RESUMO
Background: Ovarian cancer (OC) is a gynecological malignancy with a high mortality rate worldwide. The unfavorable prognosis of OC is mainly attributed to the recurrent propensity. Recently, mortality from OC has exhibited a downward trend. These favorable patterns are likely to be driven by advancements in novel therapeutic regimens. However, there is a lack of visualize analysis of the application of these new drugs on women with recurrent OC (ROC). Therefore, we aimed to provide a bibliometric analysis of the evolving paradigms in the ROC treatment. Methods: Documents on ROC treatment were systematically collected from the MEDLINE database and Web of Science Core Collection (WOSCC). The retrieved documents were exported in the plain text file format, and files were named and saved to the paths specified by the Java application. Microsoft Excel (version 2010), Citespace (6.2.R4) and VOSviewer (1.6.19) were used for data analysis, and included the following: 1) annual publication trend; 2) contributions of countries, institutions and authors; 3) co-citation of journals and references; and 4) co-occurrence of keywords. Results: A total of 914 documents published in the MEDLINE and 9,980 ones in WOSCC were retrieved. There has been an upward trend in the productivity of publications on ROC treatment on by years. The United States was the leading contributor in this field, and the University of Texas System stood out as the most productive institution. Giovanni Scambia and Maurie Markman were the research leaders in the field of ROC treatment. The journal Gynecologic Oncology had the highest citation frequency. The reference entitled with "Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer" got highest centrality of 0.14 in the co-citation network. Keyword analysis revealed that the focus of current ROC treatment was on platinum-based anticancer drugs, paclitaxel, angiogenesis inhibitors (AIs), immune checkpoint inhibitors (ICIs) and poly (ADP-ribose) polymerase inhibitors (PARPis). Conclusion: Scholars from a multitude of countries have been instrumental in the advancement of ROC treatment. The research hotspots and trend in the field of predominantly originated from leading international journals and specialized periodicals focused on gynecologic oncology. Maintenance therapy using AIs or (and) PARPis has emerged as a significant complement to platinum-based chemotherapy for patients with ROC.
RESUMO
Purpose: The purpose of this study was to investigate the molecular mechanisms underlying anti-vascular endothelial growth factor (anti-VEGF) efficacy and response variability in neovascular age-related macular degeneration (nAMD) using longitudinal proteomic and metabolomic analysis alongside three-dimensional lesion measurements. Methods: In this prospective study, 54 treatment-naive patients with nAMD underwent "3+ pro re nata" (3+PRN) anti-VEGF regimens followed for at least 12 weeks. Aqueous humors were collected pre- and post-treatment for proteomic and metabolomic analysis. Three-dimensional optical coherence tomography (OCT) and OCT angiography assessed different types of nAMD lesion volumes and areas. Results: There were 1350 proteins and 1268 metabolites that were identified in aqueous humors, with 301 proteins and 353 metabolites significantly altered during anti-VEGF treatment, enriched in pathways of angiogenesis, energy metabolism, signal transduction, and neurofunctional regulation. Sixty-seven changes of (Δ) molecules significantly correlated with at least one type of ΔnAMD lesion. Notably, proteins FGA, TALDO1, and ASPH significantly decreased during treatment, with their reductions correlating with greater lesion regression in at least two lesion types. Conversely, despite that YIPF3 also showed significant downregulation, its decrease was associated with poorer regression in total nAMD lesion and subretinal hyper-reflective material. Conclusions: This study identifies FGA, TALDO1, and ASPH as potential key molecules in the efficacy of anti-VEGF therapy, whereas YIPF3 may be a key factor in poor response. The integration of longitudinal three-dimensional lesion analysis with multi-omics provides valuable insights into the mechanisms and response variability of anti-VEGF treatment in nAMD.
