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Central serous chorioretinopathy (CSC) is a vision-threatening disease with no validated treatment and unclear pathogenesis. It is characterized by dilation and leakage of choroidal vasculature, resulting in the accumulation of subretinal fluid, and serous detachment of the neurosensory retina. Numerous studies have demonstrated that melatonin had multiple protective effects against endothelial dysfunction, vascular inflammation, and blood-retinal barrier (BRB) breakdown. However, the effect of melatonin on CSC, and its exact pathogenesis, is not well understood thus far. In this study, an experimental model was established by intravitreal injection of aldosterone in rats, which mimicked the features of CSC. Our results found that melatonin administration in advance significantly inhibited aldosterone-induced choroidal thickening and vasodilation by reducing the expression of calcium-activated potassium channel KCa2.3, and attenuated tortuosity of choroid vessels. Moreover, melatonin protected the BRB integrity and prevented the decrease in tight junction protein (ZO-1, occludin, and claudin-1) levels in the rat model induced by aldosterone. Additionally, the data also showed that intraperitoneal injection of melatonin in advance inhibited aldosterone-induced macrophage/microglia infiltration, and remarkably diminished the levels of inflammatory cytokines (interleukin-6 [IL-6], IL-1ß, and cyclooxygenase-2), chemokines (chemokine C-C motif ligand 3, and C-X-C motif ligand 1), and matrix metalloproteinases (MMP-2 and MMP-9). Luzindole, as the nonselective MT1 and MT2 antagonist, and 4-phenyl-2-propionamidotetraline, as the selective MT2 antagonist, neutralized the melatonin-induced inhibition of choroidal thickening and choroidal vasodilation, indicating that melatonin might exert the effects via binding to its receptors. Furthermore, the IL-17A/nuclear factor-κB signaling pathway was activated by intravitreal administration of aldosterone, while it was suppressed in melatonin-treated in advance rat eyes. This study indicates that melatonin could serve as a promising safe therapeutic strategy for CSC patients.
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Coriorretinopatia Serosa Central , Melatonina , Aldosterona/uso terapêutico , Animais , Coriorretinopatia Serosa Central/induzido quimicamente , Coriorretinopatia Serosa Central/tratamento farmacológico , Corioide/irrigação sanguínea , Ligantes , Melatonina/farmacologia , Melatonina/uso terapêutico , RatosRESUMO
Recent studies indicate circular RNAs are related to dysregulation of vascular endothelial cell function, yet the underlying mechanisms have remained elusive. Here, we characterized the functional role of circular RNA USP1 (circ-USP1) in the regulation of the blood-tumour barrier (BTB) permeability and the potential mechanisms. In the current study, the circ-USP1 expressing level was up-regulated in glioma cerebral microvascular endothelial cells (GECs) of the BTB model in vitro. Knockdown of circ-USP1 disrupted the barrier integrity, increased its permeability as well as reduced tight junction-related protein claudin-5, occludin and ZO-1 expressions in GECs. Bioinformatic prediction and luciferase assay indicated that circ-USP1 bound to miR-194-5p and suppressed its activity. MiR-194-5p contributed to circ-USP1 knockdown-induced increase of BTB permeability via targeting and down-regulating transcription factor FLI1. Furthermore, FLI1 regulated the expressions of claudin-5, occludin and ZO-1 in GECs through binding to their promoter regions. Single or combined treatment of circ-USP1 and miR-194-5p effectively promoted anti-tumour drug doxorubicin across BTB to induce apoptosis of glioma cells. Overall, this present study identified the crucial regulation of circ-USP1 on BTB permeability via miR-194-5p/FLI1 axis-mediated regulation of tight junction proteins, which might facilitate the development of therapeutics against human gliomas.
