Characteristics of tear film lipid layer in young dry eye patients.

BACKGROUND/PURPOSE: To investigate the characteristics of subjective symptoms and objective parameters among young patients with dry eye disease (DED) and compare them with those of older patients. METHODS: We retrospectively enrolled 675 patients with DED who were divided into three age groups (20-41 years [younger], 41-60 years [middle], and >60 years [older]) (n = 143, 304, and 228, respectively). Subjective symptoms were evaluated using Standardized Patient Evaluation of Eye Dryness (SPEED) and Ocular Surface Disease Index (OSDI) questionnaires. Aqueous tear secretion was evaluated with the Schirmer test II. The number of expressible meibomian glands was evaluated with a slit-lamp-aided standardized evaluator. Lipid layer thickness (LLT), blink/incomplete blink rates and meibography were measured with the LipiView® II interferometer. The extent of the meibomian gland dropout was graded using a meiboscale. RESULTS: The younger age group had higher subjective symptom severity, as reflected by higher SPEED (p < 0.001) and OSDI scores (p = 0.051). The SPEED scores negatively correlated with LLT in all patients (r = -0.136, p < 0.001). Younger patients also had thinner average LLT (p < 0.001), lower meiboscale (p < 0.001) and a higher number of expressible meibomian glands (p < 0.001). Additionally, they had significantly more total blinks (p < 0.001), incomplete blinks (p < 0.001), and incomplete blink rate (p = 0.006). CONCLUSION: Manifestations of DED vary with age. In our cohort, younger age patients had more symptoms and blinks, which may have resulted from thinner LLT as the structure and function of the meibomian glands were affected less than in middle and older age patients.

Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer.

Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in tumor-associated endothelial cells, where it modulates tumor-promoting angiogenesis, and it is also found on the surface of tumor cells. Currently, there are no Ab therapeutics targeting VEGFR2 approved for the treatment of prostate cancer or leukemia. Therefore, development of novel efficacious anti-VEGFR2 Abs will benefit cancer patients. We used the Institute of Cellular and Organismic Biology human Ab library and affinity maturation to develop a fully human Ab, anti-VEGFR2-AF, which shows excellent VEGFR2 binding activity. Anti-VEGFR2-AF bound Ig-like domain 3 of VEGFR2 extracellular region to disrupt the interaction between VEGF-A and VEGFR2, neutralizing downstream signaling of the receptor. Moreover, anti-VEGFR2-AF inhibited capillary structure formation and exerted Ab-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity in vitro. We found that VEGFR2 is expressed in PC-3 human prostate cancer cell line and associated with malignancy and metastasis of human prostate cancer. In a PC-3 xenograft mouse model, treatment with anti-VEGFR2-AF repressed tumor growth and angiogenesis as effectively and safely as US FDA-approved anti-VEGFR2 therapeutic, ramucirumab. We also report for the first time that addition of anti-VEGFR2 Ab can enhance the efficacy of docetaxel in the treatment of a prostate cancer mouse model. In HL-60 human leukemia-xenografted mice, anti-VEGFR2-AF showed better efficacy than ramucirumab with prolonged survival and reduced metastasis of leukemia cells to ovaries and lymph nodes. Our findings suggest that anti-VEGFR2-AF has strong potential as a cancer therapy that could directly target VEGFR2-expressing tumor cells in addition to its anti-angiogenic action.

Synergic Effect of Intravitreal Bevacizumab and Systemic Corticosteroid in Treating Systemic Inflammatory Response Syndrome (SIRS) Associated Purtscher-like Retinopathy.

PURPOSE: To demonstrate the treatment effect of combined intravitreal bevacizumab (IVB) and systemic steroid for systemic inflammatory response syndrome (SIRS)-related Purtscher-like retinopathy (PuR). METHODS: Retrospective case report. RESULTS: A 19-year-old patient experienced bilateral blurred vision after urinary tract infection-induced SIRS. Typical bilateral PuR was found in fundus examination and fluorescein angiography. Optical coherence tomography (OCT) revealed severe cystoid macular edema (CME) and OCT angiography revealed marked vascular defects in both superficial and deep plexuses. Intravitreal injection of bevacizumab 1.25 mg was first performed in the right eye along with systemic corticosteroid therapy. One week later, marked improvement in visual acuity and CME was noted in the right eye, but not in the non-IVB-treated left eye. IVB was then performed in the left eye and achieved much improvement 8 days later. CONCLUSION: This report clearly demonstrated the synergic effect of IVB and systemic steroids for CME on SIRS-related PuR.

