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1.
Transl Vis Sci Technol ; 10(13): 10, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34751744

RESUMO

Purpose: The purpose of this study was to engineer deep learning (DL) models that can identify myopic maculopathy in patients with high myopia based on optical coherence tomography (OCT) images. Methods: An artificial intelligence (AI) system was developed using 2342 qualified OCT macular images from 1041 patients with pathologic myopia admitted to the Affiliated Eye Hospital of Wenzhou Medical University (WMU). We adopted an ResNeSt101 architecture to train five independent models to identify the following five myopic maculopathies: macular choroidal thinning, macular Bruch membrane (BM) defects, subretinal hyper-reflective material (SHRM), myopic traction maculopathy (MTM), and dome-shaped macula (DSM). We tested the models with an independent test dataset that included 450 images obtained from 297 patients with high myopia. Focal loss was used to address class imbalance, and optimal operating thresholds were determined according to the Youden Index. The performance was quantified using the area under the receiver operating characteristic (AUC), sensitivity, specificity, and confusion matrix. Results: For the identification of myopic maculopathy, the AUCs of receiver operating characteristic (ROC) curves were 0.927 to 0.974 for 5 myopic maculopathies. Our AI system achieved sensitivities equal to or even better than those of junior retinal specialists (56.16-99.73%). The diagnosis of it is also interpretable that we provide visual explanations clearly via heatmaps. Conclusions: We developed a convolutional neural network (CNN)-based DL AI system for detection and classification of myopic maculopathy in patients with high myopia using OCT macular images. Our AI system achieved sensitivities equal to or even better than those of junior retinal specialists. Translational Relevance: This AI system can be widely applied in sophisticated situations in large-scale high myopia screening.

2.
Natl Sci Rev ; 8(3): nwaa297, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34676096

RESUMO

Receptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10 times the effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to the ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the receptor binding domain, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19.

3.
Comput Struct Biotechnol J ; 19: 4961-4969, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527200

RESUMO

G Protein-Coupled Receptors (GPCRs) are one of the largest membrane protein receptor family in human, which are also important targets for many drugs. Thence, it's of great significance to judge whether a protein is a GPCR or not. However, identifying GPCRs by experimental methods is very expensive and time-consuming. As more and more GPCR primary sequences are accumulated, it's feasible to develop a computational model to predict GPCRs precisely and quickly. In this paper, a novel method called EMCBOW-GPCR has been proposed to improve the accuracy of identifying GPCRs based on natural language processing (NLP). For representing GPCRs, three word-embedding models and a bag-of-words model are used to extract original features. Then, the original features are thrown into a Deep-learning algorithm to extract features further and reduce the dimension. Finally, the obtained features are fed into Extreme Gradient Boosting. As shown with the results comparison, the overall prediction metrics of EMCBOW-GPCR are higher than the state of the arts. In order to be convenient for more researchers to use EMCBOW-GPCR, the method and source code have been opened in github, which are available at https://github.com/454170054/EMCBOW-GPCR, and a user-friendly web-server for EMCBOW-GPCR has been established at http://www.jci-bioinfo.cn/emcbowgpcr.

4.
Cell Immunol ; 369: 104438, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34530343

RESUMO

While environmental aeroallergens and epithelial alarmins such as IL-33 are firmly implicated in asthma, the possible role of Streptococcus pneumoniae (S. pneumoniae) antigens is less clear. To explore this, wild-type BALB/c mice were repeatedly challenged per-nasally with IL-33 and inactivated S. pneumoniae, either agent alone or diluent control. Some animals were rested then later re-challenged with inactivated S. pneumoniae alone. Serum concentrations of S. pneumoniae lysates-specific IgE were measured in patients with asthma and control subjects. Interestingly, in the presence of IL-33, repeated exposure to inactivated S. pneumoniae induced asthma-like pathological changes accompanied by a systemic adaptive immune response. Subsequent re-exposure of the sensitized animals to inactivated S. pneumoniae alone was able to induce such changes. The concentration of S. pneumoniae lysates-specific IgE was significantly elevated in the asthma patients. These data suggest that antigens derived from infectious microorganisms may participate in generating the mucosal inflammation which characterizes asthma.