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Glioma/sangue , Glioma/patologia , MicroRNAs/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , RNA Circular/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Sequência de Bases , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Glioma/genética , Células HEK293 , Humanos , MicroRNAs/genética , Permeabilidade , Proteínas de Junções Íntimas/metabolismoRESUMO
Blood-tumour barrier (BTB) has been known to significantly attenuate the efficacy of chemotherapy for glioma. In this report, we identified that insulin-like grown factor 2 mRNA-binding protein 2 (IGF2BP2) was over-expressed in glioma microvessel and glioma endothelial cells (GECs). Knockdown of IGF2BP2 decreased the expression of lncRNA FBXL19-AS1 and tight junction-related proteins, thereby promoting BTB permeability. FBXL19-AS1 was over-expressed and more enriched in the cytoplasm of GECs. In addition, FBXL19-AS1 could bind to 3'-UTR of ZNF765 mRNA and down-regulate ZNF765 mRNA expression through STAU1-mediated mRNA decay (SMD). The low expression of ZNF765 was discovered in GECs and verified to increase BTB permeability by inhibiting the promoter activities of tight junction-related proteins. Meanwhile, ZNF765 also inhibited the transcriptional activity of IGF2BP2, thereby forming a feedback loop in regulating the BTB permeability. Single or combined application of silenced IGF2BP2 and FBXL19-AS1 improved the delivery and antitumor efficiency of doxorubicin (DOX). In general, our study revealed the regulation mechanism of IGF2BP2/FBXL19-AS1/ZNF765 axis on BTB permeability, which may provide valuable insight into treatment strategy for glioma.
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Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas F-Box/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Microambiente Tumoral , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Degradação do RNAm Mediada por Códon sem Sentido , Permeabilidade , Ligação Proteica , Estabilidade de RNA , Transcriptoma , Microambiente Tumoral/genéticaRESUMO
Polypyrrole films doped with Cl-, SO42- and 4-toluene sulfonic ions (PPy/Cl-, PPy/SO42-, PPy/Ts-) with different polymerization charges were prepared by electrochemical polymerization. PPy/Ts- films exhibited good electrochemical properties when their polymerization charges were 0.5 C cm-2 and 1 C cm-2. However, PPy/Cl- and PPy/SO42- films exhibited markedly larger specific capacitance than those of PPy/Ts- films when their polymerization charges increased to 2 C cm-2 or 4 C cm-2. A simple model was suggested for explaining the relation between the electrochemical properties and thickness of the PPy films. According to the model, the incremental polymerization bulk of PPy/Ts- films from 1 C cm-2 to 2 C cm-2 is "inactive", which resulted in the reduction of the specific capacitance by half. X-ray diffraction patterns indicated that PPy/Ts- films possessed a more ordered structure, which limited ion diffusion in the PPy matrix. Therefore, the high crystallinity of the PPy film does not always mean good capacitance properties. In the cycle stability test, the PPy/Ts- film exhibited better stability, which should be closely related to its more ordered structure. It is noteworthy that we present a newly developed method to estimate the appropriate thickness of electrode materials, which is significant in the preparation of energy-storage devices.
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Purpose: The present study aimed to evaluate the effect of acrizanib, a small molecule inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), on physiological angiogenesis and pathological neovascularization in the eye and to explore the underlying molecular mechanisms. Methods: We investigated the potential role of acrizanib in physiological angiogenesis using C57BL/6J newborn mice, and pathological angiogenesis using the mouse oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (CNV) models. Moreover, vascular endothelial growth factor (VEGF)-treated human umbilical vein endothelial cells (HUVECs) were used as an in vitro model for studying the molecular mechanism underlying acrizanib's antiangiogenic effects. Results: The intravitreal injection of acrizanib did not show a considerable impact on physiological angiogenesis and retinal thickness, indicating a potentially favorable safety profile. In the mouse models of OIR and CNV, acrizanib showed promising results in reducing pathological neovascularization, inflammation, and vascular leakage, indicating its potential efficacy against pathological angiogenesis. Consistent with in vivo results, acrizanib blunted angiogenic events in VEGF-treated HUVECs such as proliferation, migration, and tube formation. Furthermore, acrizanib inhibited the multisite phosphorylation of VEGFR2 to varying degrees and the activation of its downstream signal pathways in VEGF-treated HUVECs. Conclusions: This study suggested the potential efficacy and safety of acrizanib in suppressing fundus neovascularization. Acrizanib functioned through inhibiting multiple phosphorylation sites of VEGFR2 in endothelial cells to different degrees. Translational Relevance: These results indicated that acrizanib might hold promise as a potential candidate for the treatment of ocular vascular diseases.
