which therefore elevates ß-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3ß are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3ß, which thus activates the WNT/ß-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future.

14.
Ocul Surf ; 18(4): 783-794, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32735949

RESUMO

PURPOSE: Dry eye disease (DED) is a common and multifactor-induced autoimmune ocular surface disease. Environmental factors, such as desiccating stress (DS) and hyperosmolarity, affect the corneal epithelium to induce ocular surface inflammation in DED. We aimed to explore the potential mechanisms by which innate immunity and pyroptosis are initiated in the mucosal epithelium in response to environmental stress. METHODS: Experimental dry eye was established in C57BL/6 J mice and genetic mice on the background of C57BL/6 J mice by subcutaneous injection of scopolamine and exposure to a desiccating environment. SDHCEC cell line was subjected to hyperosmolarity stress (450 mOsM). The phenol red thread tear test and corneal epithelial defects evaluation were used as assessments of severity of DED. RNA-sequencing, quantitative real-time PCR, western blotting and immunofluorescence staining were performed in this study. RESULTS: Loss-of-function studies indicated that genetic deletion of GSDMD alleviates DS-induced corneal epithelium defects, and GSDMD is needed for IL-33 processing. We further found that NLRP12 collaborates with NLRC4 inflammasome to initiate GSDMD-dependent pyroptosis, which requires TLR4-induced caspase-8 (CASP8) activation in the mucosal corneal epithelium in response to DS. CONCLUSIONS: These findings provide compelling evidence that GSDMD-dependent pyroptosis plays a pivotal role in DED. A novel mechanism involving NLRP12 and NLRC4 inflammasomes-induced GSDMD-dependent pyroptosis, accompanied by IL-33 processing is responsible for ocular surface epithelial defects in response to environmental stress. GSDMD is required for IL-33 processing and the subsequent amplification of inflammatory cascades. These findings reveal novel therapeutic targets for treating DED.


Assuntos
Síndromes do Olho Seco , Piroptose , Animais , Proteínas Reguladoras de Apoptose , Proteínas de Ligação ao Cálcio , Interleucina-33 , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação a Fosfato
15.
Int J Ophthalmol ; 13(5): 761-765, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32420223

RESUMO

AIM: To investigate the rates of emulsification in silicone oil (SO) tamponades of differing viscosities used during pars plana vitrectomy (PPV) in the treatment of complicated vitreoretinal diseases. METHODS: This study was a prospective randomized clinical trial. Totally 290 cases with greater likelihoods of secondary detachment were included and randomly grouped into either Siluron 2000 (n=143) or Siluron 5000 (n=147) SO tamponades with 23-gauge PPV. Patient follow-ups and data analyses were conducted 1, 3, 6, and 12mo post-surgery. RESULTS: The time of the SO emulsification ranged from 1 to 17mo, with a mean of 7.3±4.2mo. The Siluron 5000 group showed a slower emulsification rate in comparison to the Siluron 2000 group. The Siluron 2000 group took a shorter time to show signs of emulsification, necessitating earlier SO removal. However, there were no significant differences in the occurrence of complications, including secondary retinal detachment, cataract, corneal abnormality, high intraocular pressure and hypotony. CONCLUSION: The Siluron 2000 SO tamponade shows a faster rate of emulsification than the Siluron 5000 SO, necessitating earlier removal. Both groups show similar results in terms of anatomical success and visual acuity outcome, and there is no significant difference between the SOs regarding the occurrence of complications.

16.
Opt Express ; 28(6): 8132-8144, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32225444

RESUMO

Photon-limited imaging technique is desired in tasks of capturing and reconstructing images by detecting a small number of photons. However, it is still a challenge to achieve high photon-efficiency. Here, we propose a novel photon-limited imaging technique that explores the consistency of photon detection probability in a single pulse and light intensity distribution in a single-pixel correlated imaging system. We demonstrated theoretically and experimentally that our technique can reconstruct a high-quality 3D image by using only one pulse each frame, thereby achieving a high photon efficiency of 0.01 detected photons per pixel. Long-distance field experiments for 100 km cooperative target and 3 km practical target are conducted to verify its feasibility. Compared with the conventional single-pixel imaging, which requires hundreds or thousands of pulses per frame, our technique saves two orders of magnitude in the consumption of total light power and acquisition time.

