A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization.

Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

HIV-1 gp120 amplifies astrocyte elevated gene-1 activity to compromise the integrity of the outer blood-retinal barrier.

OBJECTIVE: This study aims to investigate the functions and mechanistic pathways of Astrocyte Elevated Gene-1 (AEG-1) in the disruption of the blood-retinal barrier (BRB) caused by the HIV-1 envelope glycoprotein gp120. DESIGN: We utilized ARPE-19 cells challenged with gp120 as our model system. METHODS: Several analytical techniques were employed to decipher the intricate interactions at play. These included PCR, Western blot, and immunofluorescence assays for the molecular characterization, and transendothelial electrical resistance (TEER) measurements to evaluate barrier integrity. RESULTS: We observed that AEG-1 expression was elevated, whereas the expression levels of tight junction proteins ZO-1, Occludin, and Claudin5 were downregulated in gp120-challenged cells. TEER measurements corroborated these findings, indicating barrier dysfunction. Additional mechanistic studies revealed that the activation of NFκB and MMP2/9 pathways mediated the AEG-1-induced barrier destabilization. Through the use of lentiviral vectors, we engineered cell lines with modulated AEG-1 expression levels. Silencing AEG-1 alleviated gp120-induced downregulation of tight junction proteins and barrier impairment while concurrently inhibiting the NFκB and MMP2/9 pathways. Conversely, overexpression of AEG-1 exacerbated these pathological changes, further compromising the integrity of the BRB. CONCLUSION: Gp120 upregulates the expression of AEG-1 and activates the NFκB and MMP2/9 pathways. This in turn leads to the downregulation of tight junction proteins, resulting in the disruption of barrier function.

Evaluation of retinal and choroidal thickness changes in overweight and obese adults without ocular symptoms by swept-source optical coherence tomography.

AIM: To evaluate the relationship of overweight and obesity with retinal and choroidal thickness in adults without ocular symptoms by swept-source optical coherence tomography (SS-OCT). METHODS: According to the body mass index (BMI) results, the adults enrolled in the cross-sectional study were divided into the normal group (18.50≤BMI<25.00 kg/m2), the overweight group (25.00≤BMI<30.00 kg/m2), and the obesity group (BMI≥30.00 kg/m2). The one-way ANOVA and the Chi-square test were used for comparisons. Pearson's correlation analysis was used to evaluate the relationships between the measured variables. RESULTS: This research covered the left eyes of 3 groups of 434 age- and sex-matched subjects each: normal, overweight, and obesity. The mean BMI was 22.20±1.67, 26.82±1.38, and 32.21±2.35 kg/m2 in normal, overweight and obesity groups, respectively. The choroid was significantly thinner in both the overweight and obesity groups compared to the normal group (P<0.05 for all), while the retinal thickness of the three groups did not differ significantly. Pearson's correlation analysis showed that BMI was significantly negatively correlated with choroidal thickness, but no significant correlation was observed between BMI and retinal thickness. CONCLUSION: Choroidal thickness is decreased in people with overweight or obesity. Research on changes in choroidal thickness contributes to the understanding of the mechanisms of certain ocular disorders in overweight and obese adults.

Prediction Model of Ocular Metastases in Gastric Adenocarcinoma: Machine Learning-Based Development and Interpretation Study.

Background: Although gastric adenocarcinoma (GA) related ocular metastasis (OM) is rare, its occurrence indicates a more severe disease. We aimed to utilize machine learning (ML) to analyze the risk factors of GA-related OM and predict its risks. Methods: This is a retrospective cohort study. The clinical data of 3532 GA patients were collected and randomly classified into training and validation sets in a ratio of 7:3. Those with or without OM were classified into OM and non-OM (NOM) groups. Univariate and multivariate logistic regression analyses and least absolute shrinkage and selection operator were conducted. We integrated the variables identified through feature importance ranking and further refined the selection process using forward sequential feature selection based on random forest (RF) algorithm before incorporating them into the ML model. We applied six ML algorithms to construct the predictive GA model. The area under the receiver operating characteristic (ROC) curve indicated the model's predictive ability. Also, we established a network risk calculator based on the best performance model. We used Shapley additive interpretation (SHAP) to identify risk factors and to confirm the interpretability of the black box model. We have de-identified all patient details. Results: The ML model, consisting of 13 variables, achieved an optimal predictive performance using the gradient boosting machine (GBM) model, with an impressive area under the curve (AUC) of 0.997 in the test set. Utilizing the SHAP method, we identified crucial factors for OM in GA patients, including LDL, CA724, CEA, AFP, CA125, Hb, CA153, and Ca2+. Additionally, we validated the model's reliability through an analysis of two patient cases and developed a functional online web prediction calculator based on the GBM model. Conclusion: We used the ML method to establish a risk prediction model for GA-related OM and showed that GBM performed best among the six ML models. The model may identify patients with GA-related OM to provide early and timely treatment.