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Neovascularização de Coroide , Doenças Retinianas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Humanos , Camundongos , Proliferação de Células , Células Cultivadas , Neovascularização de Coroide/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos Endogâmicos C57BL , Oxigênio/metabolismo , Fosforilação , Doenças Retinianas/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Purpose: The aim of this study was to elucidate the role of Sema4D in the pathogenesis of senescence-associated choroidal neovascularization (CNV) and to explore its underlying mechanisms. Methods: In this study, we utilized a model of laser-induced CNV in both young (3 months old) and old (18 months old) mice, including those with or without Sema4D knockout. The expression and localization of Sema4D in CNV were assessed using PCR, Western blot, and immunostaining. Subsequently, the morphological and imaging examinations were used to evaluate the size of CNV and vascular leakage. Finally, the expression of M2 markers, senescence-related markers, and molecules involved in the RhoA/ROCK pathway was detected. Results: We found that Sema4D was predominantly expressed in macrophages within CNV lesions, and both the mRNA and protein levels of Sema4D progressively increased following laser photocoagulation, a trend more pronounced in old mice. Moreover, Sema4D knockout markedly inhibited M2 polarization in senescent macrophages and reduced the size and leakage of CNV, particularly in aged mice. Mechanistically, aging was found to upregulate RhoA/ROCK signaling, and knockout of Sema4D effectively suppressed the activation of this pathway, with more significant effects observed in aged mice. Conclusions: Our findings revealed that the deletion of Sema4D markedly inhibited M2 macrophage polarization through the suppression of the RhoA/ROCK pathway, ultimately leading to the attenuation of senescence-associated CNV. These data indicate that targeting Sema4D could offer a promising approach for gene editing therapy in patients with neovascular age-related macular degeneration.
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Neovascularização de Coroide , Modelos Animais de Doenças , Macrófagos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Semaforinas , Transdução de Sinais , Quinases Associadas a rho , Proteína rhoA de Ligação ao GTP , Animais , Neovascularização de Coroide/metabolismo , Neovascularização de Coroide/genética , Neovascularização de Coroide/patologia , Camundongos , Macrófagos/metabolismo , Quinases Associadas a rho/metabolismo , Semaforinas/genética , Semaforinas/metabolismo , Transdução de Sinais/fisiologia , Proteína rhoA de Ligação ao GTP/metabolismo , Antígenos CD/metabolismo , Antígenos CD/genética , Western Blotting , Masculino , AngiofluoresceinografiaRESUMO
The increase in the concentration of CO2 in the atmosphere has attracted widespread attention. To explore the effect of elevated CO2 on lettuce growth and better understand the mechanism of elevated CO2 in lettuce cultivation, 3 kinds of lettuce with 4 real leaves were selected and planted in a solar greenhouse. One week later, CO2 was applied from 8:00 a.m. to 10:00 a.m. on sunny days for 30 days. The results showed that the growth potential of lettuce was enhanced under CO2 enrichment. The content of vitamin C and chlorophyll in the three lettuce varieties increased, and the content of nitrate nitrogen decreased. The light saturation point and net photosynthetic rate of leaves increased, and the light compensation point decreased. Transcriptome analysis showed that there were 217 differentially expressed genes (DEGs) shared by the three varieties, among which 166 were upregulated, 44 were downregulated, and 7 DEGs were inconsistent in the three materials. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that these DEGs involved mainly the ethylene signaling pathway, jasmonic acid signaling pathway, porphyrin and chlorophyll metabolism pathway, starch and sucrose metabolism pathway, etc. Forty-one DEGs in response to CO2 enrichment were screened out by Gene Ontology (GO) analysis, and the biological processes involved were consistent with KEGG analysis. which suggested that the growth and nutritional quality of lettuce could be improved by increasing the enzyme activity and gene expression levels of photosynthesis, hormone signaling and carbohydrate metabolism. The results laid a theoretical foundation for lettuce cultivation in solar greenhouses and the application of CO2 fertilization technology.
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Dióxido de Carbono , Lactuca , Dióxido de Carbono/análise , Transcriptoma , Clorofila/metabolismo , Perfilação da Expressão GênicaRESUMO
Purpose: To evaluate differences in the choroidal vortex vein drainage system (VV) in eyes between patients with central serous chorioretinopathy (CSC) and unaffected individuals using ultra-widefield optical coherence tomography angiography (UWF-OCTA). Methods: In this cross-sectional observational study, 40 eyes of patients with CSC and 28 eyes of healthy volunteers were included. The analysis involved the use of UWF-OCTA to analyze the proportion of the choroidal vortex vein drainage system (VV%), choroidal thickness, choroidal vascular volume (CVV), and choroidal vascularity index (CVI) of the VV in each drainage quadrant. The location relationship between the leakage points in fluorescein angiography and the VV was also explored. Results: A within-group analysis of VV% showed a statistically significant difference in the CSC group (P < 0.001) but not in the control group (P = 0.270). Compared to healthy eyes, CSC eyes had a significantly larger CVV and higher CVI in all regions (all P < 0.05). The superotemporal (ST) drainage system had the largest CVV and thickest choroidal layer among the four drainage quadrants (all P < 0.05) in CSC eyes. The leakage rate in the ST quadrant was significantly higher than that in the inferotemporal quadrant (P < 0.001). Conclusions: CSC eyes have an asymmetric vortex vein drainage system, with relative hyperperfusion in all VV. Further, the preferential drainage route of the submacular choroid may be the ST drainage system in CSC eyes. Translational Relevance: Targeting the imbalanced drainage system could be a potential therapeutic approach for CSC.
