Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and ...Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.展开更多
Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding o...Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.展开更多
Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effect...Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effects.Regional chemotherapy for UM liver metastases includes hepatic ar ter y infusion(HAI),transarterial chemoembolization(TACE),and isolated hepatic perfusion(IHP).In this review,we aim to examine the efficacy of regional chemotherapy and compare HAI,TACE,and IHP in terms of overall survival(OS).The three approaches showed no obvious difference in OS results.展开更多
Background: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults. However, identification of the effective biomarker for the diagnosis and treatment of UVM remains to be explored. Calcium and in...Background: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults. However, identification of the effective biomarker for the diagnosis and treatment of UVM remains to be explored. Calcium and integrin-binding protein 1 (CIB1) is emerging as an important factor in tumor progression. Purpose: To determine the contribution of CIB1 in the diagnosis of UVM. Method: Immunohistochemical staining is used to detect the CIB1 expression level, while Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN online tools were used to analyze patient survival and CIB1 correlation genes in UVM. Integrative analysis using STRING and GeneMANIA predicted the correlated genes with CIB1 in UVM. Results: CIB1 expression level in UVM was significantly enhanced when compared with that in paracancerous tissues. A higher CIB1 expression level resulted in a significantly worse disease-free survival as well as overall survival. Moreover, the survival probability of patients was associated with body weight and gender of the patients with UVM. The correlated genes with CIB1 in UVM, and the similarity of the genes in UVM expression and survival heatmap were verified. Furthermore, Gene ontology enrichment analysis revealed that CIB1 and its correlated genes are significantly enriched in ITGA2B-ITGB3-CIB1 complex, regulation of intracellular protein transport and regulation of ion transport. Conclusions: Our novel findings suggested that CIB1 might be a potential diagnostic predictor for UVM, and might contribute to the potential strategy for UVM treatment by targeting CIB1.展开更多
Objective: The present study aimed to investigate circular RNA(circRNA) expression in uveal melanoma(UM).Methods: First,we used microarray to compare the expression profiles of circRNA in five UM samples and five norm...Objective: The present study aimed to investigate circular RNA(circRNA) expression in uveal melanoma(UM).Methods: First,we used microarray to compare the expression profiles of circRNA in five UM samples and five normal uvea tissues.Next,bioinformatics analyses,including gene ontology(GO) analysis and pathway analysis,were applied to study these differentially expressed circRNAs to predict pathogenic pathways that may be involved.Quantitative real-time polymerase chain reaction(qRT-PCR) in 20 UM samples and 20 normal uvea samples was used to confirm the circRNA expression profiles obtained from the microarray data.Finally,we analyzed the interaction between validated circRNAs and their potential cancer-associated miRNA targets.Results: In total,50,579 circRNAs [fold change(FC) ≥2.0; P<0.05],including 20,654 up-regulated and 29,925 down-regulated circRNAs,were identified as differentially expressed between UM tissues and normal uvea tissues.We used qRT-PCR to verify seven dysregulated circRNAs indicated by the microarray data,including hsa_circ_0119873,hsa_circ_0128533,hsa_circ_0047924,hsa_circ_0103232,hsa-circRNA10628-6,hsa_circ_0032148 and hsa_circ_0133460,which may be promising candidates to study future molecular mechanisms.Conclusions: This study explored,for the first time,the abnormal expression of circRNAs in UM and described the expression profile of circRNAs,providing a new potential target for the mechanism of UM and future treatment of UM.展开更多
AIM: To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microR NA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 a...AIM: To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microR NA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 and its downstream targets.METHODS: Quantitative reverse transcription polymerase chain reaction(qR T-PCR) was used to detect microR NA-21 expression in normal uveal tissue and uveal melanoma cell lines. Lenti-virus expression system was used to construct OCM-1, MuM-2 B and M619 cell line with stable overexpression and inhibition of microR NA-21. In vitro cell function tests such as cell proliferation, cell apoptosis, cell circle and abilities of migration and invasion were examined by MTT, Brd U assay, flow cytometry, transwell assay and Matrigel invasion assay respectively. The target gene was predicted by bioinformatics and confirmed by using a