Modified technique for reconstruction of large cyclodialysis cleft with capsular tension ring and continuous and cerclage sutures without scleral flaps.

To present a modified technique for the reconstruction of a large cyclodialysis cleft with capsular tension ring (CTR) and continuous and cerclage sutures without scleral flaps in 12 cases. The mean visual acuity was 0.75 ± 0.47 logarithm of the minimal angle of resolution (logMAR), and the average intraocular pressure (IOP) was 3.35 ± 0.41 mmHg before surgery. Ultrasound biomicroscopy (UBM) revealed a ciliary cleft of 4.3 ± 3.5 clock hours. We performed the modified technique for the reconstruction of a large cyclodialysis cleft. Postoperative visual acuity improved to 0.48 ± 0.26 logMAR, and the IOP improved to 15.88 ± 3.81 mmHg. Postoperative UBM showed that cyclodialysis disappeared in the whole circumference of 12 eyes. The postoperative complications included 42% (5 eyes) with a temporary elevation of IOP and 16% (2 eyes) with a posterior shift of the ciliary body. No other complications were detected during the follow-up. Based on the results, our modified technique might be useful for most cyclodialysis clefts.

Determining Gender-Based Differences in Retinal and Choroidal Thickness in Underweight Individuals via Swept-Source Optical Coherence Tomography.

Despite improvements in reducing hunger in recent years, undernutrition remains a global public health problem. This study utilizes the swept-source optical coherence tomography (SS-OCT) technique to assess changes in retinal and choroidal thickness in underweight subjects. Ophthalmic examinations were conducted on all adults participating in this cross-sectional research. Depending on their body mass index (BMI), the participants were divided into two groups: the underweight group and the normal group. The study included the right eyes of the underweight adults and an equal number of age- and gender-matched normal-weight subjects. The retinal thickness showed no significant difference between the underweight and normal groups (P > 0.05 for all). In males, the retina of the center and inner ring in the underweight group was significantly thinner than that in the normal group, while no such results were found in females. The choroid in the underweight group was significantly thinner compared to that in the normal group (all P < 0.05). Being underweight may affect choroidal thickness in both males and females. In comparison with underweight females, underweight males may experience more retinal damage. These findings contribute to a better understanding of the pathogenesis underlying specific ocular diseases in malnourished individuals.

Retinal thickness and fundus blood flow density changes in chest pain subjects with dyslipidemia.

AIM: To assess the retinal thickness and fundus blood flow density changes in chest pain patients with dyslipidemia using optical coherence tomography angiography (OCTA). METHODS: All subjects with chest pain as the main symptom accepted a comprehensive ophthalmological examination. According to the serum lipid levels, the participants were divided into the control group and the dyslipidemia group. The retina thickness and fundus blood flow density were determined using OCTA. RESULTS: The study enrolled 87 left eyes from 87 adults with dyslipidemia and 87 left eyes from age- and sex-matched participants without dyslipidemia. The retina of dyslipidemia subjects was significantly thinner than that of the controls in the inferior (P=0.004 and P=0.014, respectively) and temporal (P=0.015 and P=0.019, respectively) regions, both inner and outer layers. In terms of blood flow density in the macula or optic disk, there was a decreasing trend in the dyslipidemia group compared with the control group, especially in the inferior and temporal regions. CONCLUSION: Dyslipidemia may contribute to the decrease in retinal thickness and fundus blood flow density. Further validation of the association between abnormal lipid metabolism and fundus microcirculation alterations needs to be carried out in chest pain patients.

Idiopathic Epiretinal Membrane Surgery in Patients Aged Over 80 Years: Efficacy and Safety.