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Coriorretinopatia Serosa Central , Humanos , Coriorretinopatia Serosa Central/diagnóstico por imagem , Coriorretinopatia Serosa Central/cirurgia , Tomografia de Coerência Óptica , Estudos Transversais , Angiofluoresceinografia , Corioide/diagnóstico por imagemRESUMO
Purpose: This study aimed to investigate the age-dependent anti-angiogenic capability of melatonin in choroidal neovascularization (CNV) and to explore the underlying molecular mechanisms. Methods: In the present study, a laser-induced CNV model was established in both young (three months of age) and old (18 months of age) mice, and the size of CNV lesions and vascular leakage was detected by morphological and imaging examination. Next, Western blot and immunostaining were used to observe the levels of M2 markers, senescence-related markers, and molecules involved in IL-10/STAT3 pathway. Additionally, colivelin was used to study the effect of IL-10/STAT3 pathway activation on the expression of M2 markers and senescence-related markers by Western blot and immunostaining. Finally, the effects of colivelin on melatonin-induced reduction of CNV size and vascular leakage in mice at different ages were assessed using morphological and imaging examination. Results: Our results revealed that aging promoted M2 macrophage/microglia polarization, and aggravated CNV and vascular leakage. Melatonin significantly inhibited the M2 polarization of senescent macrophage/microglia and reduced the CNV area and vascular leakage. Moreover, melatonin markedly suppressed IL-10/STAT3 pathway activation in the macrophage/microglia of old mice, and STAT3 activator colivelin reversed the suppressive effect of melatonin on M2 polarization of senescent macrophage/microglia and laser-induced CNV in old mice. Conclusions: Our data demonstrated that melatonin significantly prevented the M2 polarization of senescent macrophage/microglia by inhibiting the IL-10/STAT3 pathway, and eventually attenuated senescence-associated CNV. These findings suggested that melatonin could serve as a promising therapeutic agent to treat CNV and other age-related ocular diseases.
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Neovascularização de Coroide , Melatonina , Camundongos , Animais , Microglia/metabolismo , Melatonina/farmacologia , Melatonina/uso terapêutico , Melatonina/metabolismo , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-10/uso terapêutico , Neovascularização de Coroide/metabolismo , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Purpose: Strategies for neuroprotection are the main targets of glaucoma research. The neuroprotective properties of SRT2104 administration have been proven in central nervous system degeneration diseases through the activation of nicotinamide adenine dinucleotide-dependent deacetylase-silence information regulator 1 (Sirt1). Here, we investigated whether SRT2104 could protect the retina from ischemia/reperfusion (I/R) injury and the underlying mechanisms. Methods: SRT2104 was intravitreally injected immediately after I/R induction. RNA and protein expression were detected by quantitative real-time PCR and Western blot. Protein expression and distribution were examined by immunofluorescence staining. Retinal structure and function were analyzed by hematoxylin and eosin staining, optical coherence tomography, and electroretinogram. Optic nerve axons were quantified using toluidine blue staining. Cellular apoptosis and senescence were evaluated by TUNEL assay and SA-ß-gal staining. Results: The protein expression of Sirt1 decreased dramatically after I/R injury and SRT2104 administration effectively enhanced the stability of Sirt1 protein without significantly influencing Sirt1 mRNA synthesis. SRT2104 administration alone exerted no influence on the structure and function of normal retinas. However, SRT2104 intervention significantly protected the inner retinal structure and neurons; partially restored retinal function after I/R injury. I/R-induced cellular apoptosis and senescence were effectively alleviated by SRT2104 administration. Additionally, SRT2104 intervention markedly reduced neuroinflammation, including reactive gliosis, retinal vascular inflammation, and the overexpression of pro-inflammatory cytokines after I/R injury. Mechanistically, I/R-induced acetylation of p53, NF-κB p65, and STAT3 was significantly reversed by SRT2104 intervention. Conclusions: We demonstrated that SRT2104 exerted potent protective effects against I/R injury by enhancing Sirt1-mediated deacetylation and suppressing apoptosis, senescence, and neuroinflammation-related pathways.