dual luciferase reporter assay. The expression of p53 and its suspected downstream targets LIM and SH3 protein 1(LASP1) and glutathione S transferase pi(GST-Pi) were determined by qR T-PCR in mR NA level and Western blotting analysis in protein level. Finally, the effect of microR NA-21 in a xenograft tumor model was assessed in four-week-old BALB/c nude mice. RESULTS: Compared to normal uveal melanoma, expressions of micro RNA-21 were significantly higher in uveal melanoma cell lines. Overexpression of microR NA-21 promoted proliferation, migration, and invasion of OCM-1, M619 and MuM-2 B cells, while inhibition of microR NA-21 reveal opposite effects. Wild type p53 was identified as a target gene of micro RNA-21-3 p, and proved by dual luciferase reporter assay. Up-regulated micro RNA-21 inhibited the expression of wild type p53 gene, and the increased expression of LASP1 in mR NA level and protein level, while down-regulated microR NA-21 presented opposite way. However, GST-pi showed the potential pattern as expected, but relative mR NA level showed no statistically significant difference in OCM-1 cells. Furthermore, the mR NA expression of GST-pi was decreased in microR NA-21 overexpressing Mu M-2 B, and increased in M619 cells with inhibition of microR NA-21. In vivo, inhibition of microR NA-21 reduced tumor growth with statistically significant difference.CONCLUSION: These findings provide novel insight into molecular etiology of microR NA-21 in uveal melanoma cell lines, and suggest that microR NA-21 might be a potential candidate for the diagnosis and prognostic factor of human uveal melanoma.展开更多
AIM: To explore the effect of parthenolide(PTL) on human uveal melanoma(UM) cells(C918 and SP6.5 cells) and its molecular mechanism. METHODS: Carboxyfluorescein succinimidyl amino ester(CFSE) assays and cell counting ...AIM: To explore the effect of parthenolide(PTL) on human uveal melanoma(UM) cells(C918 and SP6.5 cells) and its molecular mechanism. METHODS: Carboxyfluorescein succinimidyl amino ester(CFSE) assays and cell counting kit-8(CCK-8) were performed to detect the cell viability. Flow cytometry was used to analyze cell cycle and apoptosis. Quantitative realtime polymerase chain reaction(qRT-PCR) and Western blot assays were performed to measure proliferation-related and apoptosis-related factors.RESULTS: Firstly, PTL decreased the viability of C918 and SP6.5 cells in a dose-dependent manner, and the effect of PTL on C918 cells was stronger than on SP6.5;however, it did not affect normal cells. Secondly, PTL increased the proportion of cell number at cell cycle G1 phase in C918 cells, and decreased the proportion of cell number at S phase, but the proportion did not change at G2 phase. In addition, PTL induced the apoptosis of C918 cells, and decreased the expressions of Cyclin D1, B-cell lymphoma-2(Bcl-2) and B-cell lymphoma-extra large(Bcl-XL). Also, PTL increased Cyclin inhibition protein 1(P21), Bcl-2-associated X protein(Bax), Cysteinyl aspartate specific proteinas-3(Caspase-3) and Caspase-9 expression. However, the expression of Caspase-8 was not changed. CONCLUSION: PTL inhibites proliferation and induces apoptosis in UM cells by arresting G1 phase and regulating mitochondrial pathway, however, it does not affect normal cells.展开更多
AIM:To investigate the role of microRNA-145(miRNA-145)and microRNA-205(miRNA-205)in proliferation and invasion of uveal melanoma(UM)cells.METHODS:The expression level of miRNA-145 and miR NA-205 from samples of UM pat...AIM:To investigate the role of microRNA-145(miRNA-145)and microRNA-205(miRNA-205)in proliferation and invasion of uveal melanoma(UM)cells.METHODS:The expression level of miRNA-145 and miR NA-205 from samples of UM patients were determined by real-time polymerase chain reaction(RT-PCR).The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205.Several epithelial-to-mesenchymal transition(EMT)-related proteins were screened by Western blotting.UM clinical samples from The Cancer Genome Atlas(TCGA)were applied to search for potential protein interaction.Pearson’s correlation analysis was applied to estimate co-expression between genes.Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205.RESULTS:The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples.Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miR NA-205 overexpression.The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42(CDC42).After database searching and sequence alignment,we identified that Neuropilin 1(NRP1)had binding sites for both miRNA-145 and miRNA-205.CONCLUSION:The miRNA-145 and miRNA-205 can reduce the proliferation,migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.展开更多