5.
Cell Immunol ; 366: 104395, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34198027

RESUMO

Although contributions of IL-33 to pulmonary diseases, including asthma, have been well documented, the complexity of such regulation warrants additional exploration. To better understand the involvement of IL-33, we used a murine asthma surrogate based on sensitisation and challenge with dust mite extract in the presence/absence of IL-33. Murine models were established with Dermatophagoides farinae (Der f) to establish (1) the effect of co-administered rmIL-33; (2) the effect of prior glucocorticoid intervention; (3) the effect of IL-33 on challenge with sub-threshold dosage Der f. The effects of rmIL-33 on bone marrow-derived dendritic cells were explored in vitro. Mice challenged with Der f combined with IL-33 compared with diluent control evinced significantly more airways inflammation and local cytokine production which was less sensitive to inhibition by dexamethasone. IL-33 also induced airways hyperresponsiveness, eosinophilic inflammation and cytokine production in lung tissues of animals exposed to sub-threshold dosage of Der f. In vitro, IL-33-stimulated DCs showed a significantly elevated capacity to stimulate CD4+ T cell proliferation and cytokine production and were also significantly more resistant to dexamethasone-induced apoptosis. Our data suggest that IL-33 reduces the threshold for allergen-induced inflammation of the airways in acorticosteroid-resistant fashion possibly in part through acting on DCs, a phenomenon which may be relevant to the development of severe, corticosteroid-resistant airways obstruction in human asthmatic patients.


Assuntos
Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Inflamação/imunologia , Interleucina-33/metabolismo , Sistema Respiratório/imunologia , Animais , Antialérgicos/uso terapêutico , Antígenos de Dermatophagoides/imunologia , Asma/tratamento farmacológico , Diferenciação Celular , Células Cultivadas , Dermatophagoides farinae , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Resistência a Medicamentos , Feminino , Humanos , Inflamação/tratamento farmacológico , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos BALB C
6.
Oxid Med Cell Longev ; 2021: 9980444, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34285767

RESUMO

A growing amount of evidence has confirmed the crucial role of the prolyl isomerase PIN1 in aging and age-related diseases. However, the mechanism of PIN1 in age-related hearing loss (ARHL) remains unclear. Pathologically, ARHL is primarily due to the loss and dysfunction of hair cells (HCs) and spiral ganglion cells (SGCs) in the cochlea. Therefore, in this study, we aimed to investigate the role of PIN1 in protecting hair cells and auditory HEI-OC1 cells from senescence. Enzyme-linked immunosorbent assays, immunohistochemistry, and immunofluorescence were used to detect the PIN1 protein level in the serum of ARHL patients and C57BL/6 mice in different groups, and in the SGCs and HCs of young and aged C57BL/6 mice. In addition, a model of HEI-OC1 cell senescence induced by H2O2 was used. Adult C57BL/6 mice were treated with juglone, or juglone and NAC, for 4 weeks. Interestingly, we found that the PIN1 protein expression decreased in the serum of patients with ARHL, in senescent HEI-OC1 cells, and in the cochlea of aged mice. Moreover, under H2O2 and juglone treatment, a large amount of ROS was produced, and phosphorylation of p53 was induced. Importantly, PIN1 expression was significantly increased by treatment with the p53 inhibitor pifithrin-α. Overexpression of PIN1 reversed the increased level of p-p53 and rescued HEI-OC1 cells from senescence. Furthermore, PIN1 mediated cellular senescence by the PI3K/Akt/mTOR signaling pathway. In vivo data from C57BL/6 mice showed that treatment with juglone led to hearing loss. Taken together, these findings demonstrated that PIN1 may act as a vital modulator in hair cell and HEI-OC1 cell senescence.