Assuntos
Inibidores da Angiogênese , Angiofluoresceinografia , Injeções Intravítreas , Proteômica , Ranibizumab , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Degeneração Macular Exsudativa , Humanos , Tomografia de Coerência Óptica/métodos , Inibidores da Angiogênese/uso terapêutico , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/metabolismo , Masculino , Feminino , Idoso , Degeneração Macular Exsudativa/tratamento farmacológico , Degeneração Macular Exsudativa/metabolismo , Degeneração Macular Exsudativa/diagnóstico , Angiofluoresceinografia/métodos , Ranibizumab/uso terapêutico , Idoso de 80 Anos ou mais , Humor Aquoso/metabolismo , Bevacizumab/uso terapêutico , Metabolômica/métodos , Acuidade Visual , Imageamento Tridimensional , MultiômicaRESUMO
BACKGROUND: Lenvatinib is a tyrosine kinase inhibitor that can improve progression-free survival in patients with thyroid cancer and hepatocellular carcinoma. However, it is limited by adverse cardiovascular events, including hypertension and cardiac dysfunction. Activation of endoplasmic reticulum stress is involved in cardiomyocyte apoptosis. OBJECTIVE: This study aimed to confirm whether the cardiotoxicity of lenvatinib is associated with endoplasmic reticulum stress by targeting the activating transcription factor 6 (ATF6), inositol- requiring enzyme 1α (IRE1α) and protein kinase RNA-like ER kinase (PERK) signaling pathways. METHODS: Male C57/BL6 mice were intragastric administration with 30 mg/kg/day lenvatinib. Electrocardiography (ECG) and echocardiography were used to detect arrhythmias and cardiac function. Neonatal rat cardiomyocytes were treated with lenvatinib for 48h. Cell counting kit (CCK8), 2´,7´-dichlorodihydrofluoresceine diacetate (H2DCFHDA), Hoechst 33258 and dihydrorhodamine 123 were respectively used for evaluating cell viability, the level of reactive oxygen species (ROS), nuclear morphological changes and mitochondrial membrane potential (MMP) level. RESULTS: Lenvatinib remarkably decreased the posterior wall thickness of left ventricle during diastole and systole but caused little decrease to the left ventricular ejection fraction (LVEF, %). Furthermore, lenvatinib greatly prolonged the corrected QT interval (QTc) and altered the morphology of cardiomyocytes. No dramatic difference in fibrosis was found in mouse cardiac slices. Lenvatinib upregulates apoptosis-related protein expression. In addition, lenvatinib increased ERS-related protein expression (GRP78, CHOP, and ATF6) and enhanced PERK phosphorylation. In neonatal rat cardiac myocytes, lenvatinib markedly decreased the viability of cardiomyocytes and induced apoptosis. Furthermore, ROS production increased and MMP decreased. Similar to the mice experiment, lenvatinib caused upregulation of apoptosis-related and ERS-related proteins and increased the phosphorylation levels of PERK and IRE1α. CONCLUSION: Lenvatinib-induced cardiotoxicity is associated with ERS-induced apoptosis by targeting the ATF6, IRE1α, and PERK signaling pathways.
RESUMO
PURPOSE: To report the novel imaging findings in persistent placoid maculopathy (PPM) from the first case series of Asian subjects. DESIGN: Retrospective observational case series. SUBJECTS: Patients with PPM from 2013 to 2023. METHODS: Medical records and multimodal images from each visit were analyzed. MAIN OUTCOME MEASURES: Imaging and follow-up findings. RESULTS: Twenty-one eyes of 16 patients were included. Mean age was 61 (range, 48-84) years old. Five patients showed bilateral involvement. Persistent placoid maculopathy lesions were unremarkable on color fundus photography, autofluorescence, and fluorescein angiography. Hypofluorescent spots with a lichen-like appearance presented in all phases of indocyanine green angiography, which were most prominent in the late phase and presented in a fused (71%) or clustered (29%) pattern. The hypofluorescence correlated with the lesions between the retinal pigment epithelium (RPE) and Bruch's membrane (BM) with moderate reflectivity on OCT, and the thickness ranged from slit-like to mound-like. The intensity of hypofluorescence sometimes varied in the same eye and correlated with the thickness of sub-RPE lesions on OCT. No abnormal blood flow signals were detected in either the sub-RPE space or choriocapillaris slab of OCT angiography across the PPM lesions. Peripapillary (5 eyes, 24%) and extra posterior pole (2 eyes, 10%) involvements were seen, the former sparing the ß zones of optic discs. Ten eyes of 7 patients were followed up (median, 26 months; range, 2-121 months). During follow-up, the lichen-like lesions spread and migrated slowly without changing the plane patterns of the first visit and were limited to sub-RPE growth. The fused lichen-like pattern sprawled around the enlarged base. The clustered lichen-like pattern gradually loosened. Ten eyes (48%, 9 eyes in the fused pattern, 1 eye in the clustered pattern) had secondary choroidal neovascularization (CNV) at the first visit, with type I (6 eyes, 5 of which were polypoidal choroidal vasculopathy) and type II (4 eyes). No new CNV developed during follow-up. CONCLUSION: Persistent placoid maculopathy lesions were located in the sub-RPE space, as determined by multimodal imaging. Spreading and migration between the RPE and BM may account for their unique lichen-like appearance and progression pattern. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Assuntos
Neovascularização de Coroide , Líquens , Degeneração Macular , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Lâmina Basilar da Corioide , Epitélio Pigmentado da Retina , Estudos RetrospectivosRESUMO
Cardiovascular diseases (CVDs) continue to be a significant global health concern. Many studies have reported promising outcomes from using MSCs and their secreted exosomes in managing various cardiovascular-related diseases like myocardial infarction (MI). MSCs and exosomes have demonstrated considerable potential in promoting regeneration and neovascularization, as well as exerting beneficial effects against apoptosis, remodeling, and inflammation in cases of myocardial infarction. Nonetheless, ensuring the durability and effectiveness of MSCs and exosomes following in vivo transplantation remains a significant concern. Recently, novel methods have emerged to improve their effectiveness and robustness, such as employing preconditioning statuses, modifying MSC and their exosomes, targeted drug delivery with exosomes, biomaterials, and combination therapy. Herein, we summarize the novel approaches that intensify the therapeutic application of MSC and their derived exosomes in treating MI.