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Neuroproteção , Traumatismo por Reperfusão , Camundongos , Animais , Sirtuína 1/metabolismo , Doenças Neuroinflamatórias , Traumatismo por Reperfusão/prevenção & controle , Apoptose , Inflamação , IsquemiaRESUMO
Purpose: KC7F2 is a novel molecule compound that can inhibit the translation of hypoxia-inducible factor 1α (HIF1α). It has been reported to exhibit potential antiangiogenic effect. We hypothesized that KC7F2 could inhibit oxygen-induced retinal neovascularization (RNV). The purpose of this study was to investigate this assumption. Methods: Oxygen-induced retinopathy (OIR) models in C57BL/6J mice and Sprague-Dawley rats were used for in vivo study. After intraperitoneal injections of KC7F2, RNV was detected by immunofluorescence and hematoxylin and eosin staining. Retinal inflammation was explored by immunofluorescence. EdU incorporation assay, cell counting kit-8 assay, scratch test, transwell assay, and Matrigel assay were used to evaluate the effect of KC7F2 on the proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC) induced by vascular endothelial growth factor (VEGF) in vitro. Protein expression was examined by Western blot. Results: KC7F2 treatment (10 mg/kg/d) in OIR mice significantly attenuated pathological neovascularization and decreased the number of preretinal neovascular cell nuclei, without changing the avascular area, which showed the same trends in OIR rats. Consistently, after the KC7F2 intervention (10 µM), cell proliferation was inhibited in VEGF-induced HUVEC, which was in agreement with the trend observed in the retinas of OIR mice. Meanwhile, KC7F2 suppressed VEGF-induced HUVEC migration and tube formation, and decreased the density of leukocytes and microglia colocalizing neovascular areas in the retinas. Moreover, the HIF1α-VEGF pathway activated in retinas of OIR mice and hypoxia-induced HUVEC, was suppressed by KC7F2 treatment. Conclusions: The current study revealed that KC7F2 was able to inhibit RNV effectively via HIF1α-VEGF pathway, suggesting that it might be an effective drug for RNV treatment.
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Dissulfetos/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Neovascularização Retiniana , Retinopatia da Prematuridade , Sulfonamidas/farmacologia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hipóxia , Recém-Nascido , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica , Oxigênio/metabolismo , Oxigênio/toxicidade , Ratos , Ratos Sprague-Dawley , Neovascularização Retiniana/tratamento farmacológico , Neovascularização Retiniana/metabolismo , Neovascularização Retiniana/prevenção & controle , Retinopatia da Prematuridade/tratamento farmacológico , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
There is an urgent need for developing electromechanical sensor with both ultralow detection limits and ultrahigh sensitivity to promote the progress of intelligent technology. Here we propose a strategy for fabricating a soft polysiloxane crosslinked MXene aerogel with multilevel nanochannels inside its cellular walls for ultrasensitive pressure detection. The easily shrinkable nanochannels and optimized material synergism endow the piezoresistive aerogel with an ultralow Young's modulus (140 Pa), numerous variable conductive pathways, and mechanical robustness. This aerogel can detect extremely subtle pressure signals of 0.0063 Pa, deliver a high pressure sensitivity over 1900 kPa-1, and exhibit extraordinarily sensing robustness. These sensing properties make the MXene aerogel feasible for monitoring ultra-weak force signals arising from a human's deep-lying internal jugular venous pulses in a non-invasive manner, detecting the dynamic impacts associated with the landing and take-off of a mosquito, and performing static pressure mapping of a hair.
