Effect of vascular endothelial growth factor 165 on dopamine level in the retinas of guinea pigs with form-deprivation myopia.

Background: Myopia is the most common refractive error because excessive increase in the axial length of a myopic eye leads to the thinning of the posterior scleral pole and can cause serious complications resulting in blindness. Thus, myopia has become a great concern worldwide. Dopamine (DA) plays a role in the development of myopia. Moreover, in Parkinson's disease, it has been proved that vascular endothelial growth factor 165 (VEGF165) can promote the survival and recovery of DA neurons, resulting in increased DA secretion in the striatum, thereby treating neuropathy. Therefore, we speculate that VEGF165 can also promote the release of DA in the retina to inhibit the occurrence and development of myopia. We aimed to investigate the effect of VEGF165 on DA levels in the retinas of guinea pigs with form-deprivation myopia (FDM) and the effects of DA on myopia prevention and control. Methods: Healthy 3-week-old pigmented guinea pigs were randomly divided into blank, FDM, phosphate buffer saline (PBS), 1, 5, and 10 ng groups. The FDM model was established by covering the right eye continuously with a translucent latex balloon pullover for 14 days. The pigs in the PBS, 1, 5, and 10 ng groups were injected with PBS buffer and 1, 5, and 10 ng of VEGF165 recombinant human protein, respectively, in the vitreous of the right eye before masking. The refractive error and axial length were measured before and after modeling. All retinas were used for biomolecular analyses after 14 days. Results: We found that the intravitreal injection of VEGF165 elevated DA levels in the retina and was effective in slowing the progression of myopia, and 1 ng of VEGF165 was the most effective. Moreover, the number of vascular endothelial cell nuclei in the 1 ng group was lower than that in the other VEGF165 groups. Conclusions: Our data suggest that VEGF165 has a promoting effect on DA in the retinas of guinea pigs with FDM, potentially controlling the development of myopia.

Improved Retinal Microcirculation After Cardiac Surgery in Patients With Congenital Heart Disease.

Background: Microcirculatory changes in congenital heart disease (CHD) patients undergoing cardiac surgery are not fully understood. We aimed to investigate the changes of retinal microcirculation in CHD patients after cardiac surgery by optical coherence tomography angiography (OCTA) and explore the association between retinal microcirculation and surgical outcome. Methods: This prospective observational study consisted of 71 CHD patients aged ≥6 years undergoing cardiac surgery including 19 cyanotic CHD (CCHD) and 52 acyanotic CHD (ACHD). Optical coherence tomography angiography (OCTA) was used to measure vessel density (VD) and capillary density (CD) of radial peripapillary capillary (RPC) and peripapillary, VD of superficial capillary plexus (SCP) and deep capillary plexus (DCP), thickness of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) preoperatively and 1 month postoperatively. Transthoracic echocardiography was conducted to measure macrocirculation. Results: In CCHD patients, VD and CD of RPC and peripapillary increased postoperatively (all P < 0.05). In ACHD patients, VD of peripapillary, CD of RPC and peripapillary, and RNFL thickness increased postoperatively (all P < 0.05). VD of SCP and DCP, and GCC thickness did not change significantly in CHD patients after surgery. Lower preoperative retinal microvascular density was associated with longer cardiopulmonary bypass (CPB) time and postoperative length of stay (PLOS). No correlation was found between microcirculatory and macrohemodynamic parameters (all P > 0.05). Conclusions: Improved retinal microcirculation was observed after congenital cardiac surgery and impaired preoperative retinal microvasculature was associated with prolonged CPB time and PLOS, which might provide potential information about the outcome of congenital cardiac surgery.

Epigenetic inhibition assisted chemotherapeutic treatment of lung cancer based on artificial exosomes.

We adopted a novel strategy by combining histone deacetylase (HDAC) inhibitors with traditional chemotherapeutics to treat solid tumors. However, chemotherapeutics often have a narrow therapeutic index and need multiple administrations with undesired side effects that lead to the intolerance. To reduce the non-specificity of chemotherapeutics, targeted therapy was introduced to restrict such agents in the tumor with minimum effects on other tissues. We developed bioinspired artificial exosomes (AE), which enabled to deliver chemotherapeutics to the tumors effectively after systemic administration. AE were produced by incorporating membrane proteins from cancer cells into phospholipid liposomes that mimicked the plasma membrane. The synthesized AE were used for the delivery of broad-spectrum chemotherapeutic doxorubicin (DOX) and vorinostat (SAHA), an epigenetic inhibitor. The combination of DOX and SAHA showed synergistic effects on suppressing non-small cell lung cancer cells and xenograft tumors without apparent adverse effects. AE facilitated the delivery of drugs to tumor tissue and extended the retention time of drugs within tumors. Taken together, these studies suggest that the bioengineered artificial exosomes may serve as novel delivery strategy for chemotherapeutics to treat non-small cell lung cancer.