Purpose: To evaluate the efficacy and safety of idiopathic epiretinal membrane (ERM) surgery in patients aged over 80 years. Methods: Consecutive patients who underwent pars plana vitrectomy (PPV) combined with ERM and internal limiting membrane (ILM) peeling with retrobulbar anesthesia were recruited. Based on age, the patients were divided into the elderly group (≥ 80 years of age) and the control group (< 80 years of age). The best-corrected visual acuity (BCVA) and surgical complications were regarded as the main measurement indicators. Results: This study included 43 eyes from 43 patients aged 80 to 91 years and 86 eyes from 86 patients aged 54 to 79 years. Surgical intervention substantially improved BCVA both in the elderly and control groups (p = 0.005 and p < 0.001, respectively). Statistical analyses showed no significant difference in the incidence of surgical complications between the two groups (p = 0.631). The operations in either group were not delayed or canceled for the reason of complications of retrobulbar anesthesia, severe anxiety, or physical discomfort in the perioperative period. Moreover, no patient required a second operation. Also, no stroke, myocardial infarction, or death occurred during the follow-up period. All the surgical complications were treated satisfactorily. Conclusion: Our outcomes indicate that PPV combined with ERM and ILM peeling with retrobulbar anesthesia is effective and safe in elderly patients aged 80 years or older. Based on age alone, we believe that advancing age should not be the risk factor for idiopathic ERM surgery.

Prediction model of ocular metastasis from primary liver cancer: Machine learning-based development and interpretation study.

BACKGROUND: Ocular metastasis (OM) is a rare metastatic site of primary liver cancer (PLC). The purpose of this study was to establish a clinical predictive model of OM in PLC patients based on machine learning (ML). METHODS: We retrospectively collected the clinical data of 1540 PLC patients and divided it into a training set and an internal test set in a 7:3 proportion. PLC patients were divided into OM and non-ocular metastasis (NOM) groups, and univariate logistic regression analysis was performed between the two groups. The variables with univariate logistic analysis p < 0.05 were selected for the ML model. We constructed six ML models, which were internally verified by 10-fold cross-validation. The prediction performance of each ML model was evaluated by receiver operating characteristic curves (ROCs). We also constructed a web calculator based on the optimal performance ML model to personalize the risk probability for OM. RESULTS: Six variables were selected for the ML model. The extreme gradient boost (XGB) ML model achieved the optimal differential diagnosis ability, with an area under the curve (AUC) = 0.993, accuracy = 0.992, sensitivity = 0.998, and specificity = 0.984. Based on these results, an online web calculator was constructed by using the XGB ML model to help clinicians diagnose and treat the risk probability of OM in PLC patients. Finally, the Shapley additive explanations (SHAP) library was used to obtain the six most important risk factors for OM in PLC patients: CA125, ALP, AFP, TG, CA199, and CEA. CONCLUSION: We used the XGB model to establish a risk prediction model of OM in PLC patients. The predictive model can help identify PLC patients with a high risk of OM, provide early and personalized diagnosis and treatment, reduce the poor prognosis of OM patients, and improve the quality of life of PLC patients.

Retinal alterations in evaluation of rheumatoid arthritis with chloroquine treatment: A new approach.

OBJECTIVE: To evaluate the effect of hydroxychloroquine on conjunctival and retinal microvascular density in rheumatoid arthritis (RA) patients. METHODS: Ten healthy controls, 10 RA patients who had not been treated with hydroxychloroquine, and 10 RA patients who had been treated with chloroquine for more than 5 years were recruited. Optical coherence tomography (OCTA) was used to examine the conjunctival and superficial and deep retinal microvascular density and compared the differences in microvascular density between the three groups. RESULTS: The vascular density in RA group in superficial microvascular was significantly lower than that in control group (p < 0.001). Compared with RA group, the chloroquine group showed statistically significantly lower microvascular (p < 0.001) and deep microvascular (p = 0.018). Superficial microvascular was positively correlated with conjunctival vessel density in RA patients (r = 0.868, p = 0.0048). CONCLUSIONS: The use of chloroquine could further reduce the vascular density in the absence of statistical difference in the course of the disease.

Nigericin Boosts Anti-Tumor Immune Response via Inducing Pyroptosis in Triple-Negative Breast Cancer.

Although immune checkpoint inhibitors improved the clinical outcomes of advanced triple negative breast cancer (TBNC) patients, the response rate remains relatively low. Nigericin is an antibiotic derived from Streptomyces hydrophobicus. We found that nigericin caused cell death in TNBC cell lines MDA-MB-231 and 4T1 by inducing concurrent pyroptosis and apoptosis. As nigericin facilitated cellular potassium efflux, we discovered that it caused mitochondrial dysfunction, leading to mitochondrial ROS production, as well as activation of Caspase-1/GSDMD-mediated pyroptosis and Caspase-3-mediated apoptosis in TNBC cells. Notably, nigericin-induced pyroptosis could amplify the anti-tumor immune response by enhancing the infiltration and anti-tumor effect of CD4+ and CD8+ T cells. Moreover, nigericin showed a synergistic therapeutic effect when combined with anti-PD-1 antibody in TNBC treatment. Our study reveals that nigericin may be a promising anti-tumor agent, especially in combination with immune checkpoint inhibitors for advanced TNBC treatment.