Low ambient temperature correlates with the severity of dry eye symptoms.

PURPOSE: The symptoms of dry eye disease (DED) are influenced by environmental factors, but the effect of ambient temperature is less certain. Our purpose was to investigate the relationship between the severity of DED symptoms and the ambient temperature. MATERIALS AND METHODS: This retrospective study reviewed the symptom scores, including ocular surface disease index (OSDI) and standardized patient evaluation of eye dryness (SPEED), as well as tear film parameters of first-time DED patients between June 2018 and June 2019. The contribution of tear film parameters and environmental factors, including ambient temperature, humidity, wind speed, and the concentration of air pollutants, to the severity of dry eye symptoms was evaluated by univariate and multivariate linear regression analyses. RESULTS: There were 351 patients included aged 52.8 ± 13.6 years, and 257 (73.2%) were female. The average tear film break-up time, Schirmer test value, and lipid layer thickness were 2.6 ± 0.7 s, 5.5 ± 4.3 mm, and 64.1 ± 6.0 µm, respectively. The average OSDI and SPEED were 41.8 ± 19.8 and 12.1 ± 5.1, respectively. In winter, the patients reported higher OSDI and SPEED. Both scores were significantly correlated with low ambient temperature. Regression analysis showed that low ambient temperature and Schirmer test value contributed to higher OSDI, while low ambient temperature and younger age contributed to higher SPEED. CONCLUSION: Low ambient temperature plays a significant role in DED symptom severity.

Combined intravitreal ranibizumab and posterior subtenon triamcinolone acetonide injections for patients with diabetic macular edema refractory to intravitreal ranibizumab monotherapy.

PURPOSE: The purpose of this study is to compare the efficacy of intravitreal ranibizumab (IVR) alone and concurrent IVR with posterior subtenon triamcinolone acetonide (PSTA) injection for patients with diabetic macular edema (DME) refractory to IVR monotherapy. MATERIALS AND METHODS: We enrolled 43 eyes of 43 patients with DME who received at least three times of IVR, which resulted in poor anatomical responses, with central foveal thickness (CFT) reduction <10% and postinjection CFT >300 µm. All the eyes received initial 3 monthly then pro re nata (PRN) IVR 0.5-mg injections. Twenty eyes continued PRN injections and 23 eyes received combined IVR 0.5 mg and PSTA 40 mg with at least 1-year follow-up. Best-corrected visual acuity (BCVA) and CFT were recorded from 1-month to 1-year follow-up. RESULTS: Following switch to combined therapy, the mean BCVA significantly improved from 0.61 ± 0.32 logarithm of the minimum angle of resolution (logMAR) to 0.45±0.39 logMAR at 6 month (P = 0.003), 0.43±0.35 logMAR at 9 months (P < 0.001), and 0.48±0.45 logMAR at 1 year (P = 0.03). In eyes with IVR alone, no significant VA improvement was noted throughout the year. Significantly better BCVA was noted in the combined group at 6-month, 9-month, and 1-year follow-up compared to IVR-alone group. The timing of combined therapy showed a significant association with 1-year BCVA (t = 3.25, P = 0.018). CONCLUSION: Concurrent IVR and PSTA resulted in significantly better visual outcomes in 1-year follow-up for those refractory to preceding ranibizumab monotherapy for DME. Early addition of PSTA predicted a better visual outcome.

Age, Initial Central Retinal Thickness, and OCT Biomarkers Have an Influence on the Outcome of Diabetic Macular Edema Treated With Ranibizumab- Tri-center 12-Month Treat-and-Extend Study.