7.
Materials (Basel) ; 14(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064837

RESUMO

Research on the preparation and performance of graphene composite materials has become a hotspot due to the excellent electrical and mechanical properties of graphene. Among such composite materials, zinc oxide/graphene (ZnO/graphene) composite films are an active research topic. Therefore, in this study, we used the vacuum thermal evaporation technique at different evaporation voltages to fabricate an amorphous ZnO/graphene composite film on a flexible polyethylene terephthalate (PET). The amorphous ZnO/graphene composite film inherited the great transparency of the graphene within the visible spectrum. Moreover, its electrical properties were better than those of pure ZnO but less than those of graphene, which is not consistent with the original theoretical research (wherein the performance of the composite films was better than that of ZnO film and slightly lower than that of graphene). For example, the bulk free charge carrier concentrations of the composite films (0.13, 1.36, and 0.47 × 1018 cm-3 corresponding to composite films with thicknesses of 40, 75, and 160 nm) were remarkably lower than that of the bare graphene (964 × 1018 cm-3) and better than that of the ZnO (0.10 × 1018 cm-3). The underlying mechanism for the abnormal electrical performance was further demonstrated by X-ray photoelectron spectroscopy (XPS) detection and first-principles calculations. The analysis found that chemical bonds were formed between the oxide (O) of amorphous ZnO and the carbon (C) of graphene and that the transfer of the π electrons was restricted by C=O and C-O-C bonds. Given the above, this study further clarifies the mechanism affecting the photoelectric properties of amorphous composite films.

8.
J Bone Miner Res ; 36(8): 1521-1534, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33950576

RESUMO

Osteogenesis imperfecta (OI) is a congenital genetic disorder mainly manifested as bone fragility and recurrent fracture. Mutation of COL1A1/COL1A2 genes encoding the type I collagen are most responsible for the clinical patients. Allogenic mesenchymal stem cells (MSCs) provide the potential to treat OI through differentiation into osteoblasts. Autologous defective MSCs have not been utilized in OI treatment mainly because of their impaired osteogenesis, but the latent mechanism has not been well understood. Here, the relative signaling abnormality of adipose-derived mesenchymal stem cells (ADSCs) isolated from OI type I mice (Col1a1+/-365 mice) was explored. Autologous ADSCs transfected by retrovirus carrying human COL1A1 gene was first utilized in OI therapy. The results showed that decreased activity of Yes-associated protein (YAP) due to hyperactive upstream Hippo kinases greatly contributed to the weakened bone-forming capacity of defective ADSCs. Recovered collagen synthesis of autologous ADSCs by COL1A1 gene modification normalized Hippo/YAP signaling and effectively rescued YAP-mediated osteogenesis. And the COL1A1 gene engineered autologous ADSCs efficaciously improved the microstructure, enhanced the mechanical properties and promoted bone formation of Col1a1+/-365 mice after femoral bone marrow cavity delivery and might serve as an alternative source of stem cells in OI treatment. © 2021 American Society for Bone and Mineral Research (ASBMR).


Assuntos
Células-Tronco Mesenquimais , Osteogênese Imperfeita , Tecido Adiposo , Animais , Colágeno Tipo I/genética , Humanos , Camundongos , Mutação , Osteogênese , Osteogênese Imperfeita/terapia , Fenótipo
9.
Micromachines (Basel) ; 12(3)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800478

RESUMO

The capillary action between two solid surfaces has drawn significant attention in micro-objects manipulation. The axisymmetric capillary bridges and capillary forces between a spherical concave gripper and a spherical particle are investigated in the present study. A numerical procedure based on a shooting method, which consists of double iterative loops, was employed to obtain the capillary bridge profile and bring the capillary force subject to a constant volume condition. Capillary bridge rupture was characterized using the parameters of the neck radius, pressure difference, half-filling angle, and capillary force. The effects of various parameters, such as the contact angle of the spherical concave gripper, the radius ratio, and the liquid bridge volume on the dimensionless capillary force, are discussed. The results show that the radius ratio has a significant influence on the dimensionless capillary force for the dimensionless liquid bridge volumes of 0.01, 0.05, and 0.1 when the radius ratio value is smaller than 10. The effectiveness of the theorical approach was verified using simulation model and experiments.