RESUMO
INTRODUCTION: Attenuating cardiac fibroblasts activation contributes to reducing excessive extracellular matrix deposition and cardiac structural remodeling in hypertensive hearts. Acacetin plays a protective role in doxorubicin-induced cardiomyopathy and ischemia/reperfusion injury. The aim of this study was to investigate the potential molecular mechanisms underlying the protective role of acacetin on hypertension-induced cardiac fibrosis. METHODS: Echocardiography, histopathological methods, and Western blotting techniques were used to evaluate the anti-fibrosis effects in spontaneous hypertensive rat (SHR) which were daily intragastrically administrated with acacetin (10 mg/kg and 20 mg/kg) for 6 weeks. Angiotensin II (Ang II) was used to induce cellular fibrosis in human cardiac fibroblasts (HCFs) in the absence and presence of acacetin treatment for 48 h. RESULTS: Acacetin significantly alleviated hypertension-induced increase in left ventricular (LV) posterior wall thickness and LV mass index in SHR. The expressions of collagen-1, collagen-III, and alpha-smooth muscle actin (α-SMA) were remarkedly decreased after treatment with acacetin (n = 6, p < 0.05). In cultured HCFs, acacetin significantly attenuated Ang II-induced migration and proliferation (n = 6, p < 0.05). Moreover, acacetin substantially inhibited Ang II-induced upregulation of collagen-1 and collagen-III (n = 6, p < 0.05) and downregulated the expression of alpha-SMA in HCFs. Additionally, acacetin decreased the expression of TGF-ß1, p-Smad3/Smad3, and p-AKT and p-mTOR but increased the expression of Smad7 (n = 6, p < 0.05). Further studies found that acacetin inhibited TGF-ß1 agonist SRI and AKT agonist SC79 caused fibrotic effect. CONCLUSION: Acacetin inhibits the hypertension-associated cardiac fibrotic processes through regulating TGF-ß/Smad3, AKT/mTOR signal transduction pathways.
Assuntos
Cardiomiopatias , Hipertensão , Humanos , Ratos , Animais , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/farmacologia , Miocárdio/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Transdução de Sinais , Colágeno/metabolismo , Colágeno/farmacologia , Colágeno Tipo I/metabolismo , Colágeno Tipo I/farmacologia , Hipertensão/tratamento farmacológico , Serina-Treonina Quinases TOR , Fibroblastos/patologia , FibroseRESUMO
Primary liver cancer (PLC) that originates in the liver is a malignant tumor with the worst prognosis. Hepatocellular carcinoma (HCC) is the most common type of PLC. Most PLC cases are diagnosed at advanced stages mainly due to their insidious onset and rapid progression. Patients with PLC undergo surgical intervention or localized treatment, but their survival is often affected by its high relapse rate. Medical treatment is the primary option for patients with liver cancer, especially with advanced extrahepatic metastases. Molecular targeted therapy exerts an anti-tumor effect by acting on various signaling pathways involved in molecular pathogenesis; however, high drug resistance and low therapeutic responsiveness of PLC to molecular targets challenge the treatment option. In recent years, after surgical intervention, radiotherapy, chemotherapy, and/or molecular targeted therapy, autologous cell immunotherapy has been adopted for PLC. As a typical autologous cell immunotherapy, CAR T-cell therapy uses genetically modified T cells to express tumor-specific chimeric antigen receptors (CARs). Its targeting ability, persistent nature, and tumor-killing function result in a significant impact on the treatment of hematological tumors. However, no breakthrough has happened in the research specific to the curation of lung cancer, liver cancer, breast cancer, and other common solid tumors. In this context, a combination of molecular targeted therapy and CAR T-cell therapy was used to treat a patient with advanced HCC to achieve a partial remission(PR) and facilitate further liver transplantation.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/patologia , Imunoterapia Adotiva , Carcinoma Hepatocelular/patologia , alfa-Fetoproteínas/metabolismo , Linfócitos T , Receptores de Antígenos de Linfócitos T , Recidiva Local de Neoplasia/metabolismoRESUMO
Previous studies have suggested that circular RNAs (circRNAs) play important regulatory roles in cancer progression. Previous evidence exhibited the aberrant upregulation of circ_0061140 in ovarian cancer. However, the detailed role of circ_0061140 in ovarian cancer progression and its associated mechanism remain largely unknown and need further exploration. The expression of circ_0061140, microRNA-761 (miR-761) and leucine zipper and EF-hand containing transmembrane protein 1 (LETM1) was checked by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) or western blot. Cell Counting Kit-8 (CCK8), colony formation, 5-Ethynyl-2'-deoxyuridine (EdU), flow cytometry, wound healing, transwell, and tube formation assays were conducted to assess cell functions. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to confirm the interaction between miR-761 and circ_0061140 or LETM1. Xenograft tumor model was established to analyze the role of circ_0061140 in tumor growth in vivo. Circ_0061140 expression was notably up-regulated in ovarian cancer tissues and cell lines. Circ_0061140 knockdown suppressed the proliferation, migration, invasion, and angiogenesis and triggered the apoptosis of ovarian cancer cells. Circ_0061140 directly interacted with miR-761, and circ_0061140 silencing-mediated anti-tumor effects were partly abolished by miR-761 knockdown in ovarian cancer cells. LETM1 was a direct target of miR-761, and LETM1 overexpression partly counteracted miR-761-induced anti-tumor effects. Circ_0061140 could up-regulate LETM1 expression by sponging miR-761. Circ_0061140 knockdown significantly suppressed xenograft tumor growth in vivo. Circ_0061140 aggravated ovarian cancer progression through miR-761-dependent regulation of LETM1.
