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Abstract Compelling evidence has revealed a novel function of the STAT pathway in the pathophysiology of uveal melanoma (UM); however, its regulatory mechanisms remain unclear. Here, we analyzed the clinical prognostic value of STAT family genes in UM patients using bioinformatics approaches and found that high STAT6 expression is associated with poor prognosis. Furthermore, cellular experiments and a nude mouse model demonstrated that STAT6 promotes UM progression through the autophagy pathway both in vivo and in vitro. Next, RIP-PCR revealed that STAT6 protein binds to LINC01637 mRNA, which in turn regulates STAT6 expression to promote UM growth. Finally, molecular docking indicated that STAT6 is a target of Zoledronic Acid, which can delay UM tumorigenicity by inhibiting STAT6 expression. Taken together, our results indicate that the STAT6/LINC01637 axis promotes UM progression via autophagy and may serve as a potential therapeutic target for UM.

Abstract Background The pathogenesis of thyroid-associated orbitopathy (TAO) remains incompletely understand. The interaction between immunocytes and orbital fibroblasts (OFs) play a critical role in orbital inflammatory and fibrosis. Accumulating reports indicate that a significant portion of plasma exosomes (Pla-Exos) are derived from immune cells; however, their impact upon OFs function is unclear. Methods OFs were primary cultured from inactive TAO patients. Exosomes isolated from plasma samples of patients with active TAO and healthy controls (HCs) were utilized for functional and RNA cargo analysis. Functional analysis in thymocyte differentiation antigen-1+ (Thy-1+) OFs measured expression of inflammatory and fibrotic markers (mRNAs and proteins) and cell activity in response to Pla-Exos. RNA cargo analysis was performed by RNA sequencing and RT-qPCR. Thy-1+ OFs were transfected with miR-144-3p mimics/inhibitors to evaluate its regulation of inflammation, fibrosis, and proliferation. Results Pla-Exos derived from active TAO patients (Pla-ExosTAO−A) induced stronger production of inflammatory cytokines and hyaluronic acid (HA) in Thy-1+ OFs while inhibiting their proliferation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and single sample gene set enrichment analysis (ssGSEA) suggested that the difference in mRNA expression levels between Pla-ExosTAO−A and Pla-ExosHC was closely related to immune cells. Differential expression analysis revealed that 62 upregulated and 45 downregulated miRNAs in Pla-ExosTAO−A, with the elevation of miR-144-3p in both Pla-Exos and PBMCs in active TAO group. KEGG analysis revealed that the target genes of differentially expressed miRNA and miR-144-3p enriched in immune-related signaling pathways. Overexpression of the miR-144-3p mimic significantly upregulated the secretion of inflammatory cytokines and HA in Thy-1+ OFs while inhibiting their proliferation. Conclusion Pla-Exos derived from patients with active TAO were immune-active, which may be a long-term stimulus casual for inflammatory and fibrotic progression of TAO. Our finding suggests that Pla-Exos could be used as biomarkers or treatment targets in TAO patients.

BackgroundThe impact of baseline triglyceride-glucose (TyG) index and abnormal low or high-density lipoprotein cholesterol (LDL-C or HDL-C) levels on all-cause and cardiovascular disease (CVD) mortality remains unclear. This study aimed to investigate the relationship between TyG index and LDL-C or HDL-C and all-cause and CVD mortality.MethodsThis retrospective cohort study analyzed data from health examinations of 69,068 older adults aged ≥60 in Xinzheng City, Henan Province, China, between January 2013 and January 2023. Cox proportional risk regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of the TyG index and LDL-C or HDL-C about all-cause and CVD mortality. Restricted cubic spline was used to assess the dose-response relationship.ResultsDuring 400,094 person-years of follow-up (median follow-up 5.8 years [interquartile range 3.0-9.12]), 13,664 deaths were recorded, of which 7,045 were due to CVD. Compared with participants in the second quartile of the TyG index, participants in the fourth quartile had a 16% increased risk of all-cause mortality (HR: 1.16, 95% CI: 1.12,1.22), and an 8% increased risk of CVD mortality (HR: 1.08, 95% CI: 1.01,1.16). Similar results were observed in LDL-C and HDL-C, with all-cause and CVD mortality risks for participants in the fourth quartile compared with participants in the third quartile for LDL-C of (HR: 1.07, 95% CI: 1.02,1.12) and (HR: 1.09, 95% CI: 1.01,1.17), respectively. The risk of all-cause and CVD mortality in participants in the fourth quartile group compared with those in the second HDL-C quartile group was (HR: 1.10, 95% CI: 1.05,1.16) and (HR: 1.11, 95% CI: 1.04,1.18), respectively. We found that the TyG index was nonlinearly associated with all-cause and CVD mortality (P non-linear 0.05). HDL-C, on the other hand, was in contrast to LDL-C, which showed a non-linear association with CVD mortality. We did not observe a significant interaction between TyG index and LDL-C or HDL-C (P >0.05).ConclusionTyG index and LDL-C or HDL-C increased the risk of all-cause and CVD mortality, especially a high TyG index combined with abnormal LDL-C.