10.
J Immunol Res ; 2021: 6687555, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33860064

RESUMO

Clinically, severe bacterial infection can cause septicemia and multiple organ dysfunction syndrome, especially liver injury. CD38 is closely related to many inflammatory pathways, but its role in liver injury caused by bacterial infection remains unclear. The purpose of this study is to discuss the specific role of CD38 in bacterial liver injury. Eight-week-old male C57BL/6 mice (WT, CD38-/- and CD38-/-TLR4mut) were used and stimulated with Escherichia coli (ATCC25922) or PBS, intraperitoneally. After 3 hours of bacterial stimulation, serum was collected to detect ALT and AST concentration, and liver tissue was harvested for hematoxylin and eosin staining and bacterial culture. The mRNA expressions of TLR4, NLRP3, IL-1ß, IL-18, and GSDMD were quantitatively determined by RT-qPCR. The expressions of TLR4, MyD88, TRIF, NF-κB p65, NLRP3, GSDMD, and cytokines were detected by Western blot. The expression and localization of ERK1/2 were detected by immunohistochemistry and Western blot. The results showed that bacterial stimulation could upregulate the expression of inflammatory cytokines, leading to hepatic dysfunction. Moreover, bacterial stimulation of CD38-deficient mice can aggravate the inflammatory response, the expressions of TLR4, NF-κB, and ERK1/2 were significantly increased, and the biomarkers related to pyroptosis also manifested more obvious pyroptosis. However, TLR4 mutation significantly alleviated inflammation and pyroptosis in the liver caused by bacteria, on the basis of CD38 deficiency. Overall, CD38 knockout exacerbates bacteria-induced liver damage through TLR4-NLRP3-GSDMD-mediated pyroptosis.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Falência Hepática Aguda/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Sepse/complicações , Receptor 4 Toll-Like/metabolismo , ADP-Ribosil Ciclase 1/genética , Animais , Modelos Animais de Doenças , Escherichia coli/imunologia , Humanos , Inflamassomos/imunologia , Inflamassomos/metabolismo , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Falência Hepática Aguda/microbiologia , Falência Hepática Aguda/patologia , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Knockout , Piroptose/imunologia , Sepse/imunologia , Sepse/microbiologia , Sepse/patologia
11.
Eur J Pharm Sci ; 161: 105780, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667664

RESUMO

Estrogen receptor (ER) is a potential target receptor for ER-positive cancer therapy including breast cancers, gastric cancers, and human acute myeloblastic leukaemia. In order to reduce the side-effects of mitoxantrone (MTO), estrone-targeted liposomes for MTO delivery via ER were designed for selectively targeting cancer cells. In previous studies, MTO-loaded estrogen receptor targeted and sterically stabilized liposome (ES-SSL-MTO; ES: estrone, is known to bind the ER) had been synthesized and showed a very high antiproliferative effect with IC50 value of 0.7 ng/mL. Based on these, further studies including in vivo targeting efficacy and antitumor activity, acute toxicity and pharmacokinetics of MTO liposomes were carried out. The results showed SSL (sterically stabilized liposome, PEGylated liposome, PEG: Polyethylene Glycol) could reduce drug metabolism, improve the stability of liposomes, prolong in vivo circulation time of drugs, reduce the toxicity of MTO. But SSL could not be enriched in tumor tissues. However, estrone (ES)-targeted liposomes could be delivered to tumor sites. ES-SSL could effectively enter into ER-expressing tumor cellsand be accumulated, prolong the circulation time in vivo, reduce side effects of drug. ES-SSL-MTO could provide higher bioavailability than MTO, enhance the anti-tumor effect and the safety of MTO, reduce the toxicity and side effects of MTO and improve the therapeutic effect of MTO. These facts proved ES-SSL is a useful tumor-targeting drug delivery system for MTO.


