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).

Impacts of air pollution and meteorological conditions on dry eye disease among residents in a northeastern Chinese metropolis: a six-year crossover study in a cold region.

The purpose of this study is to explore the associations among dry eye disease (DED), air pollution, and meteorological conditions in the cold region of a northeastern Chinese metropolis (i.e., Changchun). Data on ambient air pollutants and meteorological parameters as well as diagnosed DED outpatients during 2015-2021 were collected. The associations between DED and environmental factors were analysed at multiple time scales using various statistical methods (i.e., correlation, regression and machine learning). Among the 10,809 DED patients (21,617 eyes) studied, 64.60% were female and 35.40% were male. A higher frequency of DED was observed in March and April, followed by January, August and October. Individual and multiple factor models showed the positive importance of particles with aerodynamic diameters <10 µm (PM10), carbon monoxide (CO), and ozone (O3) among normal air pollutants and air pressure (AP), air temperature (AT) and wind speed (WS) among normal meteorological parameters. Air pollutants (PM10, nitrogen dioxide: NO2) and meteorological parameters (AT, AP) have combined impacts on DED occurrence. For the first time, we further explored the associations of detailed components of atmospheric particles and DED, suggesting potential emission sources, including spring dust from bare soil and roads and precursor pollutants of summer O3 formation from vehicles and industry in Northeast China. Our results revealed the quantitative associations among air pollutants, meteorological conditions and DED outpatients in cold regions, highlighting the importance of coordinated policies in air pollution control and climate change mitigation.

3% diquafosol sodium eye drops in Chinese patients with dry eye: a phase IV study.

Introduction: The efficacy and safety of 3% diquafosol sodium eye drops in Chinese patients with dry eye in the real-world setting remains unclear. Methods: 3099 patients with dry eye symptoms were screened according to Asia Dry Eye Society latest recommendation. Among them, 3000 patients were enrolled for a phase IV study. We followed up with multiple clinical characteristics including corneal fluorescein staining, tear break up time, Schirmer's tests, visual acuity, intraocular pressure, and others. The follow ups were performed at baseline, 2 weeks and 4 weeks after treatment. Results: Based on the results of corneal fluorescein staining and tear break up time, all age and gender subgroups exhibited obvious alleviation of the symptoms among the patients with dry eye, and the data in elderly group showed the most significant alleviation. All the adverse drug reactions (ADRs, 6.17%) were recorded, among which 6% local ocular ADRs were included. Meanwhile, mild ADRs (91.8%) accounted for the most. Most of the ADRs (89.75%) got a quick and full recovery, with an average time at 15.6 days. 1.37% of patients dropped out of the study due to ADRs. Discussion: The use of 3% diquafosol sodium eye drop is effective and safe in the treatment of dry eye, with a low incidence of ADRs showing mild symptoms. This trial was registered at Chinese Clinical Trial Registry ID: ChiCTR1900021999 (Registration Date: 19/03/2019).

Effect of Intense Pulsed Light to Mitigate Meibomian Gland Dysfunction for Dry Eye Disease.

BACKGROUND: This retrospective study aimed to evaluate the effect of intense pulsed light treatment (IPL) combined with meibomian gland expression (MGX) in treating meibomian gland dysfunction (MGD) related dry eye disease (DED) for the first time in Northeast China. METHODS: Thirty-one MGD-related dry eye patients were managed by IPL-MGX from October to December 2019 in The First Hospital of Jilin University. Those patients had single IPL-MGX treatment with one follow-up visit, and no topical eye drops used were included in the study. General checkup and data collection helped in determining the age, sex, diagnosis, status of the MG, first noninvasive tear break-up time (1st NIBUT), average NIBUT, the height of tear film, and additional medical history. RESULTS: There was an improvement in the function of the meibomian gland (MG), with a significant decrease in the MG dropouts in the upper eyelid (Rt eye, p = 0.0047; Lt eye, p = 0.0158) and lower eyelid (Rt eye, p = 0.0017; Lt eye, p = 0.0027) plus the average NIBUT (Rt eye, p = 0.0264) also showed improvement after the IPL-MGX treatment. Though no significant difference was reached with the average NIBUT of the Lt eye (p = 0.5256) and the NIBUT grade (Rt eye, p = 0.0578; Lt eye, p = 0.0588), there was an increased duration of the average NIBUT and improved NIBUT grading. The negative results may be because of the maximum severity of DED and the limited treatment times. CONCLUSIONS: The result suggests that IPL-MGX was effective in treating MGD-related DED.