Assuntos
MicroRNAs , Neoplasias Ovarianas , RNA Circular , Animais , Feminino , Humanos , Apoptose , Proteínas de Ligação ao Cálcio , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Proteínas de Membrana , MicroRNAs/genética , Neoplasias Ovarianas/genética , Transdução de Sinais , RNA Circular/metabolismoRESUMO
Mitochondrial dysfunction in the endothelium contributes to the progression of hypertension and plays an obligatory role in modulating vascular tone. Acacetin is a natural flavonoid compound that has been shown to possess multiple beneficial effects, including vasodilatation. However, whether acacetin could improve endothelial function in hypertension by protecting against mitochondria-dependent apoptosis remains to be determined. The mean arterial pressure (MAP) in Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) administered with acacetin intraperitoneally for 2 h or intragastrically for six weeks were examined. The endothelial injury was evaluated by immunofluorescent staining and a transmission electron microscope (TEM). Vascular tension measurement was performed to assess the protective effect of acacetin on mesenteric arteries. Endothelial injury in the pathogenesis of SHR was modeled in HUVECs treated with Angiotensin II (Ang II). Mitochondria-dependent apoptosis, the opening of Mitochondrial Permeability Transition Pore (mPTP) and mitochondrial dynamics proteins were determined by fluorescence activated cell sorting (FACS), immunofluorescence staining and western blot. Acacetin administered intraperitoneally greatly reduced MAP in SHR by mediating a more pronounced endothelium-dependent dilatation in mesenteric arteries, and the vascular dilatation was reduced remarkably by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis. While acacetin administered intragastrically for six weeks had no apparent effect on MAP, it improved the endothelium-dependent dilatation in SHR by activating the AKT/eNOS pathway and protecting against the abnormalities of endothelium and mitochondria. Furthermore, acacetin remarkably inhibited Ang II induced apoptosis by inhibiting the increased expression of Cyclophilin D (CypD), promoted the opening of mPTP, ROS generation, ATP loss and disturbance of dynamin-related protein 1 (DRP1)/optic atrophy1 (OPA1) dynamics in HUVECs. This study suggests that acacetin protected against endothelial dysfunction in hypertension by activating the AKT/eNOS pathway and modulating mitochondrial function by targeting mPTP and DRP1/OPA1-dependent dynamics.
Assuntos
Flavonas , Hipertensão , Hipotensão , Animais , Ratos , Trifosfato de Adenosina/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Pressão Sanguínea , Peptidil-Prolil Isomerase F , Endotélio Vascular/metabolismo , Flavonas/metabolismo , Flavonas/farmacologia , Hipertensão/metabolismo , Hipotensão/metabolismo , Mitocôndrias/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , VasodilataçãoRESUMO
The rostral ventrolateral medulla (RVLM) is a pivotal region in the central regulation of blood pressure (BP). It has been documented that silent information regulator 2 homolog 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent multifunctional transcription regulatory factor, has many cardiovascular protective effects. However, the role and significance of SIRT1 in the central regulation of cardiovascular activity, especially in RVLM, remains unknown. Therefore, the aim of this study was to explore the role and underlying mechanism of SIRT1 in the central regulation of cardiovascular activity in hypertension. Spontaneously hypertensive rats (SHRs) were given resveratrol (RSV) via intracerebroventricular (ICV) infusion or injected with SIRT1-overexpressing lentiviral vectors into the RVLM. In vitro experiments, angiotensin II (Ang II)-induced rat pheochromocytoma cell line (PC12 cells) were transfected with forkhead box protein O1 (FOXO1) small interfering RNA (siRNA) before treatment with RSV. Our results showed that SIRT1 activation with RSV or overexpression in the RVLM significantly decreased BP and sympathetic outflow of SHRs. Furthermore, SIRT1 overexpression in the RVLM significantly decreased reactive oxygen species (ROS) production and facilitated the forkhead box protein O1 (FOXO1) activation, accompanied by upregulation of the ROS-detoxifying enzyme superoxide dismutases 1 (SOD1) in the RVLM of SHRs. In PC12 cells, it was found that Ang II could induce oxidative stress and downregulate the SIRT1-FOXO1-SOD1 signaling pathway, which indicated that the suppressed expression of SIRT1 in the RVLM of SHRs might relate to the elevated central Ang II level. Furthermore, the enhanced oxidative stress and decreased SIRT1-FOXO1-SOD1 axis induced by Ang II were restored by treatment with RSV. However, these favorable effects mediated by SIRT1 activation were blocked by FOXO1 knockdown. Based on these findings, we concluded that SIRT1 activation or overexpression in the RVLM exerts anti-hypertensive effect through reducing oxidative stress via SIRT1-FOXO1-SOD1 signaling pathway, which providing a new target for the prevention and intervention of hypertension.