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Fenômenos Mecânicos , Animais , HumanosRESUMO
OBJECTIVE: To compare the effectiveness of platelet-rich plasma (PRP), autologous blood (AB), and corticosteroid injections in patients with lateral epicondylitis. TYPE OF STUDY: Network meta-analysis. LITERATURE SURVEY: Randomized controlled trials (RCTs) that compared any two forms of injections among PRP, AB, and corticosteroid for the treatment of lateral epicondylitis were searched from inception to 30 November 2018, on PubMed, Embase, and Cochrane library. METHODOLOGY: Two researchers independently selected and assessed the quality of RCTs with the Cochrane Risk of Bias Tool. All relevant data from the included studies were extracted and heterogeneity was checked by Cochran's Q test and inconsistency statistic (I2 ). Publication bias was evaluated by constructing contour-enhanced funnel plots. Stata 15 software was applied for pairwise meta-analysis and network meta-analysis. To explore the efficacy between different follow-up periods, we considered the duration within 2 months to be short term, whereas 2 months or more was considered long term. SYNTHESIS: Twenty RCTs (n = 1271) were included in this network meta-analysis. According to ranking probabilities, corticosteroid ranked first for visual analog score (VAS) (surface under the cumulative ranking [SUCRA] = 90.7), modified Nirschl score (82.9), maximum grip strength (69.5), modified Mayo score (MMS) (77.9), and Patient-Related Tennis Elbow Evaluation (PRTEE) score (93.3) for the short-term period. For the long-term period, PRP ranked first for VAS (94.3), pressure pain threshold (99.8), Disabilities of Arm Shoulder and Hand (DASH) score (75.2), MMS (88.2), and the PRTEE score (81.8). CONCLUSION: PRP was associated with more improvement in pain intensity and function in the long term than were the comparators. However, in the short term, corticosteroids were associated with the most improvement.
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Corticosteroides/uso terapêutico , Transfusão de Sangue Autóloga , Plasma Rico em Plaquetas , Cotovelo de Tenista , Humanos , Injeções Intra-Articulares , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Cotovelo de Tenista/tratamento farmacológicoRESUMO
Rapid urban expansion often leads to substantial encroachment on ecological lands and destruction of natural environments. We developed a new cellular automata model (named CACEO) that uses cross-entropy optimization (CEO) to reproduce and project urban expansion into coastal areas and to assess urban encroachment on ecological lands. The CEO algorithm automatically searches for the near-optimal CA parameters and is capable of objectively parameterizing CA models to predict multi-objective scenarios. We calibrated CACEO by simulating urban expansion at Wenzhou from 1995 to 2005, validated the model from 2005 to 2015 using real data, and then predicted urban expansion for 2025 and 2035. End-state overall accuracies were 93.8% for 2005 and 94.4% for 2015, while figure-of-merit metrics were 27.9% for 2005 and 19.1% for 2015. We predicted four different scenarios to year 2025 and 2035: (1) a business-as-usual (BAU)-scenario using benchmark settings; (2) a District-scenario based on a district-oriented urban development strategy; (3) a Road-scenario based on a road network-oriented urban development strategy; and (4) a Coast-scenario based on a coast-oriented urban development strategy. Each scenario predicts a substantially different pattern of urban encroachment on ecological land and significant loss of farmland, forest, wetland and grassland. These scenarios should be useful in adjusting urban development strategies at Wenzhou and elsewhere.
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Conservação dos Recursos Naturais , Reforma Urbana , Algoritmos , China , Entropia , FlorestasRESUMO
The existence of blood-tumor barrier (BTB) severely restricts the efficient delivery of antitumor drugs to cranial glioma tissues. Various strategies have been explored to increase BTB permeability. RNA-binding proteins and circular RNAs have recently emerged as potential regulators of endothelial cells functions. In this study, RNA-binding protein KH RNA-binding domain containing, signal transduction associated 3 (KHDRBS3) and circular RNA DENND4C (cDENND4C) were enriched in GECs. KHDRBS3 bound to cDENND4C and increased its stability. The knockdown of cDENND4C increased the permeability of BTB via downregulating the expressions of tight junction-related proteins. The miR-577 was lower expressed in GECs. The overexpressed miR-577 increased the permeability of BTB by reducing the tight junction-related protein expressions, and vice versa. Furthermore, cDENND4C acted as a molecular sponge of miR-577, which bound to miR-577 and inhibited its negative regulation of target genes ZO-1, occludin and claudin-1 to regulate BTB permeability. Single or combined treatment of KHDRBS3, cDENND4C, and miR-577 effectively promoted antitumor drug doxorubicin (DOX) across BTB to induce apoptosis of glioma cells. Collectively, the present study indicated that KHDRBS3 could regulate BTB permeability through the cDENND4C/miR-577 axis, which enhanced doxorubicin delivery across BTB. These findings may provide a novel strategy for chemotherapy of brain tumors.
