Inhibition of ferroptosis by POLE2 in gastric cancer cells involves the activation of NRF2/GPX4 pathway.

Gastric cancer results in great cancer mortality worldwide, and inducing ferroptosis dramatically improves the malignant phenotypes of gastric cancer. DNA polymerase epsilon subunit 2 (POLE2) plays indispensable roles in tumorigenesis; however, its involvement and molecular basis in ferroptosis and gastric cancer are not clear. Human gastric cancer cells were infected with lentiviral vectors to knock down or overexpress POLE2, and cell ferroptosis was detected. To further validate the involvement of nuclear factor erythroid 2-related factor 2 (NRF2) and glutathione peroxidase 4 (GPX4), lentiviral vectors were used. POLE2 expression was elevated in human gastric cancer cells and tissues and closely correlated with clinicopathological features in gastric cancer patients. POLE2 knockdown was induced, while POLE2 overexpression inhibited ferroptosis of human gastric cancer cells, thereby modulating the malignant phenotypes of gastric cancer. Mechanistic studies revealed that POLE2 overexpression elevated NRF2 expression and activity and subsequently activated GPX4, which then prevented lipid peroxidation and ferroptosis in human gastric cancer cells. In contrast, either NRF2 or GPX4 silence significantly prevented POLE2 overexpression-mediated inductions of cell proliferation, migration, invasion and inhibition of ferroptosis. POLE2 overexpression inhibits ferroptosis in human gastric cancer cells through activating NRF2/GPX4 pathway, and inhibiting POLE2 may be a crucial strategy to treat gastric cancer.

Cyanopyridoimidazole/1,2-Aminothiol Click Reaction: A Novel Bioorthogonal Reaction for Synthesis of Radiotracers.

We herein described the design and synthesis of the cyanopyridoimidazoles (CPIs) as new bioorthogonal click reagents toward 1,2-aminothiol groups. Kinetic and density functional theory-based studies of the synthetic compounds revealed that incorporating an electron-withdrawing substituent into the CPI scaffold lowers its lowest unoccupied molecular orbital energy, consequently increasing reactivity. Optimized CPI 8a showed rapid reactivity and high stability in physiological conditions and has been demonstrated to be suitable for various radiotracer synthetic methods. Based on the new bioorthogonal reaction, a [67Ga]Ga-labeled prostate-specific membrane antigen-targeted probe was successfully prepared for in vivo imaging of prostate cancer in an animal model.

The disposable bandage soft contact lenses therapy and anterior segment optical coherence tomography for management of ocular graft-versus-host disease.

PURPOSE: To identify the ocular surface changes of ocular graft-versus-host disease (GVHD) using anterior segment optical coherence tomography (AS-OCT) and examine the efficacy of disposable bandage soft contact lens (BSCL) treatment in ocular GVHD patients. METHODS: This study is a prospective, Phase II clinical trial. Nineteen patients diagnosed with chronic GVHD based on the NIH criteria and ocular symptoms of NIH eye score 2 or greater were enrolled. Disposable BSCL was applied to the GVHD-affected eyes with topical antibiotic coverage. Ocular exams, eye symptom surveys, and AS-OCT were performed with signed informed consent. Patients were followed for one to three months. RESULTS: Thirty-eight eyes of 19 patients with ocular GVHD underwent BSCL treatment in this study. AS-OCT scans were done in 14 out of 19 patients. The mean best-corrected visual acuity at enrollment, 2-week, and 4-week visits was 0.180, 0.128, and 0.163 logMAR, respectively. Twenty-four out of 25 eyes (96 %) that initially presented with conjunctival inflammation, twenty-three out of 30 eyes (76.7 %) that initially presented with punctate epithelial erosion, and 8 out of 15 (53.3 %) eyes that initially presented with filamentous keratopathy showed improvement after wearing BSCL for 2 to 4 weeks. AS-OCT revealed corneal epithelial irregularity, abnormal meibomian gland orifice, and conjunctival hyperemia, in patients with ocular GVHD. CONCLUSIONS: BSCL treatment provided significant subjective and objective improvements in ocular GVHD patients. Meanwhile, we found that AS-OCT can be a promising diagnostic tool to characterize the ocular surface changes associated with ocular GVHD.