Purpose: To quantify interocular differences in the retinal microvasculature between disparate eyes and explore associations between the retinal microvasculature and visual field abnormalities within the same asymmetric thyroid-associated ophthalmopathy (TAO) patients. Methods: Within the same asymmetric TAO eye, the eye with a severer visual field abnormality (based on the mean deviation [MD]) was considered a severe eye, and the fellow eye was considered mild. The densities of radial peripapillary capillary (RPC) and superficial retinal capillary plexuses (SRCP) were determined using optical coherence tomography angiography. Interocular differences in RPC and SRCP densities were analyzed. A generalized estimating equation (GEE) was used to form a predictive model for visual field abnormalities. Pearson's correlation was used to show the correlation between MD and the densities of RPC and SRCP. Results: In 57 asymmetric TAO patients, the global RPC density in severe eyes was lower than that in mild eyes (P < 0.001), but there was no significant difference in SRCP density between the two groups (P = 0.114). In a multivariate GEE model with MD as the outcome, MD was associated only with global RPC density (coefficient β=0.327, P < 0.001). The global RPC density was correlated with MD (r = 0.360, P = 0.003) in severe eyes, but not in mild eyes (r = 0.179, P = 0.092). No significant correlation was observed between global SRCP density and MD in either group (Both P > 0.05). Conclusions: RPC density decreased significantly and correlated with visual field abnormalities in severe eyes of TAO patients. Alterations in RPC density may contribute to visual field abnormalities in TAO eyes.

Abstract Background Retinal degeneration (RD) is a group of disorders on irreversible vision loss. Multiple types of stem cells were used in clinical trials for RD treatment. However, it remains unknown what kinds of stem cells are most effective for the treatment. Therefore, we investigated the subretinal transplantation of several types of stem cells, human adipose-derived stem cells (hADSCs), amniotic fluid stem cells (hAFSCs), bone marrow stem cells (hBMSCs), dental pulp stem cells (hDPSCs), induced pluripotent stem cell (hiPSC), and hiPSC-derived retinal pigment epithelium (RPE) cells for protection effects, paracrine effects and treatment efficiency in an RD disease model rats. Methods The generation and characterization of these stem cells and hiPSC-derived RPE cells were performed before transplantation. The stem cells or hiPSC-derived RPE cell suspension labelled with CellTracker Green to detect transplanted cells were delivered into the subretinal space of 3-week-old RCS rats. The control group received subretinal PBS injection or non-injection. A series of detections including fundus photography, optomotor response (OMR) evaluations, light–dark box testing, electroretinography (ERG), and hematoxylin and eosin (HE) staining of retinal sections were conducted after subretinal injection of the cells. Results Each stem cell, hiPSC-derived RPE cell or PBS (blank experiment) was successfully transplanted into at least six RCS rats subretinally. Compared with the control rats, RCS rats subjected to subretinal transplantation of any stem cells except hiPSCs showed higher ERG waves (p

Abstract Background Idiopathic orbital inflammation (IOI) is a nonspecific orbital inflammatory disease with the third highest prevalence among orbital diseases, and its pathogenesis is associated with T-cell-mediated immune responses. This study aimed to investigate the differences in T-cell receptor (TCR) expression between IOI patients and healthy subjects by high-throughput sequencing and to characterize TCR expression in patients with IOI and with respect to glucocorticoid response. Methods A total of 19 subjects were enrolled in this study and were divided into the idiopathic orbital inflammation group (IOI group, n = 13) and the healthy control group (HC group, n = 6), and within the IOI group were further divided into the glucocorticoid therapy sensitive group (IOI(EF) group, n = 6) and the glucocorticoid therapy ineffective group (IOI(IN) group, n = 7) based on the degree of effectiveness to glucocorticoid therapy. High-throughput TCR sequencing was performed on peripheral blood mononuclear cells of IOI patients and healthy control individuals using 5’ RACE technology combined with Unique Identifier (UID) digital tag correction technology. The TCR CDR3 region diversity, sharing patterns, and differential sequences between the IOI and HC groups, and between the IOI(EF) and IOI(IN) groups were analyzed. Results It was found that the diversity of TCR CDR3 in the IOI group was significantly lower than that in the HC group, and the frequency of V gene use was significantly different between groups. The diversity of TCR CDR3 in patients in the IOI(EF) group was significantly lower than that in patients in the IOI(IN) group, and the frequency of V and J gene use was significantly different between the IOI(EF) group and the IOI(IN) group. Additionally, we found 133 nucleotide sequences shared in all IOI samples and screened two sequences with higher expression from them. Conclusions Our results suggested that abnormal clonal expansion of specific T-cells exists in IOI patients and that TCR diversity may had an impact on the prognosis of glucocorticoid-treated IOI. This study may contribute to a better understanding of the immune status of IOI and provide new insights for T-cell -associated IOI pathogenesis, diagnosis and treatment prediction.