Assuntos
Antineoplásicos , Lipossomos , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Estrona , Humanos , Mitoxantrona/toxicidade , Receptores de Estrogênio
12.
Thorax ; 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589512

RESUMO

BACKGROUND: Efficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD. OBJECTIVE: To explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling. METHODS: C57BL/6, BALB/c and IL-1RL1 -/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls. RESULTS: Wild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1 -/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD. CONCLUSIONS: Exposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

13.
Cell Res ; 31(1): 25-36, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262452

RESUMO

Structural principles underlying the composition and synergistic mechanisms of protective monoclonal antibody cocktails are poorly defined. Here, we exploited antibody cooperativity to develop a therapeutic antibody cocktail against SARS-CoV-2. On the basis of our previously identified humanized cross-neutralizing antibody H014, we systematically analyzed a fully human naive antibody library and rationally identified a potent neutralizing antibody partner, P17, which confers effective protection in animal model. Cryo-EM studies dissected the nature of the P17 epitope, which is SARS-CoV-2 specific and distinctly different from that of H014. High-resolution structure of the SARS-CoV-2 spike in complex with H014 and P17, together with functional investigations revealed that in a two-antibody cocktail, synergistic neutralization was achieved by S1 shielding and conformational locking, thereby blocking receptor attachment and viral membrane fusion, conferring high potency as well as robustness against viral mutation escape. Furthermore, cluster analysis identified a hypothetical 3rd antibody partner for further reinforcing the cocktail as pan-SARS-CoVs therapeutics.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19 , Epitopos/imunologia , SARS-CoV-2/imunologia , Anticorpos de Cadeia Única/imunologia , Animais , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/farmacologia , COVID-19/imunologia , COVID-19/prevenção & controle , Chlorocebus aethiops , Modelos Animais de Doenças , Humanos , Anticorpos de Cadeia Única/farmacologia , Células Vero
14.
J Mol Neurosci ; 71(2): 293-301, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32705527

RESUMO

Horizontal gaze palsy with progressive scoliosis (HGPPS) is an autosomal recessive disorder caused by ROBO3 gene mutations. To date, the number of confirmed HGPPS cases caused by gene mutations is estimated at 76. However, HGPPS caused by ROBO3 gene mutation has not been reported in the Chinese population. In this study, the clinical data, brain imaging features, somatosensory evoked potentials (SEP), and ROBO3 gene mutations were obtained for two Chinese patients with HGPPS. The proband was an 11-year-old boy. He developed horizontal eye movement disorder at the age of 1 year and scoliosis at the age of 11 years. Two eyeballs fixed in the midline position were revealed by neurological examination. A dorsal cleft in the pons and a butterfly-shaped medulla were shown by brain magnetic resonance imaging. Again, most corticospinal bundles did not cross in the brainstem, as revealed by diffusion tensor imaging. SEP confirmed that most somatosensory projections were uncrossed. The proband's 7-year-old brother exhibited similar clinical manifestations and imaging features. The brothers had compound heterozygous mutations c.3165G>A (p.W1055X) and c.955G>A (p.E319K) of the ROBO3 gene. The c.3165G>A mutation is a novel nonsense mutation that has not been previously reported. This study reports the first two cases of HGPPS carrying a novel ROBO3 gene mutation in patients from a Chinese family, thereby expanding the disease spectrum. Reports from the literature show that missense mutation is the most common mutational type in the ROBO3 gene. Early ROBO3 gene detection is required for patients exhibiting early-onset eyeball movement disorder to confirm HGPPS disease.


Assuntos
/genética , Códon sem Sentido , Oftalmoplegia Externa Progressiva Crônica/genética , Receptores de Superfície Celular/genética , Escoliose/genética , Adulto , Criança , Imagem de Tensor de Difusão , Potenciais Somatossensoriais Evocados , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Bulbo/diagnóstico por imagem , Bulbo/patologia , Neuroimagem , Oftalmoplegia Externa Progressiva Crônica/diagnóstico por imagem , Oftalmoplegia Externa Progressiva Crônica/etnologia , Oftalmoplegia Externa Progressiva Crônica/fisiopatologia , Ponte/diagnóstico por imagem , Ponte/patologia , Tratos Piramidais/anormalidades , Tratos Piramidais/diagnóstico por imagem , Receptores de Superfície Celular/fisiologia , Escoliose/diagnóstico por imagem , Escoliose/etnologia , Escoliose/fisiopatologia
15.
Int J Nanomedicine ; 16: 8279-8303, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34992365

