miR-130a-3p Enhances the Chemosensitivity of Y79 Retinoblastoma Cells to Vincristine by Targeting PAX6 Expression.

PURPOSE: Chemoresistance remains the primary obstacle threatening the prognosis of retinoblastoma (RB). microRNAs (miRNAs) are acknowledged as critical regulators of drug resistance. This study explored the molecular mechanism of miR-130a-3p affecting the chemosensitivity of RB to vincristine (VCR). METHODS: miR-130a-3p expression of human retinal astrocytes and RB cell lines (Y79, WERI-Rb-1, SO-Rb50, and SO-Rb70) was detected using RT-qPCR. VCR-resistant RB cell line Y79/VCR was induced. miR-130a-3p expression of Y79/VCR cell line and its corresponding parental cell line was detected. Y79/VCR cells were subjected to miR-130a-3p overexpression treatment. The cell proliferation was measured using MTT assay, and the IC50 value and drug resistance index were examined using CCK-8 assay. The targeting relationship between miR-130a-3p and PAX6 was predicted through bioinformatics analysis and verified using dual-luciferase assay. Functional rescue experiments were conducted to confirm the role of PAX6 in chemosensitivity of RB cells. The effect of miR-130a-3p on tumorigenesis and VCR sensitivity was observed in vivo. RESULTS: miR-130a-3p was downregulated in VCR-resistant RB cells. Overexpression of miR-130a-3p repressed the proliferation of Y79/VCR cells and enhanced chemosensitivity. miR-130a-3p targeted PAX6 expression. Overexpression of PAX6 reversed the effect of miR-130a-3p on chemosensitivity of Y79/VCR cells. Overexpression of miR-130a-3p suppressed tumor growth and reduced VCR resistance in vivo. CONCLUSIONS: miR-130a-3p enhanced the chemosensitivity of Y79 RB cells to VCR by targeting PAX6 expression.

Disruption of LTBP4 Inhibition-Induced TGFß1 Activation Promoted Cell Proliferation and Metastasis in Skin Melanoma by Inhibiting the Activation of the Hippo-YAP1 Signaling Pathway.

Melanoma is a malignant tumor derived from melanocytes, which is the most fatal skin cancer. The present study aimed to explore and elucidate the candidate genes in melanoma and its underlying molecular mechanism. A total of 1,156 differentially expressed genes were obtained from the GSE46517 dataset of Gene Expression Omnibus database using the package "limma" in R. Based on two algorithms (LASSO and SVM-RFE), we obtained three candidate DEGs (LTBP4, CDHR1, and MARCKSL1). Among them, LTBP4 was identified as a diagnostic marker of melanoma (AUC = 0.985). Down-regulation of LTBP4 expression was identified in melanoma tissues and cells, which predicted poor prognosis of patients with melanoma. Cox analysis results discovered that LTBP4 with low expression was an independent prognostic factor for overall survival in patients with melanoma. LTBP4 inhibition reduced cell apoptosis and promoted cell proliferation and metastasis. These changes were correlated with the expression levels of caspase-3, Ki67 and E-cadherin. Further, as indicated by tumor formation study of nude mice, LTBP4 silencing improved the tumorigenic ability of melanoma cells. Knockdown of LTBP4 increased the percentage of active TGFß1 secreted by melanoma cells. CTGF, Gyr61, and Birc5 expression levels were reduced, YAP1 phosphorylation was inhibited, and YAP1 was translocated from the cytoplasm to the nucleus in melanoma cells treated with TGF-ß1. These effects were reversed by LTBP4 overexpression. As evidenced by immunofluorescent staining, Western blotting and luciferase reporter assay, LTBP4 overexpression activated the Hippo signaling pathway, which was characterized by the increased nuclear-cytoplasmic translocation of YAP1 and the enhanced phosphorylation of YAP1, MST1, and MOB1. In addition, the effects of LTBP4 overexpression on inhibiting CTGF, Cyr61 and Birc5 expression, promoting the apoptosis, and inhibiting the metastasis and proliferation of melanoma cells were reversed by the overexpression of YAP1 or MST1. In conclusion, the LTBP4-TGFß1-Hippo-YAP1 axis is a critical pathway for the progression of skin melanoma.