IntroductionThe prevalence of dental caries (DC) among students in developing countries has increased at an alarming rate, and nutritional status has been shown to be associated with DC in children and adolescents with inconsistent conclusions. We aimed to understand the trends of DC prevalence in students aged 7, 9, 12, and 14 years and to explore the relationship between DC prevalence and nutritional status.MethodsWe recruited 16,199 students aged 7, 9, 12, and 14 years in China by multi-stage, stratified, random sampling methods from 2010 to 2019. Permanent caries were measured using the Decay, Loss, and Filling (DMF) index and prevalence rate. Deciduous caries were measured using the decay, loss, and filling (dmf) index and prevalence rate. Nutritional status was assessed using body mass index (BMI) and hemoglobin levels. Logistic regression analysis was used to assess the association between nutritional status and the DC prevalence in children and adolescents, incorporating information concerning family-related factors.ResultsThe results indicated that DC prevalence increased from 39.75% in 2010 to 53.21% in 2019 in Henan province, with deciduous teeth and permanent teeth being 45.96 and 27.18%, respectively, in 2019. The total caries rate decreased with age (p

Abstract Uveal melanoma (UM) is the most frequent primary intraocular malignancy with high metastatic potential and poor prognosis. Macrophages represent one of the most abundant infiltrating immune cells with diverse functions in cancers. However, the cellular heterogeneity and functional diversity of macrophages in UM remain largely unexplored. In this study, we analyzed 63,264 single-cell transcriptomes from 11 UM patients and identified four transcriptionally distinct macrophage subsets (termed MΦ-C1 to MΦ-C4). Among them, we found that MΦ-C4 exhibited relatively low expression of both M1 and M2 signature genes, loss of inflammatory pathways and antigen presentation, instead demonstrating enhanced signaling for proliferation, mitochondrial functions and metabolism. We quantified the infiltration abundance of MΦ-C4 from single-cell and bulk transcriptomes across five cohorts and found that increased MΦ-C4 infiltration was relevant to aggressive behaviors and may serve as an independent prognostic indicator for poor outcomes. We propose a novel subtyping scheme based on macrophages by integrating the transcriptional signatures of MΦ-C4 and machine learning to stratify patients into MΦ-C4-enriched or MΦ-C4-depleted subtypes. These two subtypes showed significantly different clinical outcomes and were validated through bulk RNA sequencing and immunofluorescence assays in both public multicenter cohorts and our in-house cohort. Following further translational investigation, our findings highlight a potential therapeutic strategy of targeting macrophage subsets to control metastatic disease and consistently improve the outcome of patients with UM.

Abstract Orbital inflammatory pseudotumor (OIP) is a benign, non-specific inflammatory disorder that commonly occurs in middle-aged adults and is usually unilateral but can occur bilaterally. Its clinical manifestations have tremendous clinical heterogeneity and vary according to the site of infiltration and the degree of lesions, including orbital pain, swelling, diplopia, proptosis, restricted eye movement, and decreased visual acuity. Clinical features, Image characteristics and pathological examinations often need to be evaluated to confirm the diagnosis. Currently, there is no systematic research on the pathogenesis of OIP, which may be related to immunity or infection. The first-line treatment is glucocorticoids. Radiotherapy, immunosuppressants, and biologics can be considered for treatment-resistant, hormone-dependent, or intolerant patients. In this review, we aim to summarize and focus on new insights into OIP, including new diagnostic criteria, pathogenesis, and discoveries in new drugs and treatment strategies. In particular, we highlight the literature and find that T cell-mediated immune responses are closely related to the pathogenesis of OIP. Further exploration of the mechanism and signaling pathway of T cells in the immune process will help to identify their therapeutic targets and carry out targeted therapy to treat refractory OIP and reduce the side effects of traditional treatments.

BackgroundAlzheimer’s disease (AD) is the most common neurogenerative disorder, making up 70% of total dementia cases with a prevalence of more than 55 million people. Electroencephalogram (EEG) has become a suitable, accurate, and highly sensitive biomarker for the identification and diagnosis of AD.MethodsIn this study, a public database of EEG resting state-closed eye recordings containing 36 AD subjects and 29 normal subjects was used. And then, three types of signal features of resting-state EEG, i.e., spectrum, complexity, and synchronization, were performed by applying various signal processing and statistical methods, to obtain a total of 18 features for each signal epoch. Next, the supervised machine learning classification algorithms of decision trees, random forests, and support vector machine (SVM) were compared in categorizing processed EEG signal features of AD and normal cases with leave-one-person-out cross-validation.ResultsThe results showed that compared to normal cases, the major change in EEG characteristics in AD cases was an EEG slowing, a reduced complexity, and a decrease in synchrony. The proposed methodology achieved a relatively high classification accuracy of 95.65, 95.86, and 88.54% between AD and normal cases for decision trees, random forests, and SVM, respectively, showing that the integration of spectrum, complexity, and synchronization features for EEG signals can enhance the performance of identifying AD and normal subjects.ConclusionThis study recommended the integration of EEG features of spectrum, complexity, and synchronization for aiding the diagnosis of AD.

Abstract Background To assess the accuracy of contrast sensitivity function (CSF) in detecting dysthyroid optic neuropathy (DON) at an early stage in thyroid-associated ophthalmopathy (TAO) patients and to examine potential factors that may be linked to early visual impairments in these individuals. Methods A total of 81 TAO patients (50 non-DON and 31 DON), and 24 control subjects participated in the study. CSF was measured with the quick CSF (qCSF) method. Optical coherence tomography angiography (OCTA) images of the ganglion cell complex layer (GCCL), superficial and deep retinal capillary plexuses (SRCP and DRCP) in a 3 mm diameter area around the macula were evaluated. Results Compared with the controls, the area under the log contrast sensitivity function (AULCSF) and SRCP density were significantly reduced in non-DON and DON patients (all P

Abstract Autophagy dysfunction is one of the common causes of tumor formation and plays an important role in uveal melanoma (UM). However, little is known about the regulatory mechanisms of autophagy in UM. Here, we show that PTK6 can promote the proliferation, migration, and invasion of UM cells by inhibiting autophagy. SOCS3 can inhibit the proliferation, migration, and invasion of UM cells. Overexpression of SOCS3 can partially rescue the PTK6-induced promotion of UM cell proliferation, migration, and invasion. Mechanistically, PTK6 can bind to SOCS3, and SOCS3 can downregulate the expression of PTK6. Furthermore, PTK6 can upregulate the phosphorylation of mTOR to inhibit autophagy. Taken together, our findings demonstrate the functions of PTK6 and SOCS3 in UM cells and targeting the SOCS3-PTK6 signaling axis might be a novel and promising therapeutic strategy for patients with UM.