Rejection of Acellular Porcine Corneal Stroma Transplantation During Coronavirus Disease 2019 Pandemic.

ABSTRACT: To report 2 successfully managed cases of graft rejection with acellular porcine corneal stroma (APCS) transplantation in patients with fungal corneal ulcer. Two patients were diagnosed with fungal corneal ulcer and received APCS transplantation. Graft rejection developed due to the lost follow-up during the period of coronavirus disease 2019 outbreak. Amniotic membranes transplantation and cauterization of neovascularization was performed, respectively. The graft failure resolved successfully after the procedure. To the best of our knowledge, amniotic membranes transplantation and cauterization of new vessels are the firstly reported in treating APCS graft failure. Amniotic membranes transplantation or cauterization of neovascularization appear to be a safe and costeffective method for treating graft failure.

Air pollution and meteorological conditions significantly contribute to the worsening of allergic conjunctivitis: a regional 20-city, 5-year study in Northeast China.

This study is the first to explore the potential associations among allergic conjunctivitis (AC), air pollution, and meteorological conditions in Northeast China. Data of meteorology, ambient atmospheric pollutants, and the incidence of allergic conjunctivitis (IAC) in prefecture-level cities between the years 2014 and 2018 are analyzed. The results show an increasing trend in the AC of average growth rate per annum 7.6%, with the highest incidence in the provincial capitals. The IAC is positively correlated with atmospheric pollutants (i.e., PM2.5, PM10, CO, SO2, NO2, and O3) and meteorological factors (i.e., air temperature and wind speed), but negatively correlated with relative humidity. These results suggest that the IAC is directly proportional to pollution level and climatic conditions, and also the precedence of air pollution. We have further obtained the threshold values of atmospheric pollutants concentration and meteorological factors, a turning point above which more AC may be induced. Compared with the air quality standard advised by China and the World Health Organization (WHO), both thresholds of PM10 (70 µg m-3) and PM2.5 (45 µg m-3) are higher than current standards and pose a less environmental risk for the IAC. SO2 threshold (23 µg m-3) is comparable to the WHO standard and significantly lower than that of China's, indicating greater environmental risks in China. Both thresholds of NO2 (27 µg m-3) and O3 (88 µg m-3) are below current standards, indicating that they are major environmental risk factors for the IAC. Our findings highlight the importance of atmospheric environmental protection and reference for health-based amendment.

Use of Intense Pulsed Light to Mitigate Meibomian Gland Dysfunction for Dry Eye Disease.

Dry Eye Disease (DED) is a common ocular condition that needs prompt diagnosis and careful treatment interventions. If left untreated, it can lead to numerous sight-threatening complications, including ulceration of the cornea, blepharitis, alterations of the tear film, conjunctivitis, and in severe cases, may lead to scarring, thinning, and even perforation of the cornea. Intense pulsed light (IPL) is a non-laser high-intensity light source that has shown to play a valuable role in dry eye disease. Recent evidence from various research works has shown that IPL modifies the mechanism of meibomian gland dysfunction (MGD), which helps to relieve the symptoms of DED. In this review, we demonstrated the mechanism of action of IPL, including its benefits on DED. The emerging evidence shows that the role of IPL in DED is novel and therapeutic. These results direct us to conclude that IPL is a potentially beneficial tool and essential future therapy for dry eye disease. Advances in the treatment of DED will lead to a better quality of life. However, tools to recognize potentially severe side effects of DED earlier in order to treat or prevent them must be developed.