Postoperative severe visual impairment: surgical outcome of 165 patients with orbital tumours in the muscle cone.

OBJECTIVE: This study aimed to evaluate the risk factors of postoperative severe vision impairment (PSVI) for a primary orbital tumour in the muscle cone. METHODS: A retrospective analysis of the patients who underwent orbitotomy for primary intraconal tumours at the Tianjin Medical University Eye Hospital from January 2010 to December 2015. RESULTS: A total of 165 cases of orbitotomy for primary orbital tumours in the muscle cone were included in the study. Postoperatively, 12 cases with vision acuity ≤20/400 or ≥4 rows of vision decline and without any corrected effect were analysed as PSVI, including no light perception (NLP) for 3 cases. The multivariate logistic regression indicated that the tumour in orbital apex (P = 0.048, OR = 4.912, 95% CI: 1.011-23.866), severe optic nerve displacement (P = 0.030, OR = 6.007, 95% CI: 1.184-30.473) and intraoperative tight adhesion (P = 0.003, OR = 12.031, 95% CI: 2.282-63.441) were the independent risk factors for PSVI. CONCLUSIONS: The incidence of PSVI for the intraconal tumour was 7.3%, and the incidence of NLP was 1.8%. The tumour in orbital apex, severe optic nerve displacement and intraoperative tight adhesion were independent risk factors for PSVI.

Mutations in MC4R facilitate the angiogenic activity in patients with orbital venous malformation.

IMPACT STATEMENT: The detailed molecular mechanism of orbital venous malformation (OVM) is still not clear. Using whole exome sequencing, 4 types of melanocortin 4 receptor (MC4R) mutation were detected in 7 of 27 patients with OVM, and all types of MC4R mutations resulted in the upregulation of MC4R expression. In vitro study indicated that MC4R has impacts on the proliferation, cell cycle, migration, and tube formation of the endothelial cells. Moreover, MC4R mutations altered the downstream signaling, including cAMP concentration and the expression levels of several PI3K/AKT/mTOR downstream genes, including p21, cyclin B1, ITGA10, and ITGA11. MC4R mutations may lead to the pathogenesis of OVM through modulating the downstream signaling to alter the angiogenic activity of endothelial cells.

ELF1-mediated LUCAT1 promotes choroidal melanoma by modulating RBX1 expression.

Long noncoding RNAs (lncRNAs) are essential regulators of gene expression and biological behaviors. However, the contribution of lncRNA LUCAT1 to choroidal melanoma (CM) remains unexplored. Here, we examined the expression of LUCAT1 in CM cells by qRT-PCR and investigated its biological effects by cell counting kit-8, EdU, TUNEL, transwell assays, and Western blot. Bioinformatics tools were applied to find RNA candidates for further study. Moreover, mechanistic experiments including RNA immunoprecipitation assay, pull-down assay, and luciferase reporter assay confirmed the relation or interaction among the indicated molecules. Here, we reported ELF1 as the transcription activator of LUCAT1. Functionally, elevated expression of LUCAT1 positively regulated CM cell proliferation, metastasis, and epithelial-mesenchymal transition process. In addition, we verified the competing endogenous RNA (ceRNA) hypothesis of LUCAT1 and confirmed LUCAT1 modulates CM progression by modulating miR-514a/b-3p/RBX1 axis. Meanwhile, miR-514a/b-3p was suggested to repress CM progression, whereas RBX1 was unmasked to aggravate CM development. Of note, RBX1 overexpression rescued the inhibitory effect of LUCAT1 silence on the biological processes of CM cells. Altogether, this study unveiled the modulation axis ELF1/LUCAT1/miR-514a/b-3p/RBX1 and evidenced LUCAT1 as a promoter in CM for the first time, providing a novel insight into future treatment of CM.

Clinical Analysis of Castleman's Disease of the Lacrimal Gland.