PROteolysis TArgeting Chimeras (PROTACs) induce targeted protein degradation by hijacking the intracellular ubiquitin proteasome system, thus emerging as a new strategy for drug development. However, most PROTACs generated lack cell-type selectivity and are poorly soluble in water. To address this drawback, we developed a novel PROTAC ZL216 using aptamer AS1411 as a targeting ligand of nucleolin to conjugate with a small molecule ligand of E3 ligase VHL, which shows high aqueous solubility and serum stability. Based on the differential expression of nucleolin on the cell surface, ZL216 could bind to and internalize into breast cancer cells, but not normal breast cells. Furthermore, we revealed that ZL216 promoted the formation of a nucleolin-ZL216-VHL ternary complex in breast cancer cells and potently induced nucleolin degradation in vitro and in vivo. As a result, ZL216 inhibited the proliferation and migration of breast cancer cells. These studies demonstrate that in addition to peptides and small molecule compounds, nuclei acid aptamers can also be used to generate PROTACs, which broadens the toolbox constructing PROTACs and provides a promising strategy for development of tumor-selective PROTACs.

Abstract Background Bone fibrous dysplasia is a benign disease of bone tissue dysplasia. Vision impairment is the commonest neurological complication of craniofacial fibrous dysplasia. Most of the vision loss caused by craniofacial fibrous dysplasia is usually a gradual process. Very few present with acute visual impairment as described in our case. Case presentation We report a patient with fibrous dysplasia presenting rapidly progressive visual loss in the left eye secondary to bone cyst formation. Transnasal endoscopic surgery guided by navigation with drainage and curettage of this bone cyst and orbital decompression resulted in progressive improvement in visual acuity that returned to normal 1 month post-operatively. Conclusions In cases with acute visual loss due to fibrous dysplasia, emergency surgical treatment should be considered to preserve vision. In the surgical approach, navigation-guided nasal endoscopic surgery may be preferred because of its advantages.

BackgroundSurgical treatment of optic nerve tumors is challenging. The study’s objective was to evaluate the efficacy of a combined endoscopic transethmoid and transconjunctival approach in patients without functional vision.DesignA retrospective, noncomparative case series.MethodsRetrospective data were collected from all patients who had undergone tumor resection using this approach at the authors’ institution between 2015 and 2021. Preoperative assessments included magnetic resonance imaging and ophthalmological examinations, and re-assessments were conducted three months after surgery and regularly during the follow-up period.ResultsSeventeen patients, mean age 35 ± 19.0 years, were enrolled. Of these, 64.7% presented with visual acuity (VA) of light perception or no light perception. Gross total resection was realized in all patients. The average decline in exophthalmos was 3.63 ± 1.93 mm. Tumor histopathological analysis identified 12 optic nerve sheath meningiomas and 5 optic gliomas. The mean follow-up time was 30 months during which there was no local recurrence in any of the patients.ConclusionsThe combined endoscopic transethmoid and transconjunctival approach offers an additional choice for accessing optic nerve tumors. The procedure is both safe and effective and provides an alternative transcranial route to the orbit.

PurposeTo quantify the retinal vessel density in thyroid-associated ophthalmology (TAO) patients with visual field (VF) defect and examine its associations with mechanical and system vascular risk factors for underlying pathogenesis of VF defect in TAO.MethodsThe cohort was composed of 62 TAO eyes (39 with VF defect and 23 without VF defect). The pulse pressure (PP), intraocular pressure (IOP), ophthalmic rectus muscular index (MI), superficial retinal capillary plexus (SRCP), radial peripapillary capillary (RPC) density, and other related parameters were measured. The associations among these factors and VF mean deviation (MD) were analyzed.ResultsIn TAO patients with VF defect, reduced RPC density, higher PP, and larger horizontal and vertical MI were found (all P < 0.03) when compared to TAO patients without VF defect. The RPC density was correlated with VF MD value (r = 0.242, P = 0.029), while SRCP density was not (P = 0.419). In univariable general estimating equation (GEE) analysis with RPC density as the outcome, PP and its fluctuation showed a significant association (both P < 0.04). In the final RPC model with multivariable GEE analysis, only PP (β = -0.082, P = 0.029) showed significance while PP fluctuation (P = 0.080) did not.ConclusionsThe elevated PP was correlated with reduced retinal peripapillary perfusion in TAO resulting in VF defect. These data suggested that the system vascular factor may be important in the pathogenesis of reduced retinal perfusion resulting in visual impairment in TAO.

