Efficacy and Safety of Biosimilar QL1207 vs. the Reference Aflibercept for Patients with Neovascular Age-Related Macular Degeneration: A Randomized Phase 3 Trial.

INTRODUCTION: This trial aimed to compare the efficacy and safety between biosimilar QL1207 and the reference aflibercept for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This randomized, double-blind, phase 3 trial was conducted at 35 centers in China. Patients aged ≥ 50 years old with untreated subfoveal choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) letter score of 73-34 were eligible. Patients were randomly assigned to receive intravitreous injections of QL1207 or aflibercept 2 mg (0.05 ml) in the study eye every 4 weeks for the first 3 months, followed by 2 mg every 8 weeks until week 48, stratified by baseline BCVA ≥ or < 45 letters. The primary endpoint was BCVA change from baseline at week 12. The equivalence margin was ± 5 letters. The safety, immunogenicity, pharmacokinetics (PK), and plasma vascular endothelial growth factor (VEGF) concentration were also evaluated. RESULTS: A total of 366 patients were enrolled (QL1207 group, n = 185; aflibercept group, n = 181) from Aug 2019 to Jan 2022 with comparable baseline characteristics. The least-squares mean difference in BCVA changes was - 1.1 letters (95% confidence interval - 3.0 to 0.7; P = 0.2275) between the two groups, within the equivalence margin. The incidences of treatment-emergent adverse events (TEAE; QL1207: 71.4% [132/185] vs. aflibercept: 71.8% [130/181]) and serious TEAE (QL1207: 14.1% [26] vs. aflibercept: 12.7% [23]) appeared comparable between treatment groups, and no new safety signal was found. Anti-drug antibody, PK profiles, and VEGF concentration were similar between the two groups. CONCLUSIONS: QL1207 has equivalent efficacy to aflibercept for nAMD with similar safety profiles. It could be used as an alternative anti-VEGF agent for clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05345236 (retrospectively registered on April 25, 2022); National Medical Products Administration of China: CTR20190937 (May 20, 2019).

Palmitic acid promotes human retinal pigment epithelial cells migration by upregulating miR-222 expression and inhibiting NUMB.

High glucose promotes retinal pigment epithelial cell (RPEC) migration. However, the underlying molecular mechanisms explaining how high fatty acid levels affect RPEC migration remain largely unknown. We investigated whether and how palmitic acid (PA) impacts the migration of human RPEC cell line ARPE-19. ARPE-19 cells were treated with varying doses of palmitic acid, and the RPEC migration was evaluated by scratch and transwell migration assays. Cell viability was determined by the CCK-8 method. The levels of epithelial-mesenchymal transition (EMT)-associated proteins, including E-cadherin, vimentin, MMP2, and MMP3, were evaluated by western blot. The microRNAs and mRNAs levels were assessed by quantitative PCR. miRNA targets were predicted with online tools and validated with the luciferase reporter assay. miRNA mimics, inhibitors, and siRNA oligos were used to perform gain-of-function and loss-of-function studies. We found that PA increased viability of ARPE-19 cells, promoted their migration and EMT. PA decreased E-cadherin protein expression, and increased vimentin, MMP2, and MMP3 protein levels. Additionally, PA increased miR-222 expression in ARPE-19 cells, and functionally blocking miR-222 suppressed the PA-induced RPEC migration and EMT. NUMB was identified as a downstream target of miR-222, and NUMB knockdown abolished the effects of PA on promoting the migration and EMT of ARPE-19 cells. Therefore, PA promotes human RPEC migration by upregulating miR-222 expression and downregulating NUMB. This study unravels a novel PA-miR-222-NUMB axis that can be potentially targeted for therapy of high fat acid-related ocular diseases.

Traumatic Macular Hole: Clinical Management and Optical Coherence Tomography Features.