OBJECTIVE: To explore the clinical manifestations, imaging characteristics, and pathological characteristics of Castleman's disease of the lacrimal gland, enhance the knowledge of the disease, and improve the level of its diagnosis and treatment. METHODS: In the retrospective study, the data of 5 patients diagnosed with Castleman's disease of the lacrimal gland in Tianjin Medical University Eye Hospital from 2014 to 2018 were analyzed, and the relevant literature was reviewed. RESULTS: All the 5 patients were confirmed by pathological examination. Clinical manifestations were characterized by mass occupying lesions in the lacrimal gland area, without obvious pain, accompanied by eyelid swelling and ptosis, as well as space-occupying symptoms. Imaging examination showed that there was a soft tissue mass in the enlarged lacrimal gland area, and the mass was rich in blood flows while showing no obvious specificity, which could invade the surrounding muscles. All patients underwent surgical resection. Pathological results showed that 1 case was of the hyaline-vascular type, 3 cases were of the plasma cell type, and 1 case showed malignant transformation to plasma cell tumor. CONCLUSION: Castleman's disease of the lacrimal gland is a rare orbital lymphoproliferative disease lacking specificity in clinical manifestations and imaging examination. As there are difficulties in differentiating the disease from orbital inflammatory pseudotumor and orbital lymphoma, its diagnosis still depends on pathological examination. The disease is mainly treated with surgical resection, and the pathological type is determined postoperatively.

Ectopic orbital meningioma: a retrospective case series.

BACKGROUND: To evaluate the ophthalmic manifestations and radiographic features of ectopic orbital meningioma to improve diagnostic accuracy. METHODS: Patient data from patients admitted to our institution during a 217-month period from August 1999 to September 2017 were included. Patient ophthalmic manifestations, radiographic features (CT and MRI), diagnosis, pathology, therapeutic regimens, and prognosis were retrospectively reviewed. RESULTS: Six patients with ectopic orbital meningioma were identified. The mean age at the first visit was 33.2 years (range, 7-56 years). All six patients displayed manifestations of exophthalmos, upper eyelid oedema, and motility impairment with a mean history of illness of 20.3 months (range 3-72 months). Optical lesions were located in the superonasal extraconal compartment (3/6, 50%), bitemporal extraconal compartment (1/6, 16.7%) and orbital intraconal compartment (2/6, 33%). Radiographic features were ill-defined, heterogeneous, enhancing soft tissue masses with extraocular muscular adhesion (6/6, 100%) and calcification (1/6, 16.7%), not adjacent to the optic nerve and not extending along the dura. Six cases were treated intraoperatively with complete surgical resection, indicating that all lesions were independent of the optic nerve and sphenoid ridge. The histopathologic classification was mostly of meningothelial cells (5/6, 83%). Immunohistochemistry revealed EMA and vimentin to have positive expression in all six cases, while two cases were calponin-positive and strongly expressed in the olfactory bulb. Postoperatively, lesions caused no visual impairment, and there were no cases of recurrence. CONCLUSIONS: Ectopic orbital meningiomas are rare tumours that are not easily diagnosed without postoperative histopathology. This report highlights some of the distinguishing features of isolated orbital lesions, especially around the location of frontoethmoidal suture. Accompanying upper eyelid oedema and eye mobility restriction were observed to be dissimilar to other orbital tumours. In these cases, a diagnosis of ectopic orbital meningioma should be considered.

Poly (ADP-ribose) polymerase-1 (PARP-1) in Chinese patients with Graves' disease and Graves' ophthalmopathy.