Identification of a novel homozygous variant in the CNGA1 gene in a Chinese family with autosomal recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) is a complex group of hereditary retinal dystrophies. Although >60 genes have been identified to be associated with non­syndromic RP, the exact genetic variant remains elusive in numerous cases of RP. In the present study, a Chinese pedigree affected by RP with autosomal recessive inheritance, including a total of seven members with one affected patient and six unaffected individuals, was recruited. Comprehensive ophthalmic examinations were performed on the proband and the proband's unaffected daughter. Genomic DNA was extracted from peripheral blood. Whole­exome sequencing (WES) was performed for the affected individual. The candidate pathogenic variant was verified by direct Sanger sequencing. The affected individual presented with classical clinical symptoms of RP. A novel homozygous variant, c.265delC (p.L89Ffs*3) in the cyclic nucleotide­gated channel subunit α 1 gene was identified in the affected patient. This homozygous variant was absent in other unaffected family members and 600 ethnicity­matched healthy controls. The variant was co­segregated with the disease phenotype in an autosomal recessive manner.

Inhibition of DNA-PKcs activity re-sensitizes uveal melanoma cells to radio- and chemotherapy.

Uveal melanoma (UM) is the most common primary intraocular tumor in adults. Despite of important progress in the local therapy, high radioresistance in primary tumor and chemoresistance in metastatic disease are the major obstacles for UM therapy. Therefore, strategies to overcome resistance to radiation or chemotherapy in UM are urgently needed. In this study, we found that phosphorylation of DNA-PKcs, which is the key factor of non-homologous end joining (NHEJ) pathway, was remarkably overexpressed in ionizing radiation (IR)- and Selumetinib resistant UM cells. Increased amount of NHEJ events were also observed in resistant UM cells. Inhibition of DNA-PKcs by NU7441 significantly impaired DNA repair and re-sensitized resistant UM cells to radiation and Selumetinib both in vitro and in vivo. The results demonstrate increased DNA double strand break repair as a mechanism of resistance to ionizing radiation and Selumetinib, and identify DNA-PKcs as a promising target for radio-and chemotherapy in UM patients.

Identification of whirlin domains interacting with espin: A study of the mechanism of Usher syndrome type II.

Usher syndrome is the most common condition of combined blindness and deafness and is classified into three types (USH1­USH3). USH2 is the most commonly diagnosed of all Usher syndrome cases. There are three identified proteins (usherin, GPR98 and whirlin) that form the USH2 complex. Defects in any of these proteins may cause failure in the formation of the USH2 complex, which is the primary cause of USH2. Whirlin is a scaffold protein and is essential for the assembly of the USH2 protein complex. It has been reported that espin is an interacting partner protein for whirlin. However, which fragment of whirlin interacts with espin remains unclear. In the present study, whirlin N­ and C­terminal fragments in the pEGFP­C2 vectors were constructed. The recombinant plasmids were transfected into COS­7 cells to observe the co­localization by confocal laser scanning microscopy. The interactions between whirlin and espin were investigated by co­immunoprecipitation using the 293 cell line. It was demonstated that only the whirlin N­terminal fragment was able to interact with espin and the PR (proline­rich) region in whirlin may be important for the interaction. However, the present study did not investigate the interaction between whirlin and espin without the PR domain which warrants future research. Our findings elucidated a primary mechanism of interaction between whirlin and espin, which are crucial for further study on the USH2 complex and USH2 pathogenesis.

NONRATT021972 long-noncoding RNA: A promising lncRNA in diabetes-related diseases.

Diabetes mellitus (DM) is a principal health problem with increasing incidence worldwide. It can be associated with various systemic diseases. Long non-coding RNA (lncRNA), a member of non-coding RNA has been newly linked with various human diseases. Recent evidence from animal experiments has shown that the incidence and development of type 2 diabetes are contributed by the atypical expression of lncRNA in which the biomarker with capable clinical potential was lncRNA NONRATT021972. In this review, we demonstrated the numerous functions of NONRATT021972 in different diabetes-related diseases including diabetic neuropathy, diabetic cardiac autonomic neuropathy, myocardial ischemia, and hepatic glucokinase dysfunction. The emerging evidence shows that the role of NONRATT021972 in diabetic-related disease is novel and therapeutic. These results direct us to conclude that NONRATT021972 is a potential diagnostic and future targeted therapy for diabetes-associated diseases.