Assuntos
Anti-Hipertensivos , Hipertensão , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Proteína Forkhead Box O1/genética , Frequência Cardíaca , Hipertensão/metabolismo , Proteínas do Tecido Nervoso , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/genética , Superóxido Dismutase/genética , Superóxido Dismutase/farmacologia , Superóxido Dismutase-1RESUMO
Purpose: To investigate the clinical features of a macrophage-like cell (MLC) obtained by en face optical coherence tomography (OCT) in retinal vein occlusion (RVO). Methods: The study involved 36 patients with treatment-naïve unilateral acute RVO, including 21 branch RVO (BRVO) and 15 central RVO. Vessel density and macular thickness were quantified using OCT angiography. A 3-µm en face OCT slab on the inner limiting membrane in the optic nerve head (ONH) region or macular region was used to visualize the MLCs. The MLCs were binarized and quantified using a semiautomated method. The unaffected fellow eyes served as the control group. Results: The morphology of MLCs appeared larger and plumper in RVO eyes. The mean MLC density in the ONH and macular regions was 2.46 times and 2.86 times higher than their fellow eyes, respectively (p < 0.001). The macular MLC density of the occlusive region was significantly lower than that of the unaffected region in BRVO (p = 0.01). The ONH and macular MLC densities in the non-perfused region were significantly lower than those in the perfused region in all RVO eyes (p < 0.001). The ONH MLC density in RVO eyes was negatively correlated with radial peripapillary capillary vessel density (r = -0.413, p = 0.012). Both ONH and macular MLC densities were positively correlated with macular thickness (r = 0.505, p = 0.002; r = 0.385, p = 0.02, respectively). Conclusion: The increased density and changes of morphology characterized by OCT may indicate generalized activation and aggregation of MLCs in RVO. More MLCs are recruited in the perfused region rather than the non-perfused region. RVO eyes with a higher density of MLCs tend to suffer from the thicker macula.
Assuntos
Oclusão da Veia Retiniana , Angiofluoresceinografia/métodos , Humanos , Macrófagos , Oclusão da Veia Retiniana/diagnóstico por imagem , Vasos Retinianos , Tomografia de Coerência Óptica/métodosRESUMO
Inhibition of human ether-a-go-go-related gene (hERG) potassium channel is responsible for acquired long QT syndromes, which leads to life-threatening cardiac arrhythmia. A multikinase inhibitor, vandetanib, prolongs the progression-free survival time in advanced medullary thyroid cancer. However, vandetanib has been reported to induce significant QT interval prolongation, which limits its clinical application. Some studies have showed that ginsenoside Rg3 decelerated hERG K(+) channel tail current deactivation. Therefore, in this study, we aim to confirm whether ginsenoside Rg3 targeting hERG K(+) channel could be used to reverse the vandetanib-induced QT interval prolongation. Electrocardiogram (ECG) and monophasic action potential (MAP) were recorded using electrophysiology signal sampling and analysis system in Langendorff-perfused rabbit hearts. The current clamp mode of the patch-clamp technique was used to record transmembrane action potential. The whole-cell patch-clamp technique was used to record the hERG K+ current. In Langendorff-perfused hearts, vandetanib prolonged the QT interval in a concentration-dependent manner with an IC50 of 1.96 µmol/L. In human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), vandetanib significantly prolonged the action potential duration at 50%, 70%, and 90% repolarization (APD50, APD70, and APD90). In stable transfected human hERG gene HEK293 cells, vandetanib caused concentrate-dependent inhibition in the step and tail currents of hERG. As expected, ginsenoside Rg3 relieved vandetanib-induced QT interval prolongation in Langendorff-perfused heart and reversed vandetanib-induced APD prolongation in hiPSC-CMs. Furthermore, ginsenoside Rg3 alleviated vandetanib-induced hERG current inhibition and accelerated the process of the channel activation. Ginsenoside Rg3 may be a promising cardioprotective agent against vandetanib-induced QT interval prolongation through targeting hERG channel. These novel findings highlight the therapeutic potential of ginsenoside to prevent vandetanib-induced cardiac arrhythmia.