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Antibióticos Antineoplásicos/farmacologia , Barreira Hematoencefálica/metabolismo , Doxorrubicina/farmacologia , Glioma/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Claudina-1/metabolismo , Doxorrubicina/metabolismo , Células Endoteliais/metabolismo , Glioma/tratamento farmacológico , Glioma/genética , Humanos , MicroRNAs/genética , Ocludina/metabolismo , Permeabilidade , RNA Circular/genética , Proteínas de Ligação a RNA/genética , Junções Íntimas/metabolismo , Proteína da Zônula de Oclusão-1/metabolismoRESUMO
OBJECTIVES: Over the years, completion axillary lymph node dissection is recommended for the patients with breast cancer if sentinel lymph node metastasis is found. However, not all of these patients had nonsentinel lymph node metastasis on final histology. Some predicting models have been developed for calculating the risk of nonsentinel lymph node metastasis. The aim of our study was to validate some of the predicting models in a Chinese population. METHOD: Two hundred thirty-six patients with positive sentinel lymph node and complete axillary lymph node dissection were included. Patients were applied to 6 models for evaluation of the risk of nonsentinel lymph node involvement. The receiver-operating characteristic curves were shown in our study. The calculation of area under the curves and false negative rate was done for each model to assess the discriminative power of the models. RESULTS: There are 105 (44.5%) patients who had metastatic nonsentinel lymph node(s) in our population. Primary tumor size, the number of metastatic sentinel lymph node, and the proportion of metastatic sentinel lymph nodes/total sentinel lymph nodes were identified as the independent predictors of nonsentinel lymph node metastasis. The Seoul National University Hospital and Louisville scoring system outperformed the others, with area under the curves of 0.706 and 0.702, respectively. The area under the curve values were 0.677, 0.673, 0.432, and 0.674 for the Memorial Sloan-Kettering Cancer Center, Tenon, Stanford, and Shanghai Cancer Hospital models, respectively. With adjusted cutoff points, the Louisville scoring system outperformed the others by classifying 26.51% of patients with breast cancer to the low-risk group. CONCLUSION: The Louisville and Seoul National University Hospital scoring system were found to be more predictive among the 6 models when applied to the Chinese patients with breast cancer in our database. Models developed at other institutions should be used cautiously for decision-making regarding complete axillary lymph node dissection after a positive biopsy in sentinel lymph node.
Assuntos
Neoplasias da Mama/patologia , Linfonodos/patologia , Linfonodo Sentinela/patologia , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/cirurgia , China/epidemiologia , Feminino , Humanos , Excisão de Linfonodo , Linfonodos/cirurgia , Metástase Linfática , Pessoa de Meia-Idade , Fatores de Risco , Linfonodo Sentinela/cirurgia , Biópsia de Linfonodo SentinelaRESUMO
OBJECTIVE: To evaluate the diagnostic value of mammography, computed tomography (CT), and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for axillary lymph node staging in breast cancer patients. METHODS: From February, 2014 to October, 2015, 109 women with breast cancer received examinations with preoperative mamography, CT, and DCE-MRI. The diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the 3 modalities were evaluated using histopathologic assessments as the gold standard. RESULTS: In total, 39.4% (43/109) of the patients had axillary lymph node metastasis. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of mamography for determining lymph node metastasis were 14.0%, 84.8%, 56.9%, 37.5% and 60.0%, respectively; those of CT were 93.0%, 57.6%, 71.6%,58.8% and 92.7%, and those of DCE-MRI were 95.3%, 65.2%, 77.1%, 64.1% and 95.6%, respectively. Compared with the histopathologic result, the Kappa coefficients of mamography, CT, and DCE-MRI were -0.13, 0.459 and 0.558, respectively. The specificity of mamography was significantly higher (P<0.05), but its sensitivity, accuracy, positive predictive value, and negative predictive value were significantly lower than those of CT and DCE-MRI (P<0.05). Compared with CT, DCE-MRI had significantly higher sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for diagnosis of lymph node metastasis (P<0.05). CONCLUSION: DCE-MRI has a greater diagnostic power than CT and mammography, and CT has a greater diagnostic power than mammography for axillary lymph node metastasis in breast cancer patients. Mamography alone should be used cautiously for the diagnosis of lymph node metastasis.