Circular RNAs: Novel Promising Biomarkers in Ocular Diseases.

Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs produced by back-splicing. They are found to be expressed in eukaryotic cells and play certain roles in various cellular functions, including fibrosis, cell proliferation, differentiation, apoptosis and angiogenesis. Dysregulated circRNAs are found in several human disorders including, malignancy, vascular, inflammatory as well as nervous diseases. Although, increasing evidence suggests that circRNAs may also contribute in different ocular diseases, the outline of circRNAs in ocular diseases remains obscure. In this review we consider the current state of knowledge regarding the potential role and underlying mechanism of circRNAs in ocular diseases including pterygium, age-related cataract, glaucoma, diabetic retinopathy, retinoblastoma, retinal vascular dysfunction and hyperhomocysteinemia induced ocular diseases, emphasizing that circRNAs could be promising biomarkers for the diagnosis and prognosis evaluation. Future circRNAs-targeted intervention may become a novel therapeutic tool for the treatment of ocular diseases.

MALAT1 as a Diagnostic and Therapeutic Target in Diabetes-Related Complications: A Promising Long-Noncoding RNA.

Diabetes mellitus is a global issue with increasing incidence rate worldwide. In an uncontrolled case, it can advance to various organ-related complications leading to an increase in morbidity and mortality. Long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) appears to be a fairly novel lncRNA that is relevant to diabetes and its role in diabetic-related diseases initiation and progression have long been a subject of attention to many scholars. The expression of MALAT1 is elevated in different diabetic-related diseases. In this review, we demonstrate the various functions of MALAT1 in the different diabetes-related complications including ischemic reperfusion injury, retinopathy, cataract, atherosclerosis, cardiomyopathy, non-alcoholic steatohepatitis, gastroparesis, kidney disease, and gestational diabetes. The emerging evidence showed that the role of MALAT1 in diabetic-related complications is both pro-inflammatory and apoptosis in different cell types. These results concluded that MALAT1 is a potential diagnostic and future targeted therapy for diabetes-associated complications.

Tectonic keratoplasty using femtosecond laser lenticule in pediatric patients with corneal perforation secondary to blepharokeratoconjunctivitis: a case report and literature review.

Blepharokeratoconjunctivitis secondary to ocular demodicosis in the pediatric population is often neglected and may result in a serious sight-threatening condition. In severe cases, it can lead to corneal perforation necessitating urgent corneal transplantation. However, the shortage and high cost of donor corneas is the foremost limitation of keratoplasty in developing countries. Small-incision lenticule extraction is an advanced flapless femtosecond laser refractive procedure in which an intrastromal corneal lenticule is detached and removed to correct myopia and myopic astigmatism. We herein describe a technique in which lenticules are used for the management of corneal perforation secondary to Demodex-induced blepharokeratoconjunctivitis. The lenticule was sutured over the site of the perforated cornea using 10-0 interrupted nylon sutures. The globe integrity was maintained with a good visual outcome. Thus, tectonic keratoplasty using small-incision lenticule extraction appears to be a safe, cost-effective, and reliable alternative method for the management of corneal perforation secondary to blepharokeratoconjunctivitis.

Neuroprotective effects of overexpressed microRNA-200a on activation of glaucoma-related retinal glial cells and apoptosis of ganglion cells via downregulating FGF7-mediated MAPK signaling pathway.