MLN4924 Promotes Self-Renewal of Limbal Stem Cells and Ocular Surface Restoration.

OBJECTIVE: To study the role of MLN4924 in corneal stem cell maintenance and corneal injury repair. METHODS: In cell experiments, the Sprague-Dawley (SD) rat corneal epithelial cells were co-cultured with mitomycin C-inactivated mouse feeder cells in a supplemental hormonal epithelial medium (SHEM) with or without MLN4924. Cells were photographed using an optical microscope. Furthermore, we performed crystal violet, polymerase chain reaction (PCR), and immunofluorescence staining on limbal stem cells (LSCs). In animal experiments, we scraped the corneal epithelium with a central corneal diameter of 4 mm in SD rats. The area of the corneal epithelial defect was calculated by fluorescein sodium staining. RESULTS: LSCs in the MLN4924 group had significantly proliferated. The MLN4924 treatment evidently enhanced the clone formation rate and clone area of LSCs. The expression levels of Ki67, p63, ABCG2, Bmi1, and C/EBPδ increased in LSCs after MLN4924 treatment, whereas the expression of K12 decreased. At 12 and 24 h after scraping, the corneal epithelium recovery rate in the eyes of the MLN4924-treated rats was accelerated. CONCLUSIONS: MLN4924 can maintain stemness, reduce differentiation, promote the proliferative capacity of rat LSCs, and accelerate corneal epithelial wound healing in SD rats.

Deep learning magnetic resonance imaging predicts platinum sensitivity in patients with epithelial ovarian cancer.

Objective: The aim of the study is to develop and validate a deep learning model to predict the platinum sensitivity of patients with epithelial ovarian cancer (EOC) based on contrast-enhanced magnetic resonance imaging (MRI). Methods: In this retrospective study, 93 patients with EOC who received platinum-based chemotherapy (≥4 cycles) and debulking surgery at the Sun Yat-sen Memorial Hospital from January 2011 to January 2020 were enrolled and randomly assigned to the training and validation cohorts (2:1). Two different models were built based on either the primary tumor or whole volume of the abdomen as the volume of interest (VOI) within the same cohorts, and then a pre-trained convolutional neural network Med3D (Resnet 10 version) was transferred to automatically extract 1,024 features from two MRI sequences (CE-T1WI and T2WI) of each patient to predict platinum sensitivity. The performance of the two models was compared. Results: A total of 93 women (mean age, 50.5 years ± 10.5 [standard deviation]) were evaluated (62 in the training cohort and 31 in the validation cohort). The AUCs of the whole abdomen model were 0.97 and 0.98 for the training and validation cohorts, respectively, which was better than the primary tumor model (AUCs of 0.88 and 0.81 in the training and validation cohorts, respectively). In k-fold cross-validation and stratified analysis, the whole abdomen model maintained a stable performance, and the decision function value generated by the model was a prognostic indicator that successfully discriminates high- and low-risk recurrence patients. Conclusion: The non-manually segmented whole-abdomen deep learning model based on MRI exhibited satisfactory predictive performance for platinum sensitivity and may assist gynecologists in making optimal treatment decisions.

Choroidal and retinal thickness in patients with vitamin C deficiency using swept-source optical coherence tomography.

BACKGROUND: To investigate the effects of vitamin C on central retinal thickness and choroidal thickness. METHODS: A total of 69 patients diagnosed with vitamin C deficiency and 1:1 age- and gender-matched 69 healthy individuals with normal serum vitamin C were included in this study. Demographic characteristics of the individuals were collected. All patients underwent a comprehensive ophthalmic examination. Subfoveal choroidal thickness and retinal thickness were measured using a swept-source optical coherence tomography (SS-OCT). RESULTS: The average retinal thickness was 269.07 ± 13.51 µm in the vitamin C deficiency group and 276.92 ± 13.51 µm in the control group. The average choroidal thickness was 195.62 ± 66.40 µm in the in the vitamin C deficiency group and 238.86 ± 55.08 µm in the control group. There was a significant decrease in both average choroidal thickness and retinal thickness in vitamin C deficiency group compared with normal individuals (p < 0.001, and = 0.001 respectively). CONCLUSION: The central retinal and choroidal thickness were thinner in vitamin C deficiency group compared with normal individuals. These findings suggested that vitamin C deficiency might play an important role in retinal and choroidal diseases.