The complex and uncertain prognosis of traumatic macular hole (TMH) makes it a difficult and challenging problem in clinical management. The features of spontaneously closed TMH and the time of vitrectomy remain unclear. This retrospective study aimed to demonstrate the optical coherence tomography (OCT) features of TMH, explore the relationship between OCT parameters and visual outcomes, and further evaluate the therapeutic effect of surgical management. Seventeen TMH patients were included in this study. 13 eyes of TMH received vitrectomy surgery and 4 eyes of TMH were closed spontaneously. Baseline patient characteristics, surgical details, and 6-month postoperative follow-up clinical assessment were recorded prospectively. There was a moderate rate (4/17 eyes, 23.5%) of spontaneous closure. The mean time of hole closure was 9.5 ± 9.9 weeks, and 75% occurred within three months. In the spontaneously closed TMH eyes (n = 4), an intact ellipsoid band was observed in all four patients with a mean age of 12.0 ± 1.6 years and a smaller preoperative basal diameter of 418.0 ± 283.6 µm. Small basal diameter of the macular hole at baseline (p = 0.02) was associated with spontaneous closure of TMH acuity. In the vitrectomy surgery group (n = 13), an intact ellipsoid band was observed in four patients (4/13) with a mean age of 27.0 ± 12.7 years and a larger preoperative basal diameter of 943.0 ± 444.2 µm (p = 0.02). Vitrectomy results in a better closure rate (11/13 eyes, 84.6%). Combined with the spontaneously closed TMH eyes, the overall hole closure rate was 88.2% (15/17 eyes). After 6-month treatment for all patients, the best-corrected visual acuity (BCVA) increased to 0.59 ± 0.40 (logMAR) compared to baseline 1.01 ± 0.50 (logMAR) (p < 0.001). The ellipsoid band integrity was found to be closely correlated with visual acuity (p = 0.03). In conclusion, vitrectomy is an effective treatment for TMH. Surgical management for TMH achieved better anatomical closure and improved visual outcomes. Observation for 3 months may be considered before deciding if surgical intervention is suitable.

Effects of latanoprost on the expression of TGF-ß1 and Wnt / ß-catenin signaling pathway in the choroid of form-deprivation myopia rats.

In this study, we investigated the effect of latanoprost on the expression of TGF- ß1 and Wnt / ß - Catenin signal pathway in the choroid of form-deprivation myopia model rats. Forty rats were randomly divided into two groups: the control group and the FDM model group. Each group had 20 rats. The FDM model group was established by feeding latanoprost daily for 28 days. 15 rats in each group were used to measure the length of the ocular axis and the level of TGF-ß1 in choroidal tissue; the remaining 5 rats in each group were used for choroidal fibroblast culture. After modeling, the rats were killed, the length of the ocular axis was measured with a vernier caliper, and the level of TGF - ß1 protein and mRNA in the choroidal tissue of each group were measured with RT-PCR method. Results showed that compared with the control group, there was a significant difference in the axial length of the FDM model group (P< 0.05). There was a significant difference in the expression of TGF- ß1 protein and mRNA between the two groups (P<0.05). The cultured cells were identified as choroidal fibroblasts by immunocytochemistry. There was no significant difference (P>0.05) in the comparison of GSK3 ß protein in choroidal fibroblasts of rats in each group. TGF-ß 1 and APC protein in FDM group were significantly lower than those in the control group (P<0.05), while dcl3, p21-gsk3 ß and ß - Catenin proteins were significantly higher (P<0.05), and there was no significant difference (P>0.05) in the ratio of various indexes protein in FDM + ddk1 group and the comparison of TGF - ß1 and APC protein in FDM + ddk1 group and FDM group The expression of dcl3, p21-gsk3 ß and ß - Catenin decreased significantly (P<0.05). There was no significant difference in the expression of GSK3 ß mRNA in the choroidal fibroblasts of each group (P>0.05). The expression of TGF - ß 1 and APC mRNA in FDM group was significantly lower than that in the control group (P<0.05), while the expression of dcl3, p21-gsk3 ß and ß-catenin mRNA in FDM + ddk1 group was significantly higher than that in the control group (P<0.05) >In FDM + ddk1 group, TGF-ß 1 and APC mRNA were significantly lower than those in FDM group (P<0.05), while dcl3, p21-gsk3 ß and ß-Catenin mRNA were significantly higher (P<0.05).