RESUMO

Background: Chemotherapy is still the main first-line treatment for advanced metastatic gastric cancer, but it has the limitations of serious side effects and drug resistance. Conventional liposome has been substantially used as drug carriers, but they lack targeting character with lower drug bioavailability in tumor tissues. Based on the above problems, a novel estrogen-targeted PEGylated liposome loaded with oxaliplatin (ES-SSL-OXA) was prepared to further improve the metabolic behavior, the safety profile, and the anti-tumor efficacy of oxaliplatin. Methods: Four kinds of oxaliplatin (OXA) liposomes were prepared by film hydration method. The obtained formulations were characterized in terms of entrapment efficiency (EE), particle size, and so on by HPLC and DLS (dynamic light scanning). The morphology of ES-SSL-OXA was detected by transmission electron microscope (TEM). The in vitro and in vivo targeting effect of ES-SSL-OXA was verified by fluorescence microscopy and in vivo imaging system in gastric cancer cells (SGC-7901) and tumor-bearing athymic mice. The in vitro and in vivo antitumor efficacies of ES-SSL-OXA were investigated on SGC-7901 cells and athymic tumor-bearing mice. Pharmacokinetic, biodistribution, and acute toxicity tests of ES-SSL-OXA were performed on ICR mice. Results: The ES-SSL-OXA exhibited an average particle size of about 153.37 nm with an encapsulation efficiency of 46.20% and low leakage rates at 4°C and 25°C. In vivo and in vitro targeting study confirmed that ES-SSL-OXA could effectively target the tumor site. The antitumor activity demonstrated the strongest inhibition in tumor growth of ES-SSL-OXA. Pharmacokinetics and acute toxicity study showed that ES-SSL-OXA could significantly improve the metabolic behavior and toxicity profile of oxaliplatin. Conclusion: In this study, a novel estrogen-targeted long-acting liposomal formulation of OXA was successfully prepared. ES fragment effectively targeted the delivery system to tumor tissues which highly express estrogen receptor, providing a promising therapeutic method for gastric cancer in clinic.


Assuntos
Lipossomos , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Estrogênios , Camundongos , Camundongos Endogâmicos ICR , Oxaliplatina , Polietilenoglicóis , Neoplasias Gástricas/tratamento farmacológico , Distribuição Tecidual
16.
J Ophthalmol ; 2020: 7313909, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33014441

RESUMO

Purpose: The objective of this study was to evaluate central corneal thickness (CCT) in Chinese premature infants at different postnatal stages to study the peak point and analyze influential factors on CCT development. Methods: This was a cross-sectional study of premature infants. Initial CCT measurement was taken at 34 weeks of gestational age (GA) and at intervals until 88 weeks of postmenstrual age (PMA) was reached. The comparison and correlation analysis were carried out to access the association of CCT with gender, birth weight (BW), GA, and retinopathy of prematurity (ROP) for each PMA. The premature infants were divided into the thick CCT group and the thin CCT group according to the average CCT at 40 w. And the difference in CCT between the two groups at subsequent 52 w and 64 w was compared. Results: A total of 1726 premature infants (3463 measurements) with an average of 2.21 ± 1.57 measurements were included in this study. The CCT decreased from 34 w GA to 52 w PMA (R = 92.36, P < 0.0001) and then reached a plateau (R = 2.541, P=0.3567). Male (P < 0.05), low BW (P < 0.05), and low GA (P < 0.05) were associated with thicker CCT at the early stage of PMA. The premature infants who had thick CCT at 40 w would have thick CCT at 52 w and 64 w accordingly. Conclusions: The CCT values of premature infants decreased over time and plateaued at 52 w PMA. Gender, BW, and GA were considered as the influential factors of CCT at the early stage of PMA. Moreover, CCT at 40 w could forecast its development trend at 52 w or 64 w after birth.