Correlation of pterygium severity with IQ-domain GTPase-activating protein 1 (IQGAP1) and mast cells.

IQ-domain GTPase-activating protein 1 (IQGAP1) is a multidomain scaffold protein that is involved in cytoskeleton dynamics and tumor metastasis. Although the role of IQGAP1 in various cancers had been reported, the function of IQGAP1 in pterygium has not been studied. In this study, surgically excised pterygium and control conjunctival tissue from cataract patients were analysed by immunohistochemistry, confocal microscopy, and Western blot for IQGAP1 expression, mast cell counts, and microvascular count. Pterygium was clinically divided into mild and severe types according to Tan's classification and Kim's criteria based on translucency and vascularity of the tissue. Greater clinical severity of pterygium was associated with higher expression of IQGAP1 expression. Compared to normal conjunctival tissue, severe pterygium had significantly higher IQGAP1 expression (P = 0.005), which strongly correlated to the number of microvessels (P = 0.003) and mast cells (P = 0.01). Confocal microscopy revealed IQGAP1 colocalization with mast cell and CD31. IQGAP1 expression was higher in the pterygium body compared to the head. In conclusion, the level of IQGAP1 expression was found to be correlated to the clinical severity of pterygium. Mast cells were identified in pterygium and is suspected to be involved in promoting fibrovascular invasion.

Human antigen R protein modulates vascular endothelial growth factor expression in human corneal epithelial cells under hypoxia.

PURPOSE: Corneal avascularity is critical for corneal transparency; therefore, a tailored process has been presumed to minimize corneal neovascularization (NV). In most cell types, the transcription of vascular endothelial growth factor (VEGF) is up-regulated, and the stability of VEGF mRNA is sustained by human antigen R (HuR) during hypoxia; however, whether such response applies to corneal epithelial cells is unclear. METHODS: Human corneal epithelial cells (HCECs) and MCF-7 cells that serves as the control were incubated under 0.5% oxygen, and the levels of VEGF and HuR were examined time-dependently. The alteration of HuR was also examined in vivo using the closed-eye contact lens-induced corneal neovascularization rabbit model and immunohistochemistry. Additionally, the expression of HuR was modulated by transfection of plasmids encoding HuR or siRNA targeting HuR to validate the role of HuR in VEGF expression. RESULTS: We found that, unlike in control cells, the level of VEGF was not up-regulated, and the HuR expression was declined in HCECs following hypoxia. The HuR immunostaining intensities were decreased in corneal epithelial cells of rabbits wearing contact lenses. In addition, HuR overexpression restored the ability of HCECs to up-regulate VEGF under hypoxia; however, knockdown of HuR suppressed hypoxia-induced VEGF in control cells but did not further decrease VEGF in HCECs. These findings suggest that HCECs may modulate HuR to suppress hypoxia-mediated up-regulation of VEGF. CONCLUSION: Our study revealed a distinct regulation of VEGF via HuR in HCECs following hypoxia, which likely contributes to minimizing corneal NV and/or maintenance of corneal avascularity.

Adaptation to Endoplasmic Reticulum Stress Enhances Resistance of Oral Cancer Cells to Cisplatin by Up-Regulating Polymerase η and Increasing DNA Repair Efficiency.