17.
Signal Transduct Target Ther ; 5(1): 13, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-32296025

RESUMO

MYH9 has dual functions in tumors. However, its role in inducing tumor stemness in hepatocellular carcinoma (HCC) is not yet determined. Here, we found that MYH9 is an effective promoter of tumor stemness that facilitates hepatocellular carcinoma pathogenesis. Importantly, targeting MYH9 remarkably improved the survival of hepatocellular carcinoma-bearing mice and promoted sorafenib sensitivity of hepatocellular carcinoma cells in vivo. Mechanistic analysis suggested that MYH9 interacted with GSK3ß and reduced its protein expression by ubiquitin-mediated degradation, which therefore dysregulated the ß-catenin destruction complex and induced the downstream tumor stemness phenotype, epithelial-mesenchymal transition, and c-Jun signaling in HCC. C-Jun transcriptionally stimulated MYH9 expression and formed an MYH9/GSK3ß/ß-catenin/c-Jun feedback loop. X protein is a hepatitis B virus (HBV)-encoded key oncogenic protein that promotes HCC pathogenesis. Interestingly, we observed that HBV X protein (HBX) interacted with MYH9 and induced its expression by modulating GSK3ß/ß-catenin/c-Jun signaling. Targeting MYH9 blocked HBX-induced GSK3ß ubiquitination to activate the ß-catenin destruction complex and suppressed cancer stemness and EMT. Based on TCGA database analysis, MYH9 was found to be elevated and conferred poor prognosis for hepatocellular carcinoma patients. In clinical samples, high MYH9 expression levels predicted poor prognosis of hepatocellular carcinoma patients. These findings identify the suppression of MYH9 as an alternative approach for the effective eradication of CSC properties to inhibit cancer migration, invasion, growth, and sorafenib resistance in HCC patients. Our study demonstrated that MYH9 is a crucial therapeutic target in HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta/genética , Neoplasias Hepáticas/tratamento farmacológico , Cadeias Pesadas de Miosina/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Células-Tronco Neoplásicas/efeitos dos fármacos , Sorafenibe/farmacologia , Transativadores/genética , Ubiquitinação/efeitos dos fármacos , Proteínas Virais Reguladoras e Acessórias/genética , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/genética
18.
Mol Neurodegener ; 15(1): 26, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295623

RESUMO

BACKGROUND: Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We sought to explore the potential molecular mechanisms underlying the causal link between high IOP and glaucomatous RGCs death. METHODS: A murine retinal ischemia/ reperfusion (RIR) model and an in vitro oxygen and glucose deprivation/reoxygenation (OGDR) model were used to investigate the pathogenic mechanisms of acute glaucoma. RESULTS: Our findings reveal a novel mechanism of microglia-induced pyroptosis-mediated RGCs death associated with glaucomatous vision loss. Genetic deletion of gasdermin D (GSDMD), the effector of pyroptosis, markedly ameliorated the RGCs death and retinal tissue damage in acute glaucoma. Moreover, GSDMD cleavage of microglial cells was dependent on caspase-8 (CASP8)-hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, the newly identified nucleotide-binding leucine-rich repeat-containing receptor (NLR) family pyrin domain-containing 12 (NLRP12) collaborated with NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) downstream of the CASP8-HIF-1α axis, to elicit pyroptotic processes and interleukin-1ß (IL-1ß) maturation through caspase-1 activation, facilitating pyroptosis and neuroinflammation in acute glaucoma. Interestingly, processing of IL-1ß in turn magnified the CASP8-HIF-1α-NLRP12/NLRP3/NLRC4-pyroptosis circuit to accelerate inflammatory cascades. CONCLUSIONS: These data not only indicate that the collaborative effects of NLRP12, NLRP3 and NLRC4 on pyroptosis are responsible for RGCs death, but also shed novel mechanistic insights into microglial pyroptosis, paving novel therapeutic avenues for the treatment of glaucoma-induced irreversible vision loss through simultaneously targeting of pyroptosis.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Glaucoma/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/fisiologia , Células Ganglionares da Retina/patologia , Animais , Feminino , Glaucoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Ganglionares da Retina/metabolismo , Transdução de Sinais/fisiologia
19.
Am J Ophthalmol ; 216: 59-68, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32251654