We aimed to evaluate the genetic variation of poly (ADP-ribose) polymerase-1 (PARP-1) as risk factor in development of Graves' disease (GD) and Graves' ophthalmopathy (GO) among Chinese individuals. Patients with confirmed diagnosis of GD or healthy individuals with no clinical symptoms of hyperthyroiditis were enrolled at the Department of Ophthalmology, Tianjin First Center Hospital, China. Genetic polymorphism was studied in plasma DNA samples of subjects by polymerase chain reaction of restriction fragment length polymorphism to confirm our hypothesis. Cytokine levels were measured routinely on serum samples of subjects by sandwich ELISA technique. Patients with GG genotype (odds ratio (OR) 95% CI = 2.25 (1.35-3.73), p = 0.002) and carriers of G allele (OR = 2.03 (1.23-3.36), p = 0.006) were at high risk of developing ophthalmopathy. Polymorphism of del/ins of nuclear factor-κB1 gene (NFkB1) gene (OR = 7.1 (2.88-17.52), p < 0.0001) and PARP-1 C410T polymorphism was found to be associated with GO (p < 0.05). Cytokine level was significantly higher in patients with GD (p < 0.05), but no significant change in cytokines level among GO patients from baseline (p > 0.05). Our study results recommended that polymorphism of PARP-1 gene is more likely responsible for development of GD in Chinese individuals. We also observed that the polymorphism of gene-related del/ins to NFkB1 in development of GO.

Clinical analysis of transcranial orbitotomy approach on cranio-orbital tumors.

AIMS: The aims of this study were to investigate 21 cases of transcranial orbitotomy for cranio-orbital tumors and evaluate the clinical value of the surgical approach. METHODS: A retrospective study was done on 21 patients with cranio-orbital tumors. According to the tumors' location, shape, boundary, and invasion on the images, coronal scalp flap approach, subfrontal approach, or pterion approach for transcranial orbitotomy was performed. RESULTS: The surgical route was coronal scalp flap approach in 7 cases (including 3 cases combined with lateral orbitotomy), subfrontal approach in 6 cases, or pterion approach in 8 cases (including 1 case combined with evisceration of orbit). Tumors were en bloc resection in 4 cases, block resection or curettage in 13 cases, and incomplete resection in 4 cases. Postoperatively, the mean reduction in exophthalmos was 4 mm; maximum reduction was 11 mm. Ocular movement restriction was made better in 10 of 14 patients, whereas there was no change in 4 of 14 patients. Ophthalmoplegia occurred in 2 cases, complete ptosis occurred in 3 cases, and mydriasis occurred in 3 cases. No vision loss or cerebrospinal fluid leak was observed. Fourteen patients were followed up, including 2 patients with metastatic carcinoma who died dead because of systemic metastasis; 2 patients had a recurrence (schwannoglioma and meningioma). No recurrence was found in the other 10 patients. CONCLUSIONS: Cranio-orbital tumors can be removed effectively through transcranial orbitotomy, whereas operative approach is convenient to the surgical procedure and can offer better exposure. Being familiar with the tumors' location, adhesion, and invasion, coupled with the skilled surgical techniques, would improve the results and reduce serious complications.

[Endoscopic transnasal orbital balanced decompression technique for severe Graves' orbitopathy].

OBJECTIVE: To determine the efficacy of endoscopic transnasal orbital balanced decompression technique for the treatment of severe Graves' orbitopathy. METHODS: Six cases (12 eyes) of severe Graves'orbitopathy were included in this study. All patients were undergone endoscopic transnasal orbital balanced decompression technique (orbital inner and lower wall decompression+ lateral orbital decompression) for severe Graves'orbitopathy and serious affecting visual function or appearance. RESULTS: The follow-up ranged from 12 months to 2 years and 4 months. Postoperatively, the visual acuity markly improved from 0.23 ± 0.08 to 0.48 ± 0.13 (t=-5.749, P<0.001). Proptosis measured by exophthalmoter distictly reduced from (22.08 ± 1.08) mm to (15.67 ± 1.44) mm (t=17.924, P< 0.001). The palpebral fissures obviously reduced from (12.03 ± 0.91) mm to (8.62 ± 0.75) mm (t=9.600, P< 0.001), and orbital volume evidently increased from (26.84 ± 0.62) cm³ to (31.56 ± 1.10) cm³ (t=-16.567, P<0.001). Compared with the preoperative result, the orbital pressure was significantly decreased after operation (t=-6.759 (Y=100 g), t=-11.850 (Y=200 g), t=-6.189 (Y=300 g), P<0.001). Diplopia was appeared in 3 cases, and disappeared 3 to 5 months after surgery. CONCLUSION: Endoscopic transnasal orbital balanced decompression technique is effective for the treatment of severe Graves'orbitopathy.