Endoplasmic reticulum (ER) stress response is an adaptive program to cope with cellular stress that disturbs the function and homeostasis of ER, which commonly occurs during cancer progression to late stage. Late-stage cancers, mostly requiring chemotherapy, often develop treatment resistance. Chemoresistance has been linked to ER stress response; however, most of the evidence has come from studies that correlate the expression of stress markers with poor prognosis or demonstrate proapoptosis by the knockdown of stress-responsive genes. Since ER stress in cancers usually persists and is essentially not induced by genetic manipulations, we used low doses of ER stress inducers at levels that allowed cell adaptation to occur in order to investigate the effect of stress response on chemoresistance. We found that prolonged tolerable ER stress promotes mesenchymal-epithelial transition, slows cell-cycle progression, and delays the S-phase exit. Consequently, cisplatin-induced apoptosis was significantly decreased in stress-adapted cells, implying their acquisition of cisplatin resistance. Molecularly, we found that proliferating cell nuclear antigen (PCNA) ubiquitination and the expression of polymerase η, the main polymerase responsible for translesion synthesis across cisplatin-DNA damage, were up-regulated in ER stress-adaptive cells, and their enhanced cisplatin resistance was abrogated by the knockout of polymerase η. We also found that a fraction of p53 in stress-adapted cells was translocated to the nucleus, and that these cells exhibited a significant decline in the level of cisplatin-DNA damage. Consistently, we showed that the nuclear p53 coincided with strong positivity of glucose-related protein 78 (GRP78) on immunostaining of clinical biopsies, and the cisplatin-based chemotherapy was less effective for patients with high levels of ER stress. Taken together, this study uncovers that adaptation to ER stress enhances DNA repair and damage tolerance, with which stressed cells gain resistance to chemotherapeutics.

Molecular identification and functional characterization of GhAMT1.3 in ammonium transport with a high affinity from cotton (Gossypium hirsutum L.).

Ammonium (NH4 + ) represents a primary nitrogen source for many plants, its effective transport into and between tissues and further assimilation in cells determine greatly plant nitrogen use efficiency. However, biological components involved in NH4 + movement in woody plants are unclear. Here, we report kinetic evidence for cotton NH4 + uptake and molecular identification of certain NH4 + transporters (AMTs) from cotton (Gossypium hirustum). A substrate-influx assay using 15 N-isotope revealed that cotton possessed a high-affinity transport system with a Km of 58 µM for NH4 + . Sequence analysis showed that GhAMT1.1-1.3 encoded respectively a membrane protein containing 485, 509 or 499 amino acids. Heterologous functionality test demonstrated that GhAMT1.1-1.3 expression mediated NH4 + permeation across the plasma membrane (PM) of yeast and/or Arabidopsis qko-mutant cells, allowing a growth restoration of both mutants on NH4 + . Quantitative PCR measurement showed that GhAMT1.3 was expressed in roots and leaves and markedly up-regulated by N-starvation, repressed by NH4 + resupply and regulated diurnally and age-dependently, suggesting that GhAMT1.3 should be a N-responsive gene. Importantly, GhAMT1.3 expression in Arabidopsis improved plant growth on NH4 + and enhanced total nitrogen accumulation (∼50% more), conforming with the observation of 2-fold more NH4 + absorption by GhAMT1.3-transformed qko plant roots during a 1-h root influx period. Together with its targeting to the PM and saturated transport kinetics with a Km of 72 µM for NH4 + , GhAMT1.3 is suggested to be a high-affinity NH4 + permease that may play a significant role in cotton NH4 + acquisition and utilization, adding a new member in the plant AMT family.

In Vivo Confocal Microscopic Study of Hard Contact Lens-Induced Lipid Keratopathy Secondary to Corneal Neovascularization in a Rabbit Hypercholesterolemic Model.