Assuntos
Antitireóideos/uso terapêutico , Ginsenosídeos/uso terapêutico , Síndrome do QT Longo/induzido quimicamente , Piperidinas/efeitos adversos , Quinazolinas/efeitos adversos , Animais , Antitireóideos/farmacologia , Ginsenosídeos/farmacologia , Humanos , Piperidinas/farmacologia , Quinazolinas/farmacologia , CoelhosRESUMO
BACKGROUND: Before attending ophthalmology trainee courses in Zhongshan Ophthalmic Centre, the medical students from Sun Yat-sen University had finished two years of premedical education after the six-year medical courses including basic medical courses, clinical medical courses, clerkship, and research training in medical college. Integrated modular teaching using different problem-based teaching methods in ophthalmology was designed by the teaching steering committee of Zhongshan Ophthalmic Centre. This study aimed to evaluate the effectiveness and satisfaction scales of the integrated modular teaching among the trainee students. METHODS: A total of 100 medical students attending ophthalmology trainee courses in Zhongshan Ophthalmic Centre were enrolled and randomly allocated into 4 groups according to the teaching arrangement. The trainee courses consisted of several sessions delivered in multiple methods, such as "flipped classroom" session and team-based learning session. The pre- and post-class tests were delivered to evaluate the effectiveness of the integrated modular teaching. The satisfaction survey questionnaire was collected from all participants to investigate the degree of satisfaction. RESULTS: Compared with the first-day-test score, the total last-day-test score was significantly improved by a paired t-test (t = 3.288, P = 0.001). Nineteen students obtained a significant improvement in ranking increased by more than 10 in the last-day-test, whereas they failed to obtain a higher average score for daily performance than other students (t = 0.469, P = 0.654). According to the participant satisfaction questionnaires, these innovative teaching methods were considered as effective and satisfactory. CONCLUSIONS: Integrated modular teaching in ophthalmology trainee courses is effective and appreciated by the medical college students.
Assuntos
Educação de Graduação em Medicina/métodos , Oftalmologia/educação , Aprendizagem Baseada em Problemas/métodos , Avaliação de Programas e Projetos de Saúde , Adulto , China , Feminino , Humanos , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
Purpose: To determine whether multicolor scanning laser ophthalmoscopy (MC-SLO) was better than color fundus photography (CFP) to enhance residents and specialists' preoperative decision-making and intraoperative performance on the epiretinal membrane (ERM). Methods: Consecutive patients with idiopathic ERM were recruited prospectively. All the patients underwent MC-SLO and CFP imagings and were randomized into MC-SLO (n = 20) and CFP (n = 20) groups. Preoperatively, residents and specialists were required to have ERM delineation and select an optimal location for initial ERM peeling independently, based on the MC-SLO (MC-SLO group) or CFP (CFP group) images. Intraoperative optical coherence tomography (iOCT) was introduced to evaluate the accuracy. Results: Preoperatively, residents and specialists acted more effectively in ERM delineation and selection of initial grasping location in the MC-SLO group (both P < 0.001). In the MC-SLO group, higher resident-specialist agreements were achieved in ERM delineation (P = 0.002) and selection of initial grasping location (P = 0.035). The iOCT revealed greater interobserver (iOCT-resident and iOCT-specialist) agreements of ERM delineation in MC-SLO group (P < 0.001 and = 0.027, respectively). Surgeons acted more effectively on completely peeling the ERM in the MC-SLO group (P < 0.001). Conclusions: MC-SLO provided a better visual reference for residents and specialists in ERM delineation and the selection of an initial grasping location for the surgery, compared with CFP. Translational Relevance: MC-SLO is able to help surgeons achieve better intraoperative performance and shorten the learning process for residents.
Assuntos
Membrana Epirretiniana , Cirurgiões , Membrana Epirretiniana/diagnóstico por imagem , Humanos , Lasers , Oftalmoscopia , Acuidade Visual , VitrectomiaRESUMO
Purpose: Age-related scattered hypofluorescent spots on late-phase indocyanine green angiography (ASHS-LIA) might represent lipid accumulation in Bruch's membrane in the form of basal linear deposits (BlinD). The present study was conducted to describe the clinical characteristics of polypoidal choroidal vasculopathy (PCV) associated with ASHS-LIA. Methods: Consecutive patients with treatment-naïve PCV who underwent color fundus photography (FP), fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and spectral-domain optical coherence tomography (SD-OCT) at the Zhongshan Ophthalmic Center from June 2016 through May 2018, were reviewed. ASHS-LIA and choroidal vascular hyperpermeability (CVH) were evaluated by ICGA. Subfoveal choroidal thickness (SFCT) was assessed by SD-OCT. Results: A total of 187 patients were eligible for inclusion in this study (mean, 63.2 ± 7.6 years; range, 41-85 years). Of these patients, 117 (62.6%) showed ASHS-LIA, 57 (30.5%) had bilateral lesions and 70 (37.4%) showed CVH. Moreover, compared with patients without ASHS-LIA, PCV patients with ASHS-LIA were older (P = 0.001), more frequently had bilateral lesions (P = 0.001), and less frequently showed CVH (P = 0.006). SFCT in eyes with ASHS-LIA was significantly greater than that in eyes without ASHS-LIA after adjusting for age, sex, and CVH (P = 0.026). Nevertheless, there was no significant difference in best-corrected visual acuity or lesion characteristics between the two groups. Conclusions: ASHS-LIA, which is very common in PCV patients, might be involved in the pathogenesis of PCV. PCV with ASHS-LIA was more frequently associated with bilateral involvement, less CVH, and a thicker choroid than PCV without ASHS-LIA.