PurposeWe explored whether thyroid-associated ophthalmopathy (TAO) patients without clinical signs of dysthyroid optic neuropathy (DON) would have a selective deficit mediated by S-cone.MethodsThirty-two TAO patients without clinical signs of DON (non-DON, 42.03 ± 9.59 years old) and 27 healthy controls (41.46 ± 6.72 years old) participated in this prospective, cross-sectional study. All observers were tested psychophysically after passing color screening tests and a comprehensive ocular examination. Isolated L-, M-, and S-cone contrast thresholds were measured at 0.5 cyc/deg using Gabor patches. We calculated the area under the receiver operating characteristic (ROC) curve to quantify the ability of chromatic contrast sensitivity to detect the early visual function changes in non-DON patients.ResultsS-cone contrast sensitivity in non-DON patients was found to be lower than that of healthy controls (P < 0.001), whereas the sensitivities to L- and M-cone Gabor patches were similar between these two groups (P = 0.297, 0.666, respectively). Our analysis of the ROC curve revealed that the sensitivity to S-cone had the highest index to discriminate non-DON patients from healthy controls (AUC = 0.846, P < 0.001). The deficit of S-cone was significantly correlated with muscle index in non-DON patients (R = 0.576, P = 0.001).ConclusionThere is a selective S-cone deficit in the early stage of TAO. S-cone contrast sensitivity could serve as a sensitive measure of visual impairments associated with early DON in patients with TAO.

Abstract Background To describe the surgical technique and assess the clinical efficacy and safety of modified endoscopic transnasal orbital apex decompression in the treatment of dysthyroid optic neuropathy. Methods In this retrospective research, forty-two subjects (74 orbits) who underwent modified endoscopic transnasal orbital apex decompression for the treatment of dysthyroid optic neuropathy were enrolled. Preoperative and postoperative best-corrected visual acuity (BCVA), visual field mean deviation (MD), Hertel exophthalmometry, and new onset diplopia were assessed before and after the intervention. The Wilcoxon test was used for differential analysis. Linear mixed-models’ analyses were conducted to assess the potential predictors for BCVA change. Results Postoperatively, the mean BCVA improved from 0.70 ± 0.62 logMAR to 0.22 ± 0.33 logMAR. BCVA significantly improved in 69 eyes (93%), remained stable in 4 eyes (5%) and deteriorated in 1 eye (1%). MD of visual fields improved from −13.73 ± 9.22 dB to −7.23 ± 7.04 dB. Proptosis decreased from 19.57 ± 3.38 mm to 16.35 ± 3.01 mm. Preoperative BCVA, MD of visual fields and medical rectus diameter were independent factors associated with improvements in BCVA (P

Abstract Background Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative diseases and acts against oxidative stress but can also promote cell death, a phenomenon that is still unexplained in molecular terms. Here, we test whether HMOX1 has opposing effects during retinal degeneration and investigate the molecular mechanisms behind its pro-apoptotic role. Methods Basal and induced levels of HMOX1 in retinas are examined during light-induced retinal degeneration in mice. Light damage-independent HMOX1 induction at two different expression levels is achieved by intraocular injection of different doses of an adeno-associated virus vector expressing HMOX1. Activation of Müller glial cells, retinal morphology and photoreceptor cell death are examined using hematoxylin-eosin staining, TUNEL assays, immunostaining and retinal function are evaluated with electroretinograms. Downstream gene expression of HMOX1 is analyzed by RNA-seq, qPCR examination and western blotting. The role of one of these genes, the pro-apoptotic DNA damage inducible transcript 3 (Ddit3), is analyzed in a line of knockout mice. Results Light-induced retinal degeneration leads to photoreceptor degeneration and concomitant HMOX1 induction. HMOX1 expression at low levels before light exposure prevents photoreceptor degeneration but expression at high levels directly induces photoreceptor degeneration even without light stress. Photoreceptor degeneration following high level expression of HMOX1 is associated with a mislocalization of rhodopsin in photoreceptors and an increase in the expression of DDIT3. Genetic deletion of Ddit3 in knockout mice prevents photoreceptor cell degeneration normally resulting from high level HMOX1 expression. Conclusion The results reveal that the expression levels determine whether HMOX1 is protective or deleterious in the retina. Furthermore, in contrast to the protective low dose of HMOX1, the deleterious high dose is associated with induction of DDIT3 and endoplasmic reticulum stress as manifested, for instance, in rhodopsin mislocalization. Hence, future applications of HMOX1 or its regulated targets in gene therapy approaches should carefully consider expression levels in order to avoid potentially devastating effects.

Therapeutic hypothermia (TH) is potentially an important therapy for central nervous system (CNS) trauma. However, its clinical application remains controversial, hampered by two major factors: (1) Many of the CNS injury sites, such as the optic nerve (ON), are deeply buried, preventing access for local TH. The alternative is to apply TH systemically, which significantly limits the applicable temperature range. (2) Even with possible access for ‘local refrigeration’, cold-induced cellular damage offsets the benefit of TH. Here we present a clinically translatable model of traumatic optic neuropathy (TON) by applying clinical trans-nasal endoscopic surgery to goats and non-human primates. This model faithfully recapitulates clinical features of TON such as the injury site (pre-chiasmatic ON), the spatiotemporal pattern of neural degeneration, and the accessibility of local treatments with large operating space. We also developed a computer program to simplify the endoscopic procedure and expand this model to other large animal species. Moreover, applying a cold-protective treatment, inspired by our previous hibernation research, enables us to deliver deep hypothermia (4 °C) locally to mitigate inflammation and metabolic stress (indicated by the transcriptomic changes after injury) without cold-induced cellular damage, and confers prominent neuroprotection both structurally and functionally. Intriguingly, neither treatment alone was effective, demonstrating that in situ deep hypothermia combined with cold protection constitutes a breakthrough for TH as a therapy for TON and other CNS traumas.