RESUMO

PURPOSE: We evaluated the clinical utility of a novel anterior segment optical coherence tomography (AS-OCT) device, CASIA2, to evaluate parameters indicative of anterior chamber (AC) inflammation severity in uveitis, including AC cell number, flare, and keratic precipitates (KPs). DESIGN: Prospective evaluation of a diagnostic device. METHODS: Uveitis eyes were classified into active and inactive groups. The number of hyperreflective dots representing AC cells and optical density ratio (aqueous-to-air relative intensity [ARI] index) for flare qualification were calculated from AS-OCT images. In addition, a program was designed to quantify the posterior corneal surface smoothness (PCSS) of each image for KPs evaluation. The maximum, minimum, and average PCSS values were calculated from 128 images per eye and compared among active uveitis, inactive uveitis, and control eyes. Correlations between Standardization of Uveitis Nomenclature grade and both hyperreflective dot number and ARI index were evaluated. Receiver operating characteristic (ROC) curves were constructed to test the values of these indicators for uveitis diagnosis. RESULTS: AC hyperreflective dot count, ARI index, and maximum and average PCSS values were all significantly higher in the active uveitis group than in the inactive and control groups. Hyperreflective dot count and ARI index were associated with Standardization of Uveitis Nomenclature cell and flare grade. According to ROC curve analysis, maximum PCSS was the best indicator for the diagnosis of uveitis involving the anterior segment, meanwhile the hyperreflective dot number was the best to identify active AC inflammation from the inactive. CONCLUSIONS: Quantification of AC cell number, flare, and KPs using the CASIA2 device is a promising strategy for the objective assessment of AC inflammation.


Assuntos
Câmara Anterior/diagnóstico por imagem , Técnicas de Diagnóstico Oftalmológico/instrumentação , Inflamação/diagnóstico por imagem , Tomografia de Coerência Óptica/instrumentação , Uveíte Anterior/diagnóstico por imagem , Adulto , Algoritmos , Câmara Anterior/patologia , Contagem de Células , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROC , Adulto Jovem
20.
FEBS Open Bio ; 10(6): 1013-1020, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32069380

RESUMO

Growth hormone receptor (GHR), a member of the class I cytokine receptor family, plays key roles in cancer progression. Recently, GHR has been reported to be associated with breast cancer development, but the molecular mechanism of GHR in this malignancy is not fully understood. To investigate this issue, we stably inhibited GHR in breast cancer cell lines, which were observed to reduce cell proliferation, tumor growth and induction of apoptosis, and arrest the cell-cycle arrest at the G1-S phase transition. In addition, GHR silencing suppressed the protein levels of B-Raf proto-oncogene, serine/threonine kinase (BRAF), Mitogen-activated protein kinase kinase (MEK) and Extracellular regulated protein kinases (ERK). These findings suggest that GHR may mediate breast cell progression and apoptosis through control of the cell cycle via the BRAF/MEK/ERK signaling pathway.


Assuntos
Neoplasias da Mama/patologia , Proteínas de Transporte/metabolismo , Animais , Apoptose , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/cirurgia , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Mastectomia , Camundongos , Proteínas Proto-Oncogênicas B-raf/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
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