[The clinical analysis of cranio-orbital communicating tumors].

OBJECTIVE: To investigate the clinical manifestations, imageological features, surgical approaches and prognosis of cranio-orbital communicating tumors. METHODS: The retrospective analysis was performed in the 22 patients of cranio-orbital communicating tumors in the past three years. CT and MRI examinations were applied in all cases. Of 16 patients were treated by surgical approaches, Of 6 patients were for radiation therapy. RESULTS: Of 22 cases, 2 cases were osteoid osteoma, 3 cases were meningioma, 1 case was aneurysmal bone cyst, 2 cases were mucous cyst, 2 cases were schwannoma, 2 cases were adenoid cystic carcinoma of lacrimal gland, 2 cases were metastatic carcinoma, and 2 cases were rhabdomyosarcoma. Other 6 cases were treated by radiotherapy without pathological diagnosis. 8 cases for orbital operation including excision of orbital contents 1/8, anterior orbitotomy 3/8, and lateral orbitotomy 4/8, and 8 cases for transcranial operation including frontotemporal orbital roof approach 3/8 and pterion approach 5/8. After operation, the vision acuity of 3 cases was improved, of 10 cases was unchanged and of 3 cases was decreased. Two patients died of metastasis. Among 8 cases of transcranial operation, the complaints such as eye movement disorder, proptosis and conjunctival edema emerged in 1 case. However, among 8 cases of orbital operation, such above complaints were respectively found in 7, 5 and 6 cases. CONCLUSIONS: CT and MRI have the great value for diagnosis of cranio-orbital communicating tumors, especially combined with enhanced contrast MRI. Resection of cranio-orbital communicating tumors via the transcranial surgical approach is the effective surgical approach for cranio-orbital communicating tumors.

[Imaging feature and clinical histological analysis of 12 adenoid cystic carcinoma of the lacrimal gland].

OBJECTIVE: To study the imaging and histologic features of adenoid cystic carcinoma (ACC) of the lacrimal gland. METHODS: It was a retrospective case series study. Twelve patients with ACC of the lacrimal gland were surgically treated in Tianjin First Center Hospital from September 2009 to November 2011. The 5 men and 7 women aged from 22 to 63 years (average 42.6 years). The imaging and histologic features of 12 cases with ACC of the lacrimal gland pathologically confirmed were retrospectively reviewed. Twelve cases were performed with CT scan, 10 cases with MRI scan. All patients were followed up by telephone and reexamination in the outpatient service, and 2 patients were lost to follow-up. RESULTS: The lesions originated in the orbital lobe of the lacrimal gland. The most common presenting symptom was pain; it was followed by proptosis, ptosis, decreased visual acuity and diplopia. The 7th Edition of the American Joint Committee on Cancer TNM Classification system for Lacrimal Gland Tumors stages were as follows: T1N0M0 1 patients, T2N0M0 4 patients, T4N0M0 7 patients. Preoperative CT imaging suggested that bony involvement of the lacrimal gland fossa in 7 patients;this was histologically confirmed in 6 of the 7. Preoperative CT imaging suggested no bone involvement in 5 patients, 1 of whom had bone involvement by histology. The positive rate of CT scan was 6/7. Preoperative MRI imaging suggested that bony involvement of the lacrimal gland fossa in 7 patients;this was histologically confirmed in 6 of the 7. Preoperative MRI imaging suggested no bone involvement in 3 patients who were confirmed by histology. The positive rate of MRI scan was 6/7. Overall, 7 of 12 histologically evaluable cases had bone invasion. Five of the histologically proven 7 patients with bone involvement had a predominantly basaloid pattern, 2 mixed pattern. Three patients had local recurrence. CONCLUSIONS: The imaging for ACC of the lacrimal gland is characteristic. ACC of the lacrimal gland is associated with the high rate of bone invasion. The basaloid variety has more aggressive biologic behavior. The risk of local recurrence may be associated with the histologic types and stages of lacrimal gland adenoid cystic carcinoma.