17.
Science ; 369(6510): 1505-1509, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32703908

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we report a humanized monoclonal antibody, H014, that efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nanomolar concentrations by engaging the spike (S) receptor binding domain (RBD). H014 administration reduced SARS-CoV-2 titers in infected lungs and prevented pulmonary pathology in a human angiotensin-converting enzyme 2 mouse model. Cryo-electron microscopy characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a previously uncharacterized conformational epitope, which was only accessible when the RBD was in an open conformation. Biochemical, cellular, virological, and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncovered broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/química , Anticorpos Neutralizantes/química , Betacoronavirus/imunologia , Peptidil Dipeptidase A/imunologia , Receptores Virais/imunologia , Vírus da SARS/imunologia , Enzima de Conversão de Angiotensina 2 , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/terapia , Mapeamento de Epitopos , Humanos , Fragmentos Fab das Imunoglobulinas/química , Pulmão/imunologia , Camundongos , Pandemias , Pneumonia Viral/terapia , Domínios Proteicos , Multimerização Proteica , SARS-CoV-2 , Células Vero
18.
Arch Gerontol Geriatr ; 90: 104121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32521417

RESUMO

Health and social care services are crucial to old people. The provision of services to the elderly with care needs requires more accurate predictions of the health status of the elderly to rationalize the allocation of the limited social care resources. The traditional analytical methods have proved incapable of predicting the demands of today's society, compared to which machine learning methods can more accurately capture the nonlinear relationships between the variables. To ascertain visually the performance of these machine learning methods regarding the prediction of the elderly's care needs, we designed and verified the experiment.


Assuntos
Nível de Saúde , Aprendizado de Máquina , Idoso , Humanos
19.
Cancer Manag Res ; 12: 3513-3525, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547189

RESUMO

Purpose: For patients who have chondrosarcoma in the unresectable setting, antiangiogenic agents are reportedly effective. This multicenter, retrospective study investigated the antitumor activity of apatinib in patients with unresectable chondrosarcoma to gain insight into the biological behavior of this disease. Methods: All of the patients with unresectable chondrosarcoma who were diagnosed between October 1, 2009, and November 1, 2019, in two sarcoma centers affiliated with Peking University were evaluated. Relevant information was collected from the medical records at both centers, from which patients receiving apatinib for systemic therapy were selected for analysis. Results: In total, efficacy analysis was conducted in 33 patients with a median follow-up time of 22.1 (Q1, Q3, 14.6, 23.0) months. There were 20/33 (60.0%) conventional chondrosarcomas (grades 2-3), 5/33 (15.2%) dedifferentiated chondrosarcomas, 4/33 (12.1%) mesenchymal chondrosarcomas, 3/33 (9.1%) extraskeletal myxoid chondrosarcoma, and 1/33 (3.1%) clear-cell chondrosarcomas with 87.9% in metastatic and 12.1% in locally advanced states. The objective response rate was 6/33 (18.2%). The median progression-free survival (PFS) was 12.4 months (Q1, Q3, 7.0, 21.2), while the median overall survival has not yet been reached. Rare variants of chondrosarcoma tended to have a longer PFS than conventional chondrosarcoma (P=0.06). Based on clinicopathological factors Cox and univariate analysis, only extraskeletal myxoid chondrosarcoma and baseline target lesions <60 mm benefited from the drug apatinib (P=0.14 and P=0.00), respectively. Grade 3 or higher adverse events were frequent in 11/33 (39.3%) of patients who discontinued apatinib due to deterioration of their general condition. Conclusion: Apatinib had clinically meaningful activity in patients with inoperable high-grade chondrosarcoma. However, special caution should be made in managing toxicity due to the indolent behavior and slow growth pattern after using this drug. Patients with a smaller tumor size and extraskeletal myxoid chondrosarcoma subtype might benefit from this therapy more. Clinical Trial Registration: Registered February 7, 2020, with clinicaltrials.gov: NCT04260113.

20.
Science ; 369(6499): 77-81, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32376603

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Vacinas Virais , Animais , Anticorpos Neutralizantes/biossíntese , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/biossíntese , Anticorpos Antivirais/imunologia , Betacoronavirus/isolamento & purificação , COVID-19 , Vacinas contra COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Relação Dose-Resposta Imunológica , Feminino , Imunogenicidade da Vacina , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Projetos Piloto , Pneumonia Viral/virologia , Ratos , Ratos Wistar , SARS-CoV-2 , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologia , Células Vero , Carga Viral , Vacinas Virais/administração & dosagem , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia
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