Vitreous haemorrhage caused by unusual giant macular tear: a case report.

Macular tears rarely occur without trauma. Here, we describe a patient with vitreous haemorrhage, which was caused by an unusual giant macular tear secondary to existing branch retinal vein occlusion. A 60-year-old woman presented with vision loss in the right eye because of vitreous haemorrhage. She had a history of branch retinal vein occlusion and had been treated with retinal photocoagulation 3 years prior. As treatment for vitreous haemorrhage, the patient underwent 23-gauge pars plana vitrectomy combined with silicone oil tamponade. During the operation, a large jagged tear was observed in the macula. We presumed that stretching of the fibrous proliferating membrane secondary to branch retinal vein occlusion was responsible for the macular tear and vitreous haemorrhage. Eventually, the results of pars plana vitrectomy led to anatomical closure of the macular tear and partial restoration of visual acuity.

Clinical outcomes with large macular holes using the tiled transplantation internal limiting membrane pedicle flap technique.

AIM: To report the surgical technique and efficacy of the tiled transplantation internal limiting membrane (ILM) pedicle flap technique after vitrectomy for 33 patients with large macular hole (MH). METHODS: This study was a prospective noncontrolled interventional study. All patients were treated by vitrectomy, the tiled transplantation ILM pedicle flap and gas tamponade. All patients underwent visual acuity measurements and optical coherence tomography (OCT), during preoperative and the follow-up visits postoperative. RESULTS: Two high-myopic patient had flap dislocation during surgery. The thorough closure of MH following the tiled transplantation ILM pedicle flap technique was ultimately achieved in 31 patients observed by OCT imaging (93.94%) 1wk after surgery. Visual acuity improved from 1.51±0.31 (logMAR) preoperative to 0.92±0.30 6mo after surgery (P=0.000). There were no significant changes in OCT finding during the follow-up period from 1mo to 6mo after surgery. CONCLUSION: The tiled transplantation ILM pedicle flap technique provides bridge for retinal gliosis to achieve successful closures of the large MHs, and the microenvironment of this technique is more similar to the normal physiological conditions.

The etiological factors and variation effects of severe vitreous hemorrhage in Northern China / 国际眼科杂志(Guoji Yanke Zazhi)

·AIMS:To investigate the etiological factors and various effects of severe vitreous hemorrhage ( VH ) in Northern China.·METHODS:Files on patients presenting with VH treated with vitrectomy between January 2011 and January 2014 were retrieved from medical records.·RESULTS:A total of 1335 eyes of 1275 patients ( 735 males, 540 females) presenting with VH were included in this study. Proliferative diabetic retinopathy ( PDR ) , retinal vein occlusion ( RVO) , either retinal detachment or retinal hole (RD/RH), ocular trauma, Eales disease, and either age- related macular degeneration or polypoidal choroidal vasculopathy ( AMD/PCV ) constituted the etiology of VH in more than 90% of the patients. The most common causes of VH were ocular trauma ( 40%) , PDR (19. 5%), and Eales disease (19. 1%) in the youth group, PDR (34. 4%), RVO (30. 8%), and RD/RH (12. 2%) in the middle-aged group, and RVO ( 35. 7%) , PDR ( 26. 6%) , RD/RH (14. 6%), and AMD/PCV (8%) in the elder group.· CONCLUSION: PDR, RVO, and ocular trauma are usually the main causes of VH. Within each group, the most common causes of VH were ocular trauma and Eales disease in the youth group, PDR, RVO, and RD/RH in the middle-aged group, and RVO, PDR, RD/RH, and AMD/PCV in the elder group. In addition, we found that males with ocular trauma are at high risk for VH, PDR and Eales disease often present bilateral VHs, and PDR and RVO have a high risk of recurrence.