[Analysis of treatment and prognosis of orbital adenoid cystic carcinoma].

OBJECTIVE: To summarize the treatment outcomes of orbital adenoid cystic carcinoma and to evaluate prognostic factors. METHOD: A retrospective case series study was performed on 75 patients with orbital adenoid cystic carcinoma treated from 1991 to 2006. RESULTS: The 2- and 5-year local recurrence rate of solid type orbital adenoid cystic carcinoma was significantly higher than that of the adeno-tubiform type [2-year, 85% (17/20) vs 23.53% (8/34), chi(2) = 19.14, P = 0.000; 5-year, 100% (19/19) vs 64.52% (20/31), Fisher's exact test, P = 0.003]. The regional extension and distant metastasis of solid type were more than those of adeno-tubiform type. The 5-year local recurrence rate treated by postoperative radiation was lower than that treated with only surgical excision [70% (14/20) vs 92.86% (13/14); Fisher's exact test, P = 0.198]. The 5-year local recurrence rate in patients initially treated by orbital evisceration during the first time was lower than that of cases which evisceration procedure was used after the recurrence [25% (1/4) vs 75% (6/8), Fisher's exact test, P = 0.222]. Tumors may extend into intracalvarium, nasal cavity and temporal fossa. They may spread to the lung, bone, liver and lymph node. The 5-year metastasis rate was 25.71% (9/35). Both of the lung and bone metastasis rates were 33.33% (3/9). The overall 5-year accumulative survival was 74.29% (26/35), mortality was 25.71% (9/35), and rate of survival without tumor recurrence was 37.14% (13/35). The 10-year disease free survival rate was 17.14% (6/35). Patients were most likely to die with intracranial extension. Surgical excision with postoperative radiation improved the 5-year survival rate to 80% (16/20). CONCLUSIONS: Orbital adenoid cystic carcinoma is one of the most malignant tumors in the orbit. They have a high local recurrence rate and survival rate. Tumor histological types and the treatment procedure can influence the prognosis. Combined therapy may decrease the recurrence and increase the survival rate.

[Clinical features and therapy of benign lymphoepithelial lesion].

OBJECTIVE: To report the clinical features of benign lymphoepithelial lesion and to further characterize recommendations for its therapy strategy. METHODS: It was a retrospective case sires. Retrospective analyze the clinical characteristics, imaging features, pathological manifestation and the treatment effect from the clinical materials of 9 cases of patients with benign lymphoepithelial lesion presenting to Tianjin Eye Hospital from Jan 2006 to Dec 2007. RESULTS: The 9 cases, in which 7 cases were female, 7 cases had lesions on both eyes, demonstrated unpainful swelling of the lacrimal glands and in different degree of salivary glands or had history of tumor resection of salivary glands. Orbital CT scanning showed increased homogeneous density with clear boundary in the lacrimal gland area. Color doppler ultrasonography displayed elliptical space occupying with clear boundary and homogeneous internal echos of the lacrimal gland area. Six patients received treatment with large dose of glucocorticoid for 1 - 2 courses, and the symptoms and signs were significantly alleviated. Three patients were operated to excise the lacrimal gland masses due to imperfect treatment effect of medication or in order to make definite diagnosis. The postoperative pathological results supported the diagnosis of benign lymphoepithelial lesion. No recurrence happened in the follow-up. CONCLUSIONS: A clinical condition with swelling of either or both lacrimal gland and of any salivary gland, and accompanied with systemic relative diseases should be considered benign lymphoepithelial lesion. Imaging examinations are helpful to definite diagnosis. Most patients are sensitive to the glucocorticoid treatment. The dose of glucocorticoid should be large at the beginning of treatment. Surgical excision can be applied to the cases insensitive to medications or difficult to be diagnosed. The definite diagnosis should be made through pathological examinations.