Glaucoma is a progressive optic neuropathy and is one of the leading causes of blindness in the industrialized countries. The involvement of microRNAs (miRs) has been implicated in regulating the complex biological responses to changes in intraocular pressure. However, the therapeutic role of miR-200a on glaucoma has not been well studied yet. In this study, we confirmed the role of miR-200a in glaucoma progression and identified the related mechanism. Microarray expression profiles were used to screen the glaucoma-related genes. The relationship between miR-200a and FGF7 was validated by bioinformatics analysis and dual-luciferase reporter gene assay. Glaucoma-related parameters including the expression of CD11b and iNOS, activation of Muller cells, and apoptosis of retinal ganglion cells (RGCs) in the mouse model were measured by immunohistochemistry, MTT assay and TUNEL assay, respectively. miR-200a was reduced in glaucoma, whereas FGF7 was robustly induced. Thereby, we speculated that FGF7 was negatively regulated by miR-200a. Downregulated miR-200a could activate the MAPK signaling pathway following elevations in ERK, JNK, p38 and Bax expression and reduction in Bcl-2 expression. In the mouse model, downregulated miR-200a increased the expression of CD11b and iNOS and the apoptosis of RGCs, but stimulated the inactivation of Muller cells. However, the above-mentioned alternations induced by downregulated miR-200a were reversed after FGF7 repression. miR-200a can inhibit the FGF7-mediated MAPK signaling pathway and play a protective role on improving the glaucoma-induced optical nerve injury.

PAXX Participates in Base Excision Repair via Interacting with Pol ß and Contributes to TMZ Resistance in Glioma Cells.

Non-homologous end joining (NHEJ) is one of the major DNA repair pathway in mammalian cell that can ligate a variety of DNA ends. However, how does all NHEJ factors communicate and organize together to achieve the final repair is still not clear. PAralog of XRCC4 and XLF (PAXX) was a new factor identified recently that play an important role in NHEJ. PAXX contributes to efficient NHEJ by interacting with Ku, which is a NHEJ key factor, and PAXX deficiency cause sensitivity to DNA double-strand break repair (DSBR). We observed that PAXX-deficient cells showed slight increase of homologous recombination (HR, which is another major DSBR repair pathways in mammalian cells). More importantly, we found that PAXX contributes to base excision repair pathway via interaction of polymerase beta (pol ß). Temozolomide (TMZ) is one of the standard chemotherapies widely applied in glioblastoma. However, TMZ resistance and lack of potent chemotherapy agents can substitute TMZ. We observed that PAXX deficiency cause more sensitivity to TMZ-resistant glioma cells. In conclusion, the PAXX contributes to a variety of DNA repair pathways and TMZ resistance. Therefore, inhibition of PAXX may provide a promising way to overcome TMZ resistance and improve TMZ therapeutic effects in glioma treatment.

Lamellar keratoplasty using femtosecond laser intrastromal lenticule for limbal dermoid: case report and literature review.

Small incision refractive lenticule extraction (SMILE) is a femtosecond laser technique to correct myopia and myopic astigmatism. Herein, we report a technique where intrastromal lenticule obtained from the SMILE procedure served as a graft for lamellar keratoplasty in the management of a limbal dermoid. An 18-year-old woman presented to the clinic with a corneal-limbal mass in the right eye. Slit-lamp examination revealed a vascularized circular mass of approximately 6 mm × 5 mm, which was attached at 7 o'clock in the inferotemporal region of the corneal limbus; this suggested limbal dermoid. Anterior segment optical coherence tomography revealed superficial involvement of the cornea. The patient was treated with excision and lamellar keratoplasty by using femtosecond intrastromal lenticule. The lenticule was sutured over the cornea with 10-0 interrupted nylon sutures. On postoperative follow-up, best-corrected visual acuity was 20/20; there was no corneal neovascularization and no sign of rejection. This case of limbal dermoid was managed by simple surgical excision and lamellar keratoplasty with a SMILE-extracted lenticule. This method may serve as an alternative surgical approach for management of limbal dermoid.

The Nrf2 Signaling in Retinal Ganglion Cells under Oxidative Stress in Ocular Neurodegenerative Diseases.

Retinal ganglion cells (RGCs) are one of the important cell types affected in many ocular neurodegenerative diseases. Oxidative stress is considered to be involved in retinal RGCs death in ocular neurodegenerative diseases. More and more attention has been focused on studying the agents that may have neuroprotective effects. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key nuclear transcription factor for the systemic antioxidant defense system. This review elucidates the underlying mechanism of the Nrf2-mediated neuroprotective effects on RGCs in ocular neurodegenerative diseases, such as diabetic retinopathy and retinal ischemia-reperfusion injury. Several Nrf2 inducers that shield RGCs from oxidative stress-induced neurodegeneration via regulating Nrf2 signaling are discussed.