OBJECTIVES: In vivo confocal microscopy was used to observe the morphological presentations and anatomical correlations between corneal neovascularization (NV) and intracorneal lipid deposition in a rabbit model of contact lens (CL)-induced lipid keratopathy secondary to corneal NV. METHODS: Rabbits were divided into 3 groups: (1) 8-week normal diet, (2) 8-week high-cholesterol diet, and (3) 4-week normal diet followed by 4-week high-cholesterol diet. Corneal NV was induced by closed-eye CL. The formation and maturation of corneal NV were shown by immunohistochemical staining against CD31 and high-molecular-weight melanoma-associated antigen. In vivo confocal microscopy identified corneal NV and lipid deposition. Acquired images for each eye were arranged and mapped into subconfluent montages. RESULTS: In group 1, corneal NV sprouting formed from the peripheral to the central cornea by the end of week 4. Pericytes around vessels were shown after 2 weeks of CL wear. In group 2, lipid deposition started from the peripheral cornea and progressively covered the whole cornea. In group 3, lipid deposition was found first in the central cornea after 2 weeks of high-cholesterol diet and progressed to cover the peripheral cornea. In vivo confocal microscopy demonstrated four different patterns of intracorneal lipid deposition: spindle shapes arranged randomly or in parallel, amorphous shapes, multiangular shapes, and mixed types. Intracorneal lipid deposition was distributed from basal corneal epithelium to deep stroma. CONCLUSIONS: Intracorneal lipids tend to accumulate around newly formed corneal NV but can extend to the area covered with mature NV. In vivo confocal microscopy can demonstrate various shapes and depths of intracorneal lipid deposition.

Supramolecular Interactions Direct the Formation of Two Structural Polymorphs from One Building Unit in a One-Pot Synthesis.

Two polymorphs of supramolecular isomers, a discrete dimer and a zig-zag chain, having the same chemical composition, [Mn(Hbit)Cl2 ] (Hbit=1-methyl-2-(1H-1,2,3-triazol-4-yl)-1H-benzo[d]imidazole), were obtained solvothermally in a one-pot synthesis. The isomers differ in a number of ways: orange blocks versus pale-yellow needles, triclinic P1‾ versus orthorhombic Pbcn, double µ2 -Cl versus alternate single and triple µ2 -Cl, coordination number 5 versus 6, and antiparallel versus parallel near-neighbor orientation of Hbit. The packing in each case is driven by the supramolecular interactions, H-bonds (N-H⋅⋅⋅Cl, C-H⋅⋅⋅Cl) and π⋅⋅⋅π overlaps, calculated to be in the range 20-36 kcal mol-1 . Calculations gave a difference of only 2 kcal mol-1 in favor of the dimer, which confirms with the observation of principally the dimer at short reaction time. ESI-MS spectra of the dissolved crystals reveal the same fragments with similar distributions. The presence of two fragments at m/z 286.96 [MnIV (Hbit)Cl-2H]+ and 323.94 [MnIII (Hbit)Cl2 ]+ indicates that [Mn(Hbit)Cl2 ] is the building unit in both cases; thus, the different orientations of the ligands lead to the two polymorphs stabilized by the respective supramolecular interactions. Importantly, the chain form represents the first example with alternate single and triple µ2 -Cl bridges. The magnetic interactions are weakly antiferromagnetic in both cases, with J in the range 0.07-0.34 cm-1 ; however, high-field EPR analysis reveals moderate magneto-anisotropy with D=0.26(1) cm-1 , E=0.06(1) cm-1 and D=0.17(1) cm-1 , E=0.03(1) cm-1 , respectively.

Slow Magnetic Relaxations in Cobalt(II) Tetranitrate Complexes. Studies of Magnetic Anisotropy by Inelastic Neutron Scattering and High-Frequency and High-Field EPR Spectroscopy.