Hybrid artificial cell-mediated epigenetic inhibition in metastatic lung cancer.

HYPOTHESIS: Histone deacetylase inhibitors (HDACIs), such as vorinostat (suberoylanilide hydroxamic acid, SAHA), has become a promising approach for the treatment of metastatic lung cancer. However, HDACIs usually showed a short circulation lifetime, low specificity, and low bioavailability, which limited their therapeutic effect in this field. We supposed that the use of biomimetic nanoparticles enabled to overcome the disadvantages of HDACIs, and improved the inhibition of metastatic lung cancer. EXPERIMENTS: SAHA was encapsulated into a pH-sensitive core constructed with Poly(lactic-co-glycolic acid) (PLAG) and 1,2-dioleoyloxy-3-(trimethylammonium) propane (DOTAP), followed by the camouflage with hybrid membranes derived from red blood cells and metastatic NCI-H1299 lung cancer cells (HRPDS). The physical and chemical properties were characterized with Transmission electron microscope (TEM), Size & Zeta potential analyzer. The cellular uptake was analyzed with Confocal laser scanning microscope (CLSM) and Flow cytometry (FACS). The biological effect analysis was performed with Western blotting (WB), RNA-Sequencing (RNA-Seq), and ChIP-Sequencing (ChIP-Seq). FINDINGS: HRPDS exhibited enhanced circulation lifetime in vivo and homotypic targeting to metastatic cells in the metastatic foci, which induced significant suppression of lung cancer liver metastasis. Our work opens a new avenue for the treatment of metastatic lung cancer by epigenetic inhibition based on this style of biomimetic nanovehicle.

DETECTION OF MORPHOLOGIC PATTERNS OF DIABETIC MACULAR EDEMA USING A DEEP LEARNING APPROACH BASED ON OPTICAL COHERENCE TOMOGRAPHY IMAGES.

PURPOSE: To develop a deep learning (DL) model to detect morphologic patterns of diabetic macular edema (DME) based on optical coherence tomography (OCT) images. METHODS: In the training set, 12,365 OCT images were extracted from a public data set and an ophthalmic center. A total of 656 OCT images were extracted from another ophthalmic center for external validation. The presence or absence of three OCT patterns of DME, including diffused retinal thickening, cystoid macular edema, and serous retinal detachment, was labeled with 1 or 0, respectively. A DL model was trained to detect three OCT patterns of DME. The occlusion test was applied for the visualization of the DL model. RESULTS: Applying 5-fold cross-validation method in internal validation, the area under the receiver operating characteristic curve for the detection of three OCT patterns (i.e., diffused retinal thickening, cystoid macular edema, and serous retinal detachment) was 0.971, 0.974, and 0.994, respectively, with an accuracy of 93.0%, 95.1%, and 98.8%, respectively, a sensitivity of 93.5%, 94.5%, and 96.7%, respectively, and a specificity of 92.3%, 95.6%, and 99.3%, respectively. In external validation, the area under the receiver operating characteristic curve was 0.970, 0.997, and 0.997, respectively, with an accuracy of 90.2%, 95.4%, and 95.9%, respectively, a sensitivity of 80.1%, 93.4%, and 94.9%, respectively, and a specificity of 97.6%, 97.2%, and 96.5%, respectively. The occlusion test showed that the DL model could successfully identify the pathologic regions most critical for detection. CONCLUSION: Our DL model demonstrated high accuracy and transparency in the detection of OCT patterns of DME. These results emphasized the potential of artificial intelligence in assisting clinical decision-making processes in patients with DME.

High-Performance Dual Combination Therapy for Cancer Treatment with Hybrid Membrane-Camouflaged Mesoporous Silica Gold Nanorods.

Conventional chemotherapy usually induces significant side effects due to its inability to discriminate between cancer and normal cells. Moreover, the efficacy of cancer elimination is still unsatisfied. Here, we fabricated a nanocomposite enabling high-performance dual combination therapy (chemo/photothermal therapy). This style of novel nanocomposites was constructed with doxorubicin (DOX)-loaded mesoporous silica gold (MSG) nanorods, which were further camouflaged with hybrid membranes derived from HeLa cells and red blood cells (HRMSGD). The hybrid membrane-camouflaged structure showed enhanced circulation lifetime and cell line-specific delivery of chemotherapeutics both in vitro and in vivo. The dual combination therapy by HRMSGD showed an unattainable therapeutic effect, compared with a single treatment, and inhibited tumor growth significantly. Furthermore, the nanoplatforms were photoacoustic-responsive, which showed real-time and noninvasive tracking capability. The present study established nanoplatforms with hybrid cell membrane-camouflaged multifunctional gold nanorods, which realized the combination of homotypic targeting, noninvasive tracking, chemotherapy, and photothermal therapy. To the best of our knowledge, this is the first study to use a natural membrane to camouflage mesoporous silica-modified gold nanorods, which opened a new avenue for cancer treatment.