Purpose. The aim of the study is to compare a non-contact tonometer (NCT) and goldmann applannation tonometer (GAT) in the evaluation of intraocular pressure (IOP) and mean ocular perfusion pressure (MOPP) in patients with thyroid-associated ophthalmopathy (TAO). Methods. In this study, a total of 30 patients (16 females and 14 males) were recruited. All patients underwent a routine ophthalmic assessment and their medical history was acquired. Clinical assessment included the 24-hour measurement of intraocular pressure and blood pressure, an orbital computed tomography (CT) scan, and a visual field (VF）test. Patients were divided into two groups according to their visual field test results: a defect group with mean deviation (MD) of visual field −2 dB or lower and a normal group with MD over −2 dB. Results. Bland–Altman’s analysis showed similar results of IOP at every time point and revealed an agreement of mean IOP between the two tonometers (the deviation in the mean IOP between the two tonometers was 1 mmHg, with 95% limits of agreement of 8.8 to −6.8 mmHg). The 24-hour MOPP SD value in NCT (2.28) and GAT (1.77) showed that the two instruments had the same diagnostic efficacy (100% sensitivity, 95.8% specificity). The areas under the receiver operator characteristic (ROC) curve of the 24-hour mean ocular perfusion pressure (MOPP) SD (GAT: 0.778, NCT: 0.713; z = 0.669, P=0.504), 24-hour MOPP fluctuation (GAT:0.683, NCT:0.757; z = 0.963, P=0.336) measured by GAT and NCT had no significant difference between the two tonometers. Conclusions. The measurement of IOPs, MOPPs, and their diagnostic efficacy of visual field defect showed consistency between NCT and GAT. The study highlights the importance of monitoring the 24-hour MOPP and IOP in TAO patients. Furthermore, it suggests that the less invasive NCT can replace GAT as a long-term monitoring device in TAO patients.

An implantation cyst after orbital wall reconstruction may present as a late complication, which can cause local pain, proptosis, diplopia, and vision impairment. Previous surgical strategies prefer transconjunctival or subtarsal approach for cyst drainage, a similar approach to orbital wall reconstruction. These strategies may have risk of secondary infection. Herein, we propose an endoscopic transnasal surgical approach, through which the removal of implant and cyst drainage can be performed conveniently. The residual, medial single-layer cyst wall is generally strong enough to support the orbital soft tissues without the need for a new implant. We believe this surgical approach can simplify the procedure, reduce the complications, and prevent cyst recurrence.

Abstract Background Breast cancer is the most prevalent cancer among women worldwide. WZ35, an analog of curcumin, has been demonstrated to remarkably improve the pharmacokinetic profiles in vivo compared with curcumin. WZ35 exhibits promising antitumor activity in gastric cancer, HCC, colon cancer. However, antitumor effects of WZ35 in breast cancer and its underlying molecular mechanisms remain unclear. Methods CCK8, Flow cytometry and transwell assays were used to measure cell proliferation, cell cycle arrest, apoptosis, cell migration and invasion. We constructed xenograft mouse model and lung metastasis model to assess the antitumor activities of WZ35 in vivo. To explore the underlying molecular mechanisms of WZ35, we performed a series of overexpression and knockdown experiments. The cellular oxygen consumption rates (OCRs) was measured to assess mitochondrial dysfunction. Results We found that treatment of breast cancer cells with WZ35 exerts stronger anti-tumor activities than curcumin both in vitro and in vivo. Mechanistically, our research showed that WZ35 induced reactive oxygen species (ROS) generation and subsequent YAP mediated JNK activation in breast cancer cells. Abrogation of ROS production markedly attenuated WZ35 induced anti-tumor activities as well as YAP and JNK activation. In addition, ROS mediated YAP and JNK activation induced mitochondrial dysfunction in breast cancer cells. Conclusion Our study showed that novel anti-cancer mechanisms of WZ35 in breast cancer cells and ROS-YAP-JNK pathway might be a potential therapeutic target for the treatment of breast cancer patients.

Abstract Background To evaluate the safety and outcomes of endoscopic trans-ethmosphenoid optic canal decompression (ETOCD) for children with indirect traumatic optic neuropathy (ITON). Methods From July 1st, 2008 to July 1st, 2015, 62 children diagnosed with ITON who underwent ETOCD were reviewed. Main outcome measure was improvement in visual acuity after treatment. Results Altogether 62 children (62 eyes) with a mean age of 11.26 ± 4.14 years were included. Thirty-three (53.2%) of them had residual vision before surgery while 29 (46.8%) had no light perception (NLP). The overall visual acuity improvement rate after surgery was 54.84%. The improvement rate of patients with residual vision (69.70%) was significant higher than that of patients with no light perception (NLP) (37.9%) (P = 0.012). However, no significant difference was shown among patients with different residual vision (P = 0.630). Presence of orbital and/ or optic canal fracture and hemorrhage within the post-ethmoid and/or sphenoid sinus resulted in poor postoperative visual acuity, duration of presenting complaints did not affect final visual acuity or did not effect outcomes. Intervention performed in children presenting even after 7 days from the injury did not influence the final visual outcome. Three patients developed cerebrospinal fluid rhinorrhea and one encountered cavernous sinus hemorrhage during surgery. No other severe complications were observed. Conclusion Children with residual vision had better postoperative visual prognosis and benefited more from ETOCD than children with NLP. Intervention performed in children presenting even after 7 days from the injury did not influence the final visual outcome, however, this needs to be reassessed in children presenting long after the injury.Treatment should still be recommended even for cases of delayed presentation to hospital.