Three mononuclear cobalt(II) tetranitrate complexes (A)2[Co(NO3)4] with different countercations, Ph4P+ (1), MePh3P+ (2), and Ph4As+ (3), have been synthesized and studied by X-ray single-crystal diffraction, magnetic measurements, inelastic neutron scattering (INS), high-frequency and high-field EPR (HF-EPR) spectroscopy, and theoretical calculations. The X-ray diffraction studies reveal that the structure of the tetranitrate cobalt anion varies with the countercation. 1 and 2 exhibit highly irregular seven-coordinate geometries, while the central Co(II) ion of 3 is in a distorted-dodecahedral configuration. The sole magnetic transition observed in the INS spectroscopy of 1-3 corresponds to the zero-field splitting (2(D2 + 3E2)1/2) from 22.5(2) cm-1 in 1 to 26.6(3) cm-1 in 2 and 11.1(5) cm-1 in 3. The positive sign of the D value, and hence the easy-plane magnetic anisotropy, was demonstrated for 1 by INS studies under magnetic fields and HF-EPR spectroscopy. The combined analyses of INS and HF-EPR data yield the D values as +10.90(3), +12.74(3), and +4.50(3) cm-1 for 1-3, respectively. Frequency- and temperature-dependent alternating-current magnetic susceptibility measurements reveal the slow magnetization relaxation in 1 and 2 at an applied dc field of 600 Oe, which is a characteristic of field-induced single-molecule magnets (SMMs). The electronic structures and the origin of magnetic anisotropy of 1-3 were revealed by calculations at the CASPT2/NEVPT2 level.

Impact of Ocular Chronic Graft-versus-Host Disease on Quality of Life.

Ocular involvement can be quite symptomatic in patients with chronic graft-versus-host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P < .001), compared with patients without ocular GVHD. In conclusion, this large, multicenter, prospective study shows that ocular GVHD affects 57% of patients within 2 years of chronic GVHD diagnosis. Women, patients on higher doses of prednisone at study entry, and those with a history of acute GVHD were at higher risk for ocular GVHD. Strong evidence suggests that ocular GVHD is associated with worse overall health-related QOL.

Bandage Soft Contact Lenses for Ocular Graft-versus-Host Disease.

To examine safety and efficacy of bandage soft contact lenses (BSCLs) for ocular chronic graft-versus host disease (GVHD), we conducted a phase II clinical trial. Extended-wear BSCLs were applied under daily topical antibiotic prophylaxis. Patients completed standardized symptom questionnaires at enrollment and at 2 weeks, 4 weeks, and 3 months afterward. Ophthalmologic assessment was performed at enrollment, at 2 weeks, and afterward as medically needed. Assessments at follow-up were compared with baseline by paired t-test. Nineteen patients with ocular GVHD who remained symptomatic despite conventional treatments were studied. The mean Lee eye subscale score was 75.4 at enrollment and improved significantly to 63.2 at 2 weeks (P = .01), to 61.8 at 4 weeks (P = .005), and to 56.3 at 3 months (P = .02). The ocular surface disease index score and 11-point eye symptom ratings also improved significantly. According to the Lee eye subscale, clinically meaningful improvement was observed in 9 patients (47%) at 2 weeks, in 11 patients (58%) at 4 weeks, and in 9 patients (47%) at 3 months. Visual acuity improved significantly at 2 weeks compared with enrollment values. Based on slit lamp exam at 2 weeks, punctate epithelial erosions improved in 58% of the patients, showed stability in 16%, and worsened in 5%. No corneal ulceration or ocular infection occurred. BSCLs are a widely available, safe, and effective treatment option that improves manifestations of ocular GVHD in approximately 50% of patients. This study was registered at www.clinicaltrials.gov as NCT01616056.

Selective killing of K-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase.

INTRODUCTION: Oncogenic activation of the K-ras gene occurs in >90% of pancreatic ductal carcinoma and plays a critical role in the pathogenesis of this malignancy. Increase of reactive oxygen species (ROS) has also been observed in a wide spectrum of cancers. This study aimed to investigate the mechanistic association between K-ras-induced transformation and increased ROS stress and its therapeutic implications in pancreatic cancer. METHODS: ROS level, NADPH oxidase (NOX) activity and expression, and cell invasion were examined in human pancreatic duct epithelial E6E7 cells transfected with K-ras (G12V) compared with parental E6E7 cells. The cytotoxic effect and antitumor effect of capsaicin, a NOX inhibitor, were also tested in vitro and in vivo. RESULTS: K-ras transfection caused activation of the membrane-associated redox enzyme NOX and elevated ROS generation through the phosphatidylinositol 3'-kinase (PI3K) pathway. Importantly, capsaicin preferentially inhibited the enzyme activity of NOX and induced severe ROS accumulation in K-ras-transformed cells compared with parental E6E7 cells. Furthermore, capsaicin effectively inhibited cell proliferation, prevented invasiveness of K-ras-transformed pancreatic cancer cells, and caused minimum toxicity to parental E6E7 cells. In vivo, capsaicin exhibited antitumor activity against pancreatic cancer and showed oxidative damage to the xenograft tumor cells. CONCLUSIONS: K-ras oncogenic signaling causes increased ROS stress through NOX, and abnormal ROS stress can selectively kill tumor cells by using NOX inhibitors. Our study provides a basis for developing a novel therapeutic strategy to effectively kill K-ras-transformed cells through a redox-mediated mechanism.