Associations Between the T280M and V249I SNPs in CX3CR1 and the Risk of Age-Related Macular Degeneration.

PURPOSE: Two common single nucleotide polymorphisms (SNPs) in the CX3CR1 gene, T280M and V249I, have been reported to affect the risk of age-related macular degeneration (AMD) in several studies. The aim of the present study was to combine all published data on the relationship between these two variants and AMD susceptibility in a meta-analysis to clarify this association. METHODS: MEDLINE, EMBASE, and ISI Web of Science were searched for all eligible studies on the relationship between AMD and T280M and V249I variants. The pooled odds ratio (OR) with 95% confidence intervals (CIs) for each SNP in the allele frequency, homozygote, second codominant genotype, and dominant genotype models were calculated to evaluate the strength of this association. RESULTS: A total of 3017 AMD cases and 4096 controls from eight studies were involved in this meta-analysis. Both T280M and V249I SNPs exhibited significant associations with increased risk of AMD in the allele (T versus C: OR = 1.43, 95% CI: 1.06-1.91; A versus G: OR = 1.25, 95% CI: 1.01-1.55) and homozygous models (TT versus CC: OR = 2.11, 95% CI: 1.00-4.43; AA versus GG: OR = 1.27, 95% CI: 1.00-1.61), while no significance association was observed for the codominant genotype model. Moreover, studies showing high linkage disequilibrium between these two variants demonstrated a significantly stronger connection between these SNPs and AMD risk, compared with the moderate linkage disequilibrium group. CONCLUSIONS: Significant evidence for a relationship between T280M and V249I variants in CX3CR1 in the homozygote state with increased susceptibility to AMD was reported. Further studies are needed to confirm these findings.

Predictors of visual and anatomical outcomes for neovascular age-related macular degeneration treated with bevacizumab.

The present study aimed to evaluate the predictive factors for visual and anatomical outcomes in neovascular age-related macular degeneration (AMD) patients treated with intravitreal bevacizumab (IVB). A total of 113 patients with neovascular AMD received IVB treatment. The best corrected visual acuity (BCVA), central retinal thickness (CRT) and total macular volume (TMV) were assessed before the injection, and at 1, 2, 3 and 9 months after surgery. Changes in BCVA and these optical coherence tomography (OCT) outcomes from baseline were compared, and independent predictors were evaluated by logistic regression models. During the treatment, logarithm of the minimum angle of resolution (logMAR) significantly decreased from 1.12 to 0.83, and reductions in OCT parameters were earlier and larger. Baseline BCVA was associated with the changes in BCVA and CRT, whereas baseline OCT features significantly affected their own changes. Larger baseline logMAR and OCT features were more likely to experience a greater proportion of ≥50 µm reduction in CRT (P<0.05). The BCVA decreases were positively associated with the reductions in CRT (r=0.34, P<0.01) and TMV (r=0.41, P<0.01). Among patients with neovascular AMD, IVB resulted in earlier significant decreases in TMV and CRT, suggesting that these OCT anatomical outcomes may be considered as more sensitive responders to evaluate the treatment effects of bevacizumab.

Mutant GNAQ promotes cell viability and migration of uveal melanoma cells through the activation of Notch signaling.