We report a procedure using a pressure-controllable flute needle to remove subfoveal retention of perfluorocarbon liquid (PFCL) under silicone oil. With a two-port pars plana approach, we used a 27-gauge dental injection needle to create a retinotomy at the farthest edge of the PFCL bubble from the fovea. A 27-gauge flute needle was then inserted into the edge of the subfoveal PFCL to aspirate it with vacuum pressure. Three patients with subfoveal retained PFCL were treated by this procedure within silicone oil tamponade 1 month after the first operation. They promptly underwent successful removal of the PFCL with postoperative retinal reattachment and good visual outcome. This procedure allows safe and early treatment for subfoveal retained PFCL. Many medical institutions around the world could implement this procedure using common dental injection needles and flute needles.

Purpose. To evaluate the efficacy, feasibility, and safety of the navigation-guided endoscopy combined with deep lateral orbitotomy for removal of small tumors at the lateral orbital apex. Design. A retrospective, noncomparative case series. Methods. Retrospective analysis of ten patients (10 eyes) with small tumors at the lateral orbital apex comprised navigation-guided endoscopy combined with deep lateral orbitotomy at the Eye Hospital of Wenzhou Medical University from November 2015 to November 2017. In each case, the indication of surgery was existing or imminent visual impairment due to the tumor. The removal was believed to be complete if the mass was removed intactly during the surgery. The tumor character was confirmed by pathological examination after surgery. Patients were followed up to 3 months after surgery. Best corrected visual acuity before and after surgery was compared. Results. All tumors were completely removed by the navigation-guided endoscopic approach. The mean preoperative best corrected visual acuity was 6/15 (95% confidence interval (95% CI) 6/40–6/8.5), and the mean postoperative best corrected visual acuity was 6/10 (95% CI 6/15–6/7.5). 5 of 7 (71%) patients with vision loss gained visual improvement in different degrees after surgery, and the rest of the patients had preoperative best corrected visual acuity. Visual field of all patients also improved. 8 cavernous hemangiomas and 2 schwannomas were confirmed postoperatively by pathology. 4 patients accompanied with limitation of eye abduction, which recovered spontaneously in an average of 4 weeks. No other serious complications occurred. Conclusions. Navigation-guided endoscopy combined with deep lateral orbitotomy seems to be a feasible, efficient, and safe approach for removing small tumors at the lateral orbital apex. This trial is registered with ChiCTR1800019244.

Inflammation is a key factor in the pathogenesis of ALI. Therefore, suppression of inflammatory response could be a potential strategy to treat LPS-induced lung injury. Osthole, a natural coumarin extract, has been reported to protect against acute kidney injury through an anti-inflammatory mechanism, but its effect on ALI is poorly understood. In this study, we investigated whether osthole ameliorates inflammatory sepsis-related ALI. Results from in vitro studies indicated that osthole treatment inhibited the LPS-induced inflammatory response in mouse peritoneal macrophages through blocking the nuclear translocation of NF-κB. Consistently, the in vivo studies indicated that osthole significantly prolonged the survival of septic mice which was accompanied by inflammation suppression. In the ALI mouse model, osthole effectively inhibited the development of lung tissue injury, leukocytic recruitment, and cytokine productions, which was associated with inhibition of NF-κB nuclear translocation. These findings provide evidence that osthole was a potent inhibitor of NF-κB and inflammatory injury and suggest that it could be a promising anti-inflammatory agent for therapy of septic shock and acute lung injury.

To report a patient with traumatic orbital apex syndrome, who fully recovered visual and extraocular function following surgery. A 34-year-old male presented with visual and extraocular function disorders in his right eye following traffic accident, who was referred to our hospital 5 weeks after accident. The patient underwent endoscopic optic nerve and orbital apex decompression with topical and systemic application of nerve growth factor and steroids after a failed trial of mega-dose intravenous corticosteroids. Visual acuity improved to 20/20 at 3 weeks after surgery, and the right eye globe moved in most directions at 1 year, which remained stable at 3 years. Surgical decompression should be considered even when symptoms have been present for over a month.

Purpose. The study aimed to investigate canalicular/lacrimal sac mucosal folds (CLS-MFs) in vivo and in cadavers in order to explore their functional roles in the lacrimal drainage system. Method. The observations of CLS-MFs in vivo were performed on 16 patients with chronic dacryocystitis after undergoing an endonasal endoscopic dacryocystorhinostomy (EE-DCR). The lacrimal sacs and common canaliculi of 19 adult cadavers were dissected. The opening/closing of an orifice and mucosal fold was recorded. All of the specimens were subjected to a histological examination. Results. The upper and lower lacrimal canaliculi in all of the samples united to form a common canaliculus that opened to the lacrimal sac. CLS-MFs were observed in 10 of the 16 patients (62.5%) and 9 of the 19 cadavers (47.4%). The orifices or mucosal folds could be opened or closed when related muscles contracted or relaxed. Histological sections showed a mucosal fold at one side of an orifice. Conclusion. Common canaliculus is the most common type that the canaliculus opens to lacrimal sac. CLS-MFs exist in a certain ratio that can be opened/closed with the movement of the orifices. They may be involved in the drainage of tears or the pathogenesis of acute dacryocystitis or lacrimal sac mucocele.