Objective: We report the tri-center 1-year outcomes of a treat-and-extend (T&E) regimen in four-week intervals with ranibizumab for diabetic macular edema (DME). Methods: In this retrospective study, all eyes received 3 monthly loading injections of 0.5 mg ranibizumab, followed by a T&E regimen for DME. Regression models were used to evaluate the associating factors for visual and anatomical outcomes. Results: Ninety one eyes from 64 patients were enrolled. Mean LogMAR best-corrected visual acuity (BCVA) improved from 0.58 at baseline to 0.36 at month 12 and mean central retinal thickness (CRT) decreased from 411 µm at baseline to 290 µm at month 12. Younger age and eyes having thinner baseline CRT, with ellipsoid zone disruption (EZD), and without epiretinal membrane (ERM) were associated with better final CRT. Moreover, eyes with thicker baseline CRT tend to receive more injections. Among the parameters, only having ERM or EZD was associated with significant BCVA recovery. Conclusions: A T&E regimen with ranibizumab by 4-week intervals is effective in improving BCVA and reducing CRT with efficacy notable starting from the third month. Clinical parameters including age, initial CRT, and presence of ERM or EZD significantly influenced therapeutic outcomes. Moreover, the presence of ERM should not preclude DME patients from receiving anti-VEGF therapy. Future studies with larger cohorts are warranted.

Generation of Monoclonal Antibodies against Dengue Virus Type 4 and Identification of Enhancing Epitopes on Envelope Protein.

The four serotypes of dengue virus (DENV1-4) pose a serious threat to global health. Cross-reactive and non-neutralizing antibodies enhance viral infection, thereby exacerbating the disease via antibody-dependent enhancement (ADE). Studying the epitopes targeted by these enhancing antibodies would improve the immune responses against DENV infection. In order to investigate the roles of antibodies in the pathogenesis of dengue, we generated a panel of 16 new monoclonal antibodies (mAbs) against DENV4. Using plaque reduction neutralization test (PRNT), we examined the neutralizing activity of these mAbs. Furthermore, we used the in vitro and in vivo ADE assay to evaluate the enhancement of DENV infection by mAbs. The results indicate that the cross-reactive and poorly neutralizing mAbs, DD11-4 and DD18-5, strongly enhance DENV1-4 infection of K562 cells and increase mortality in AG129 mice. The epitope residues of these enhancing mAbs were identified using virus-like particle (VLP) mutants. W212 and E26 are the epitope residues of DD11-4 and DD18-5, respectively. In conclusion, we generated and characterized 16 new mAbs against DENV4. DD11-4 and D18-5 possessed non-neutralizing activities and enhanced viral infection. Moreover, we identified the epitope residues of enhancing mAbs on envelope protein. These results may provide useful information for development of safe dengue vaccine.

An Epitope-Substituted DNA Vaccine Improves Safety and Immunogenicity against Dengue Virus Type 2.

Dengue virus (DENV), a global disease, is divided into four serotypes (DENV1-4). Cross-reactive and non-neutralizing antibodies against envelope (E) protein of DENV bind to the Fcγ receptors (FcγR) of cells, and thereby exacerbate viral infection by heterologous serotypes via antibody-dependent enhancement (ADE). Identification and modification of enhancing epitopes may mitigate enhancement of DENV infection. In this study, we characterized the cross-reactive DB21-6 and DB39-2 monoclonal antibodies (mAbs) against domain I-II of DENV; these antibodies poorly neutralized and potently enhanced DENV infection both in vitro and in vivo. In addition, two enhancing mAbs, DB21-6 and DB39-2, were observed to compete with sera antibodies from patients infected with dengue. The epitopes of these enhancing mAbs were identified using phage display, structural prediction, and mapping of virus-like particle (VLP) mutants. N8, R9, V12, and E13 are the reactive residues of DB21-6, while N8, R9, and E13 are the reactive residues of DB39-2. N8 substitution tends to maintain VLP secretion, and decreases the binding activity of DB21-6 and DB39-2. The immunized sera from N8 substitution (N8R) DNA vaccine exerted greater neutralizing and protective activity than wild-type (WT)-immunized sera, both in vitro and in vivo. Furthermore, treatment with N8R-immunized sera reduced the enhancement of mortality in AG129 mice. These results support identification and substitution of enhancing epitope as a novel strategy for developing safe dengue vaccines.