The occurrence of guanine nucleotide binding protein (G protein), q polypeptide (GNAQ) mutations has been found to be high in the majority of uveal melanomas. However, the underlying molecular mechanism of GNAQ mutations in modulating uveal melanoma is poorly understood. The aim of the present study was to investigate the role and underlying mechanism of mutant GNAQ in the regulation of cell viability and migration of uveal melanoma cells. Uveal melanoma cells containing mutant GNAQ were transfected with scrambled or GNAQ small-interfering RNA. Compared with the control, GNAQ knockdown markedly inhibited cell viability and migration. However, tumor cells without GNAQ mutations exhibited enhanced viability and migration following transfection with HA-GαqQL. Additionally, GNAQ knockdown significantly downregulated the expression of Jag-1 (Notch ligand), Notch intracellular domain and Hes-1 (Notch target gene) in uveal melanoma cells. Conversely, the GNAQ overexpression promoted their expression. Cell viability and migration induced by GNAQ was significantly inhibited following treatment with 5 µmol/l MRK003, a Notch signaling inhibitor. Furthermore, the transfection of human influenza hemagglutinin A epitope (HA)-GαqQL into tumor cells caused Yes-associated protein (YAP) dephosphorylation and nuclear translocation, which stimulated the expression of Jag-1 and Hes-1. Positive correlations were observed between the GNAQ and Jag-1 mRNA levels and between the GNAQ and Hes-1 mRNA levels. However, no positive correlation was observed between the GNAQ and YAP mRNA levels. The results suggested that GNAQ mutation induced viability and migration of uveal melanoma cells via Notch signaling activation, which is mediated by YAP dephosphorylation and nuclear translocation.

Associations of the G1961E and D2177N variants in ABCA4 and the risk of age-related macular degeneration.

OBJECTIVE: The aim of this study was to identify the relationship between G1961E and D2177N variants in the ABCA4 gene with AMD susceptibility. DESIGN AND METHODS: All eligible studies published up to October 2014 were obtained from MEDLINE, EMBASE, and ISI Web of Science. The pooled odds ratio (OR) with 95% confidence intervals (CIs) was calculated to evaluate the strength of this association. RESULTS: Twenty-four studies enrolling 4580 AMD cases and 5180 controls were identified. Both G1961E (OR = 3.22, 95% CI: 1.74-5.95) and D2177N (OR = 2.36, 95% CI: 1.41-3.93) variations showed significant associations with increased risk of AMD. In addition, a more significant relationship in the D2177N mutation with increased risk for AMD was found in Americans (OR = 4.31, 95% CI: 1.90-9.73), while no association was demonstrated in Europeans. For Asians, no carriers of the risk factor A allele in either variant were detected in any of AMD patients and control subjects. CONCLUSIONS: Significant evidence was found for a relationship between the G1961E and D2177N variants in ABCA4 with increased susceptibility to AMD, specifically for Americans. However, large-scale studies are still required to further validate these findings in different ethnicities.

Multiple methods of surgical treatment combined with primary IOL implantation on traumatic lens subluxation/dislocation in patients with secondary glaucoma.

AIM: To describe clinical findings and complications from cases of traumatic lens subluxation/dislocation in patients with secondary glaucoma, and discuss the multiple treating methods of operation combined with primary intraocular lens (IOL) implantation. METHODS: Non-comparative retrospective observational case series. PARTICIPANTS: 30 cases (30 eyes) of lens subluxation/dislocation in patients with secondary glaucoma were investigated which accepted the surgical treatment by author in the Ophthalmology of Xi'an No.4 Hospital from 2007 to 2011. According to the different situations of lens subluxation/dislocation, various surgical procedures were performed such as crystalline lens phacoemulsification, crystalline lens phacoemulsification combined anterior vitrectomy, intracapsular cataract extraction combined anterior vitrectomy, lensectomy combined anterior vitrectomy though peripheral transparent cornea incision, pars plana lensectomy combined pars plana vitrectomy, and intravitreal cavity crystalline lens phacofragmentation combined pars plana vitrectomy. And whether to implement trabeculectomy depended on the different situations of secondary glaucoma. The posterior chamber intraocular lenses (PC-IOLs) were implanted in the capsular-bag or trassclerally sutured in the sulus decided by whether the capsular were present. MAIN OUTCOME MEASURES: visual acuity, intraocular pressure, the situation of intraocular lens and complications after the operations. RESULTS: The follow-up time was 11-36mo (21.4±7.13). Postoperative visual acuity of all eyes were improved; 28 cases maintained IOP below 21 mm Hg; 2 cases had slightly IOL subluxation, 4 cases had slightly tilted lens optical area; 1 case had postoperative choroidal detachment; 4 cases had postoperative corneal edema more than 1wk, but eventually recovered transparent; 2 cases had mild postoperative vitreous hemorrhage, and absorbed 4wk later. There was no postoperative retinal detachment, IOL dislocation, and endophthalmitis. CONCLUSION: To take early treatment of traumatic lens subluxation/dislocation in patients with secondary glaucoma by individual surgical plan based on the different eye conditions would be safe and effective, which can effectively control the intraocular pressure and restore some vision.