Therapeutic future of Fuchs endothelial corneal dystrophy: An ongoing way to explore.

Fuchs endothelial corneal dystrophy (FECD) is one of the most common corneal diseases that causes loss of visual acuity in the world. FECD is a genetically and pathogenetically heterogeneous disease that results in the failure of corneal endothelial cells to maintain fluid balance and functional homeostasis of the cornea. Corneal edema, central guttae formation, and bullae development are common corneal pathologies. Currently, the mainstay of FECD treatment is surgery. However, limited sources of corneal graft and postsurgical complications remain problematic. In recent years, with advances in medical science and technology, there have been a few promising trials of new treatment modalities for FECD. In addition to new surgical methods, novel modalities can be classified into pharmacological-associated treatment, cell therapy-associated treatment, and gene therapy-associated treatment. In this article, our primary focus is on the most recent clinical trials related to FECD, and we present a stepwise approach to enhance FECD management and ultimately improve patient outcomes. We thoroughly searched for FECD clinical trials and reviewed the study designs, methodologies, and outcomes of each trial conducted within the past decade. It is imperative for physicians to stay up-to-date with these cutting-edge treatment approaches.

Investigation of topical amniotic membrane suspension and ReGeneraTing Agent on early corneal stromal healing in rats.

Innovative topical bioregenerative materials promoting corneal stromal healing provide valuable alternatives for treating patients with deep corneal ulcers, and particularly beneficial for those with a higher anaesthetic risk. This study aimed to investigate the effects of topical amniotic membrane suspension (AMS) and ReGeneraTing Agent (RGTA) on surgically induced deep stromal ulcers in rats. Eighteen Sprague-Dawley rats were divided into 3 treatment groups: control group (topical normal saline, TID); AMS group (topical AMS, TID); RGTA group (topical RGTA, Q2D). Corneal microsurgery was used to create deep stromal ulcer. Evaluations were performed by corneal opacity grading, spectral domain optical coherence tomography (SD-OCT), histopathology, and immunohistochemistry. One-way ANOVA and Dunnett's test were used for statistical analysis. By the seventh day of treatment, both the AMS and RGTA groups showed significantly greater thickness in corneal stroma (both p-value < 0.05) than the control group. Additionally, the RGTA group exhibited a significantly higher degree of myofibroblast infiltration in the stroma and a greater level of corneal opacity (p < 0.05). No significant differences in the count of inflammatory cells were noted. In conclusion, both AMS and RGTA have demonstrated effectiveness in promoting the early stages of stromal wound healing and wound defect recovery in our research. Both AMS and RGTA have good potential for treating deep corneal ulcers in small animals practice. Further research is necessary to investigate the long-term effects and mechanism of using topical AMS and RGTA on treating deep corneal ulcer in clinical practice.

Characterizing the Robustness of Distinct Clinical Assessments in Identifying Dry Eye Condition of Animal Models.