Assuntos
Neovascularização de Coroide/patologia , Angiofluoresceinografia/métodos , Vasos Retinianos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Corioide/patologia , Neovascularização de Coroide/diagnóstico por imagem , Feminino , Humanos , Verde de Indocianina/administração & dosagem , Macula Lutea/patologia , Masculino , Pessoa de Meia-Idade , Imagem Óptica/métodos , Vasos Retinianos/diagnóstico por imagem , Estudos Retrospectivos , Acuidade VisualRESUMO
PURPOSE: To correlate multimodal retinal imaging with high-resolution epoxy resin histologic analysis aligned to in vivo tomograms in a patient with exudative aneurysmal type 1 (AT1) neovascularization and hemorrhage secondary to age-related macular degeneration (AMD). DESIGN: Case study and clinicopathologic correlation. PARTICIPANT: An 84-year-old man of European descent with AT1 neovascularization secondary to AMD with a 6-year follow-up with combined antiangiogenic and photodynamic therapy. METHODS: Multimodal imaging from each clinic visit, including fluorescein angiography, indocyanine green angiography, and OCT, was correlated with ex vivo OCT and high-resolution histologic images of the donor eye, aligned to the en face images showing hemorrhage and exudation. MAIN OUTCOME MEASURES: Location of the branching vascular network and the aneurysmal vascular dilations in angiography, correlated with histologic findings. RESULTS: Clinically, a hemorrhagic detachment of the retinal pigment epithelium (RPE) in the macular area was associated with an AT1 neovascularization extending near the optic nerve head, where the choroid, which was thin overall, was extremely thin. Resolution of the hemorrhage accompanied by progressive macular atrophy and internal changes in the reflectivity of the RPE detachment were observed. Histologic analysis suggested a physical continuity from a hyalinized choroidal artery to a capillary bed (branching vascular network) in the sub-RPE-basal lamina (BL) space without visualization of aneurysmal dilations. CONCLUSIONS: Clinicopathologic correlation of AT1 neovascularization from an intact treated eye with dye-based angiographic and OCT scans supports the proposed nomenclature of AT1 neovascularization over polypoidal choroidal vasculopathy. We described continuity of the sub-RPE-BL branching vascular network with choroidal arteries and histologic correlates of common OCT signatures of neovascular AMD. The thinness of choroid in this patient of European descent contrasts with that reported for Asian populations, in which AT1 neovascularization is associated commonly with pachychoroid disease characteristics. This case reinforces the different manifestations of AT1 neovascularization across and within diverse ethnicities and diseases.
Assuntos
Neovascularização Patológica/patologia , Hemorragia Retiniana/patologia , Degeneração Macular Exsudativa/complicações , Idoso de 80 Anos ou mais , Humanos , Masculino , Epitélio Pigmentado da Retina/patologiaRESUMO
PURPOSE: To record the coexistence of polypoidal choroidal vasculopathy (PCV) with other rare fundus diseases in a Chinese population. METHOD: In this retrospective hospital-based study, a chart review of 861 patients with newly diagnosed PCV was performed. The clinical features of rare fundus comorbidities of PCV were recorded. RESULTS: Five eyes of 5 patients aged 63.4 ± 11.22 years (0.58%) had PCV coexisting with other fundus diseases in the same eye. Of the 5 PCV patients, 2 (0.23%) had myelinated nerve fiber, 2 (0.23%) had branch retinal vein occlusion, and 1 (0.12%) had retinal angiomatous proliferation. CONCLUSION: We reported rare fundus comorbidities of PCV in a large Chinese cohort. These comorbidities included myelinated nerve fiber, branch retinal vein occlusion and retinal angiomatous proliferation. The combination might constitute an accidental occurrence.
Assuntos
Doenças da Coroide/diagnóstico , Corioide/irrigação sanguínea , Degeneração Macular/epidemiologia , Fibras Nervosas Mielinizadas/patologia , Pólipos/diagnóstico , Oclusão da Veia Retiniana/epidemiologia , Acuidade Visual , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Doenças da Coroide/epidemiologia , Comorbidade , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Macula Lutea/patologia , Degeneração Macular/diagnóstico , Masculino , Pessoa de Meia-Idade , Oftalmoscopia , Pólipos/epidemiologia , Doenças Raras , Células Ganglionares da Retina/patologia , Oclusão da Veia Retiniana/diagnóstico , Estudos Retrospectivos , Tomografia de Coerência ÓpticaRESUMO
Drusen are lipid-, mineral-, and protein-containing extracellular deposits that accumulate between the basal lamina of the retinal pigment epithelium (RPE) and Bruch's membrane (BrM) of the human eye. They are a defining feature of age-related macular degeneration (AMD), a common sight-threatening disease of older adults. The appearance of heterogeneous internal reflectivity within drusen (HIRD) on optical coherence tomography (OCT) images has been suggested to indicate an increased risk of progression to advanced AMD. Here, in a cohort of patients with AMD and drusen, we show that HIRD indicated an increased risk of developing advanced AMD within 1 year. Using multimodal imaging in an independent cohort, we demonstrate that progression to AMD was associated with increasing degeneration of the RPE overlying HIRD. Morphological analysis of clinically imaged cadaveric human eye samples revealed that HIRD was formed by multilobular nodules. Nanoanalytical methods showed that nodules were composed of hydroxyapatite and that they differed from spherules and BrM plaques, other refractile features also found in the retinas of patients with AMD. These findings suggest that hydroxyapatite nodules may be indicators of progression to advanced AMD and that using multimodal clinical imaging to determine the composition of macular calcifications may help to direct therapeutic strategies and outcome measures in AMD.