[Regulatory effects of ninjurin-1 on adhesion of myeloid cells in the retina at the early stage of diabetic rats].

OBJECTIVE: To investigate the regulatory effects of ninjurin-1 on adhesion of myeloid cells in the retina at the early stage of diabetic rats. METHODS: Experimental study. The rat diabetic model was induced by intraperitoneal injection of streptozotocin. After 2 months of diabetes induction, 27 diabetic rats were randomly chosen and assigned to 3 groups, including diabetes and phosphate buffered saline (PBS) injection group (group B), diabetes and anti-Ninj-1 injection group (group C) and diabetes and anti-IgG injection group (group D), with 9 rats in each group. Nine age matched health rats were chosen as control group (group A). Retinal leukostasis was quantified with acridine orange leukocyte fluorography. Retinal myeloid cell infiltration activity was measured by enzyme linked immunosorbent assay of myeloperoxidase (MPO). The differences of the mean values among the four groups were analyzed by one-factor analysis of variance. The multiple comparisons of the mean values among the four groups were analyzed by LSD-t analysis. RESULTS: According to the results of the acridine orange leukocyte fluorography, the numbers of leukocyte adhesion in the four groups were 49.66 ± 13.51, 153.66 ± 20.43, 85.33 ± 15.03 and 156.33 ± 11.53, respectively. The differences among them were significant (F = 143.34, P = 0.000). The numbers of leukocyte adhesion in the group C were significantly lower than that in group B (P = 0.000, 95%CI: -82.68 - -53.98). The levels of retinal MPO in the four groups were (15.66 ± 2.08), (27.66 ± 2.51), (18.02 ± 2.01) and (26.66 ± 3.21) µg/L, respectively. The differences among them were significant (F = 17.61, P = 0.010). The level of retinal MPO in the group C was significantly lower than that in group B (P = 0.010, 95%CI: -14.37 - -4.95). CONCLUSIONS: Ninj-1 may play a role in the mediation of the adhesion of myeloid cell to the rat retina of early-stage of diabetes in vivo.

Effect of alloxan time administerDrug on establishing diabetic rabbit model.

AIM: To explore the effect of alloxan time administerDrug on establishing diabetic rabbit model. METHODS: Thirty-six healthy rabbits, weighed 2-2.5kg, were randomly divided into one time administerDrug group (Group A, n=12), two times administerDrug group (Group B, n=12) and three times administerDrug group(Group C, n=12). Every rabbit was injected with alloxan of 150mg/kg. The three groups were measured for fasting blood-glucose. The success rate and death rate of each group were also calculated. RESULTS: The success rate of diabetic rabbit model in Group B was higher than that in Group A (P<0.01) but its death rate was lower than that of Group A (P<0.01); the success rate of diabetic rabbit model in Group C was highest but the death rate was the lowest in the three groups. CONCLUSION: Separate administration of alloxan can improve success rate in establishing diabetic rabbit model, decrease the death rate and keep the stability of model.