PURPOSE: The study aims to characterize the robustness of distinct clinical assessments in identifying the underlying conditions of dry eye disease (DED), with a specific emphasis on the involvement of conjunctival goblet cells. METHODS: Seven rabbits receiving surgical removal of the lacrimal and Harderian glands were divided into two groups, one with ablation of conjunctival goblet cells by topical soaking of trichloroacetic acid (TCA) to the bulbar conjunctiva (n = 3) and one without (n = 4), and the conditions of DED were assessed weekly using Schirmer test, tear breakup time (TBUT), tear osmolarity, and National Eye Institute (NEI) fluorescein staining grading. After 8 weeks, the rabbits were sacrificed, and the eyes were enucleated for histopathological examination. RESULTS: Histopathological analysis revealed corneal epithelial thinning in both groups. While TCA soaking significantly decreased the density of conjunctival goblet cells, DED rabbits without TCA also showed a partial reduction in goblet cell density, potentially attributable to dacryoadenectomy. Both groups showed significant decreases in Schirmer test and TBUT, as well as an increase in tear osmolarity. In DED rabbits with TCA soaking, tear osmolarity increased markedly, suggesting that tear osmolarity is highly sensitive to loss and/or dysfunction of conjunctival goblet cells. Fluorescein staining was gradually and similarly increased in both groups, suggesting that fluorescein staining may not reveal an early disruption of the tear film until the prolonged progression of DED. CONCLUSION: The Schirmer test, TBUT, tear osmolarity, and NEI fluorescein grading are distinct, yet complementary, clinical assessments for the evaluation of DED. By performing these assessments in definitive DED rabbit models, both with and without ablation of conjunctival goblet cells, the role of these cells in the homeostasis of tear osmolarity is highlighted. Characterizing the robustness of these assessments in identifying the underlying conditions of DED will guide a more appropriate management for patients with DED.

The ocular graft-versus-host disease: the path from current knowledge to future managements.

BACKGROUND: Graft-versus-host disease (GVHD) is one of the major complications of allogenic haematopoietic stem cell transplantation (HSCT). The manifestation of ocular GVHD (oGVHD) is variable and may involve cornea, lacrimal gland, conjunctiva, eyelid, and/or nasolacrimal duct. We reviewed and summarized the current managements of oGVHD with specific focus on the emerging therapeutic advances. METHODS: PubMed, Web of Science, and Google Scholar were searched for relevant literatures published within 20 years. Keywords used included "Graft-Versus-Host Disease", "GVHD", "ocular", "ocular surface", "ocular GVHD", "oGVHD", "dry eye", "keratitis", etc. RESULTS: Current managements of oGVHD can be classified into topical immunosuppressants, local tear-preservatory treatments, local non-pharmacological/surgical interventions, and systemic treatments. Additionally, some innovative therapies with promising treatment effects have been proposed, including topical target therapies, epitheliotrophic and neurotrophic treatments, recombinant DNase eye drops, mesenchymal stromal cell injection, and more. CONCLUSIONS: Clinical managements of oGVHD are administered in a symptom-based, stepwise manner. The advances in innovative therapies may help improve clinical outcomes, and it is essential that physicians stay updated with these novel treatment options.

The Omicron variant wave: Where are we now and what are the prospects?

The Omicron variant BA.2 is the dominant form of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in many countries, including those that have already implemented the strictest quarantine mandates that effectively contained the spread of the previous variants. Although many individuals were partially or fully vaccinated, confirmed Omicron infections have far surpassed all other variants combined in just a couple of months since the Omicron variant emerged. The ChAdOx1-S (AstraZeneca), BNT162b2 (Pfizer-BioNTech), and mRNA-1273 (Moderna) vaccines offer protection against the severe illness of SARS-CoV-2 infection; however, these currently available vaccines are less effective in terms of preventing Omicron infections. As a result, a booster dose of BNT162b2 or mRNA-1273 is recommended for individuals >12 years old who had received their second dose of the approved vaccines for >5 months. Herein, we review the studies that assessed the clinical benefits of the booster dose of vaccines against Omicron infections. We also analyzed public data to address whether early booster vaccination effectively prevented the surge of the Omicron infections. Finally, we discuss the consideration of a fourth dose of vaccine as a way to prevent possible upcoming infections.