Assuntos
Calcinose/complicações , Progressão da Doença , Degeneração Macular/complicações , Degeneração Macular/patologia , Drusas Retinianas/complicações , Idoso de 80 Anos ou mais , Lâmina Basilar da Corioide/patologia , Lâmina Basilar da Corioide/ultraestrutura , Calcinose/diagnóstico por imagem , Feminino , Atrofia Geográfica/complicações , Atrofia Geográfica/patologia , Humanos , Degeneração Macular/diagnóstico por imagem , Masculino , Imagem Multimodal , Drusas Retinianas/diagnóstico por imagem , Drusas Retinianas/patologia , Epitélio Pigmentado da Retina/patologia , Epitélio Pigmentado da Retina/ultraestruturaRESUMO
Differentiation of atrial fibroblasts into myofibroblasts plays a critical role in atrial fibrosis. Sodium tanshinone IIA sulfonate (DS-201), a water-soluble derivative of tanshinone IIA, has been shown to have potent antifibrotic properties. However, the protective effects of DS-201 on angiotensin II- (Ang II-) induced differentiation of atrial fibroblasts into myofibroblasts remain to be elucidated. In this study, human atrial fibroblasts were stimulated with Ang II in the presence or absence of DS-201. Then, α-smooth muscle actin (α-SMA), collagen I, and collagen III expression and reactive oxygen species (ROS) generation were measured. The expression of transforming growth factor-ß1 (TGF-ß1) and the downstream signaling of TGF-ß1, such as phosphorylation of Smad2/3, were also determined. The results demonstrated that DS-201 significantly prevented Ang II-induced human atrial fibroblast migration and decreased Ang II-induced α-SMA, collagen I, and collagen III expression. Furthermore, increased production of ROS and expression of TGF-ß1 stimulated by Ang II were also significantly inhibited by DS-201. Consistent with these results, DS-201 significantly inhibited Ang II-evoked Smad2/3 phosphorylation and periostin expression. These results and the experiments involving N-acetyl cysteine (antioxidant) and an anti-TGF-ß1 antibody suggest that DS-201 prevent Ang II-induced differentiation of atrial fibroblasts to myofibroblasts, at least in part, through suppressing oxidative stress and inhibiting the activation of TGF-ß1 signaling pathway. All of these data indicate the potential utility of DS-201 for the treatment of cardiac fibrosis.
Assuntos
Angiotensina II/metabolismo , Fibrilação Atrial/fisiopatologia , Miofibroblastos/metabolismo , Fenantrenos/metabolismo , Diferenciação Celular , Fibroblastos , Humanos , Transdução de SinaisRESUMO
BACKGROUND Increased small-conductance Ca2+-activated K+ current (SK), abnormal intracellular Ca2+ handling, and enhanced expression and activity of Ca2+/calmodulin-dependent protein kinase II (CaMKII) have been found in clinical and/or experimental models of atrial fibrillation (AF), but the cumulative effect of these phenomena and their mechanisms in AF are still unclear. This study aimed to test the hypothesis that CaMKII increases SK current in human chronic AF. MATERIAL AND METHODS Right atrial appendage tissues from patients with either sinus rhythm (SR) or AF and neonatal rat atrial myocytes were used. Patch clamp, qRT-PCR, and Western blotting techniques were used to perform the study. RESULTS Compared to SR, the apamin-sensitive SK current (IKAS) was significantly increased, but the mRNA and protein levels of SK1, SK2, and SK3 were significantly decreased. In AF, the steady-state Ca2+ response curve of [i]IKAS[/i] was shifted leftward and the [Ca2+]i level was significantly increased. CaMKII inhibitors (KN-93 or autocamtide-2-related inhibitory peptide (AIP)) reduced the IKAS in both AF and SR. The inhibitory effect of KN-93 or AIP on [i]IKAS[/i] was greater in AF than in SR. The expression levels of calmodulin, CaMKII, and autophosphorylated CaMKII at Thr287 (but not at Thr286) were significantly increased in AF. Furthermore, KN-93 inhibited the expression of (Thr287)p-CaMKII and SK2 in neonatal rat atrial myocytes. CONCLUSIONS SK current is increased via the enhanced activation of CaMKII in patients with AF. This finding may explain the difference between SK current and channels expression in AF, and thus may provide a therapeutic target for AF.