Purpose. To present the safety and effect of endoscopic transethmosphenoid optic canal decompression (ETOCD) for indirect traumatic optic neuropathy (ITON) patients with no-light-perception (NLP). Methods. A retrospective study performed on 96 patients (96 eyes) with NLP after ITON between June 1, 2010, and June 1, 2015, who underwent ETOCD, was reviewed. Visual outcome before and after treatment was taken into comparison. Results. The overall visual acuity improvement rate after surgery was 46.9%. The improvement rates of visual acuity of patients who received treatment within 3 days of injury, 3–7 days after injury, and later than 7 days were 63.6%, 42.9%, and 35.7%, respectively. Statistically significant difference was detected between the effective rates of within-3-day group and later-than-7-day group (χ2=5.772, P=0.016). The effective rate of atrophy group and nonatrophy group was 25.0% and 51.3%, respectively. The effective rate was significantly higher in nonatrophy group (χ2=4.417, P=0.036). Conclusion. For patients suffering from ITON with NLP, time to medical treatment within 3 days is an influential factor for visual prognosis. Optic nerve atrophy is an important predictor for visual prognosis. Treatment should still be recommended even for cases of delayed presentation to hospital.

BACKGROUND:The establishment of a suitable and stable animal model is critical for research on thyroid-associated ophthalmopathy (TAO). In clinical practice, we found that patients treated with I-131 often exhibit TAO; therefore, we aimed to establish a novel thyroid function fluctuated animal model of TAO by simulating the clinical treatment process. METHODS:We treated SD rats with I-131 to damage the thyroid and then used sodium levothyroxine (L-T4) to supplement the thyroid hormone (TH) levels every seven days, leading to a fluctuating level of thyroid hormones that simulated the status of clinical TAO patients. Rats administered normal saline were considered as a control. The weight, intraocular pressure, and serum T3, T4, TSH and TRAb levels of the rats were measured, and the pathological changes were analyzed by H&E staining and transmission electron microscopy (TEM). RESULTS:The experimental rats (TAO group) exhibited significantly reduced weight and elevated intraocular pressure compared with the control rats. Meanwhile, the serum levels of T3 and T4 were up-regulated in the TAO group, but the TSH level decreased during the 10-week study. Moreover, increased numbers of blood vessels and inflammatory cell infiltrations were observed in the orbital tissues of the TAO rats, while no abnormal changes occurred in the control rats. The orbital myofibrils in the TAO rats appeared fractured and dissolved, with twisted structures. Mitochondrial swelling and vacuoles within the endoplasmic reticulum, swelling nerve fibers, shedding nerve myelin, and macrophages were found in the TAO group. CONCLUSION:Rats treated with I-131 and sodium levothyroxine exhibited characteristics similar to those of TAO patients in the clinic, providing an effective and simple method for the establishment of a stable animal model for research on the pathogenesis and treatment of TAO.

Purpose. The aim of this study is to propose a simple and efficient combination surgery for the management of dacryocystitis with canalicular obstruction. Methods. A retrospective noncomparative case series of dacryocystitis with canalicular obstruction has been studied. Twelve patients with dacryocystitis and canalicular obstruction underwent a conventional endoscopic endonasal dacryocystorhinostomy (EE-DCR) combined with a modified canalicular repair. Postoperative observations included slit lamp, fluorescein dye disappearance test, lacrimal syringing, lacrimal endoscopy, and nasal endoscopy. Results. After 6–18 months of postoperative follow-up, the symptoms of epiphora and mucopurulent discharge disappeared completely in 10 patients, and occasional or intermittent epiphora remained in 2 patients. All of the twelve patients showed an opened intranasal ostium and normal fluorescein dye disappearance test. Patent bicanalicular irrigation was achieved in 9 patients. One patient had a partial and the other two had a complete reobstruction by lacrimal irrigation to their repaired lower canaliculus; however, all of them had a patent lacrimal irrigation to upper canaliculus. The functional success rate for the combination surgery is 83% (10/12), and anatomical success rate is 75% (9/12). Conclusion. EE-DCR combined with modified canalicular repair is a simple and efficient method for the management of dacryocystitis with canalicular obstruction.

Purpose. To report on a patient with compressive optic neuropathy secondary to an Onodi cell mucocele, who fully recovered visual function following surgery. Method. Case report. Results. A 28-year-old male was admitted with a right visual acuity of 20/100 following treatment for an initial diagnosis of optic neuritis. Subsequent examination suggested compressive optic neuropathy, and neuroimaging confirmed the presence of an Onodi mucocele compressing the optic nerve. The patient underwent a right endonasal sphenoethmoidectomy with decompression 5 weeks after the initial onset of symptoms. Three weeks following surgery, the visual acuity was 20/20, and there was complete resolution of the visual field defect, which has remained stable at 1 year. Conclusion. Onodi cell mucocele should be included in the differential diagnosis of a young patient with compressive optic neuropathy. Surgical decompression should be considered even when symptoms have been present for over a month.