Restoration of Foveal Bulge after Resolution of Diabetic Macular Edema with Coexisting Serous Retinal Detachment.

PURPOSE: To evaluate the impact of restoration of foveal bulge (FB) in optical coherence tomography (OCT) images on visual acuity after resolution of diabetic macular edema with coexisting serous retinal detachment (SRD-DME). METHODS: A total of 52 eyes with resolved SRD-DME and an intact ellipsoid zone at the central fovea were included. All eyes underwent best-corrected visual acuity (BCVA) examination and OCT scanning at baseline and follow-up visits (1, 3, and 6 months). The eyes were divided into two groups according to the presence of FB at 6 months. BCVA, central foveal thickness (CFT), height of SRD (SRDH), outer nuclear layer (ONL) thickness, photoreceptor inner segment (PIS), and outer segment (POS) length were compared between the two groups. RESULTS: A FB was found in 25 of 52 (48%) eyes at 6 months. The FB (+) group had lower SRDH at baseline, and better BCVA, longer POS length at 6 months (all P < 0.05). There was no significant difference in the CFT, ONL thickness, and PIS length at 6 months between the two groups (all P > 0.05). More eyes in the FB (+) group had complete SRD resolution at 1 month (P = 0.009) and 3 months (P = 0.012). Eyes with complete SRD resolution at 1 month (P = 0.009) or 3 months (P = 0.012) were more likely to have a FB at 6 months. CONCLUSIONS: The Presence of the FB is associated with better BCVA after resolution of SRD-DME. Eyes with lower baseline SRDH or faster SRD resolution are more likely to have a FB at 6 months.

Homotypic Targeting Delivery of siRNA with Artificial Cancer Cells.

The camouflage with cell membrane bestows nanoparticles with cell-like functions, such as specific recognition, long blood circulation, and immune escaping. For cancer therapy, the nanoparticles camouflaged with cancer cell membrane (CCM) from homologous cells show homotypic targeting delivery of small molecule compounds, photosensitizers, or enzymes to the tumors. However, effective gene therapy encounters difficulties by this approach due to the properties of nucleic acids. Herein, a cancer cell-like gene delivery system is developed using an excellent polymer poly(ß-amino ester) (PBAE) to condense small interfering RNA (siRNA) (targeting to Plk1 gene) into nanoparticles (PBAE/siPlk1) as the core, which is further camouflaged with CCM. These novel biomimetic nanoparticles CCM/PBAE/siPlk1 (CCMPP) demonstrate highly specific targeting to homotypic cancer cells, effective downregulation of PLK1 level, and inducing apoptosis of cancer cells. Based on the homotypic binding adhesion molecules on the CCM, the cellular internalization and homotypic-targeting accumulation to the tumors are clearly improved. CCMPP induces highly efficient apoptosis of cancer cells both in vitro and in vivo and results in significant tumor inhibition. The artificial cancer cells with homotypic properties can serve as a biomimetic delivery system for cancer-targeted gene therapy.

A Meta-Analysis of Cardiovascular Events Associated with Intravitreal Anti-VEGF Treatment in Patients with Retinal Vein Occlusion.

Purpose: Retinal vein occlusion is associated with an increased risk of cardiovascular diseases. Anti-vascular endothelial growth factor has been widely used as a treatment option. However, the systemic safety of intravitreal anti-vascular endothelial growth factor for retinal vein occlusion patients is still unclear.Materials and Methods: A meta-analysis was conducted to investigate all randomized controlled trials published up to February 2019 of retinal vein occlusion patients who received intravitreal anti-vascular endothelial growth factor vs. control treatments. Fixed effect models were used and results were reported as odds ratios and 95% confidence intervals.Results: Eight trials that evaluated 2320 patients were retrieved. Anti-vascular endothelial growth factor did not significantly increase the risks of cardiovascular events (odds ratio,1.54; 95% confidence interval, 0.66-3.57), hypertension (odds ratio, 0.92; 95% confidence interval, 0.63-1.33), or heart rate disorders (odds ratio,1.53; 95% confidence interval, 0.37-6.28) when compared with control treatment. Subgroup analyses did not show a significant increase of cardiovascular events in aflibercept (odds ratio,1.96; 95% confidence interval, 0.44-8.81) vs. ranibizumab trials (odds ratio, 1.47; 95% confidence interval, 0.54-4.02); 0.5 mg ranibizumab trials (odds ratio, 1.73; 95% confidence interval, 0.61-4.96) vs. 0.3 mg ranibizumab trials (odds ratio, 0.70; 95% confidence interval, 0.14-3.59); nor branch retinal vein occlusion (odds ratio, 1.32; 95% confidence interval, 0.40-4.33) vs. central retinal vein occlusion trials (odds ratio, 1.93; 95% confidence interval, 0.59-6.29).Conclusions: Intravitreal administration of anti-vascular endothelial growth factor did not significantly increase the risks of cardiovascular events, hypertension or heart rate disorders in retinal vein occlusion patients.