LncRNA Uc003xsl.1-Mediated Activation of the NFκB/IL8 Axis Promotes Progression of Triple-Negative Breast Cancer.

Aberrant activation of NFκB orchestrates a critical role in tumor carcinogenesis; however, the regulatory mechanisms underlying this activation are not fully understood. Here we report that a novel long noncoding RNA (lncRNA) Uc003xsl.1 is highly expressed in triple-negative breast cancer (TNBC) and correlates with poor outcomes in patients with TNBC. Uc003xsl.1 directly bound nuclear transcriptional factor NFκB-repressing factor (NKRF), subsequently preventing NKRF from binding to a specific negative regulatory element in the promoter of the NFκB-responsive gene IL8 and abolishing the negative regulation of NKRF on NFκB-mediated transcription of IL8. Activation of the NFκB/IL8 axis promoted the progression of TNBC. Trop2-based antibody-drug conjugates have been applied in clinical trials in TNBC. In this study, a Trop2-targeting, redox-responsive nanoparticle was developed to systematically deliver Uc003xsl.1 siRNA to TNBC cells in vivo, which reduced Uc003xsl.1 expression and suppressed TNBC tumor growth and metastasis. Therefore, targeting Uc003xsl.1 to suppress the NFκB/IL8 axis represents a promising therapeutic strategy for TNBC treatment. SIGNIFICANCE: These findings identify an epigenetic-driven NFκB/IL8 cascade initiated by a lncRNA, whose aberrant activation contributes to tumor metastasis and poor survival in patients with triple-negative breast cancer.

Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye.

Dry eye is a common ocular disease that results in discomfort and impaired vision, impacting an individual's quality of life. A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface, which limits their therapeutic effects. Therefore, it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular surface. Herein, we develop a copolymer from mono-functional POSS, PEG, and PPG (MPOSS-PEG-PPG, MPEP) that exhibits temperature-sensitive sol-gel transition behavior. This thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive, long-acting ocular delivery system. In addition, the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular surface. In comparison with other FK506 formulations and the PEG-PPG-FK506 (F127-FK506) hydrogel, this novel MPOSS-PEG-PPG-FK506 (MPEP-FK506) hydrogel is a more effective treatment of dry eye in the murine dry eye model. Therefore, delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface, which will improve its therapeutic efficacy in the management of dry eye.

Choroidal Thickness in Relation to Bone Mineral Density with Swept-Source Optical Coherence Tomography.

PURPOSE: To assess whether bone mineral density, indicated by the lumbar X-ray scan, is related to changes in choroid thickness in normal subjects. METHODS: This study included 355 patients with decreased bone mineral density and 355 age- and sex-matched healthy subjects. Lumbar BMD was measured by dual-energy X-ray absorptiometry (DXA). Choroidal thickness was measured using swept-source optical coherence tomography (SS-OCT). Blood pressure (BP), cholesterol, triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were recorded on the same day. RESULTS: There was a significant difference in average choroidal thickness between low BMD subjects and normal subjects (p=0.003). The BP, cholesterol, triglyceride, HDL, and LDL showed no significant difference between the two groups. The correlations showed that average choroidal thicknesses were associated with BMD in the entire population (r = 0.125, p=0.001). CONCLUSION: The choroidal thickness is thinner in low BMD populations compared with normal individuals. There is a strong positive correlation of choroidal thickness with BMD, regardless of age, sex, and other demographic and clinical factors.

Measuring and modeling nanoparticle transport by foam in porous media.

In this paper, an experimental study of nanoparticle transport by foam is presented. Bubbles made of N2-gas were stabilized with either a cationic surfactant (Cetyl Trimethyl Ammonium Bromide, CTAB), silica nanoparticles, or a combination of them. The concentrations of the surface active materials were selected upon foamability and stability tests. Column-flood tests were run until steady-state changing nanoparticle concentration, foam quality (fg), and flow rate. A synergistic behaviour of surfactant and nanoparticles help the formation of a strong foam. The measurements were used to validate a mechanistic model, presented in our earlier work (Li and Prigiobbe, 2020), which couples foam and nanoparticles transport with agglomeration and extended-DLVO theory. The model agrees well with the measurements and results show that an high-quality (ca. 90% gas fraction) can be used to carry nanoparticles and the efficient increases with flow velocity. This opens the opportunity for the application of foam as a carrier of nanoparticles in subsurface applications such as the remediation of contaminated sites and makes the model a valuable tool to design and predict such operations.