BACKGROUND:Metastatic liver melanoma is a rare event in the Chinese population with extremely poor prognosis.Any treatment that controls a metastatic hepatic lesion potentially prolongs survival.This study aimed to ev...BACKGROUND:Metastatic liver melanoma is a rare event in the Chinese population with extremely poor prognosis.Any treatment that controls a metastatic hepatic lesion potentially prolongs survival.This study aimed to evaluate the survival of patients with isolated liver metastases from uveal melanoma treated with partial hepatectomy or non-surgical management and to find the best therapeutic modality for these patients.METHODS:From January 1996 to September 2008,eight patients with liver metastases secondary to uveal melanoma were admitted to our hospital.Five patients underwent partial hepatectomy and 3 received other treatments(TACE,RFA,PEI).Their medical records were reviewed and overall survival was analyzed.RESULTS:The patients comprised 3 men and 5 women,with a median age of 44 years.Six patients presented with liver metastases at the time the primary tumor was diagnosed.The interval from the diagnosis of uveal melanoma to liver metastasis in the remaining 2 patients was 9.5 and 32.5 months,respectively.The median survival after the treatment of liver metastasis was 11.5 and 7.5 months in the surgical and nonsurgical groups,respectively.There was no procedure-related mortality in the whole study cohort.CONCLUSIONS:Partial hepatectomy or other therapies were safe and feasible for isolated liver metastases from uveal mela-noma.Aggressive treatment with multidisciplinary modalities may result in prolonged survival.展开更多
AIM:To evaluate the morphological changes in anterior segment in Chinese patients with uveal effusion(UE)after the attack of acute primary angle-closure(APAC)using ultrasound biomicroscopy(UBM),and to assess the clini...AIM:To evaluate the morphological changes in anterior segment in Chinese patients with uveal effusion(UE)after the attack of acute primary angle-closure(APAC)using ultrasound biomicroscopy(UBM),and to assess the clinical course and prognosis of the disease.METHODS:In a retrospective case series,26 eyes in 26 consecutive patients diagnosed with UE after the treatment of intraocular pressure(IOP)-lowering medication for the attack of APAC were enrolled. The unaffected fellow eyes served as controls. The morphological changes were observed by ultrasonography,slit lamp microscopy and gonioscopy. UBM was used to assess the degree and extent of effusion based on the analysis of parameters associated with UE.RESULTS:The mean IOP was 9.2(SD 2.1)mm Hg at the diagnosis of UE after IOP-lowering medication,while 14.1(SD,2.6)mm Hg in the fellow eyes(P=0.000). The anterior chamber depth(ACD)(P=0.000),angle opening distance at 500 μm(AOD500)(P<0.01)and anterior chamber angle(ACA)(P<0.05)were decreased significantly,while ciliary body thickness(CBT)(P<0.05)increased significantly in UE eyes. UE grade analysis showed 7 eyes in grade 1,9 eyes in grade 2,and 10 eyes in grade 3. Quadrant scores were performed of 4 eyes in 1 quadrant,3 eyes in 3 quadrants,and 19 eyes in 4 quadrants. There was the positive correlation between grade and quadrant score(R=0.644,P=0.000). The effusion on all eyes were recovered after medication,which mean IOP was 13.9(SD,2.8)mm Hg.CONCLUSION:UE is a frequent complication in Chinese patients after the attack of APAC,partially associated with hypotony. The severity of UE is correlation with height of effusion,extent of detachment,and shallower ACD.展开更多
AIM:To investigate the role of tumor microenvironment(TME)-related long non-coding RNA(lncRNA)in uveal melanoma(UM),probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHOD...AIM:To investigate the role of tumor microenvironment(TME)-related long non-coding RNA(lncRNA)in uveal melanoma(UM),probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHODS:UM expression profile data were downloaded from the Cancer Genome Atlas(TCGA)and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration.The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis(ss GSEA)method,and the immune cell infiltration of a single specimen was evaluated.Finally,the specimens were divided into high and low infiltration groups.The differential expression between the two groups was analyzed using the R package‘edge R’.Univariate,multivariate and Least Absolute Shrinkage and Selection Operator(LASSO)Cox regression analyses were performed to explore the prognostic value of TMErelated lncRNAs.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional analyses were also performed.The Connectivity Map(CMap)data set was used to screen molecular drugs that may treat UM.RESULTS:A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups.Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis.Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements.Among 269 differentially expressed lncRNAs,69 were up-regulated and 200 were down-regulated.Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age,TNM stage,tumor base diameter,and low and high risk indices had significant prognostic value.We screened the potential small-molecule drugs for UM,including W-13,AH-6809 and Imatinib.CONCLUSION:The prognostic markers identified in this study are reliable biomarkers of UM.This study expands our current understanding of the role of TME-related lncRNAs in UM genesis,which may lay the foundations for future treatment of this disease.展开更多
AIM:To evaluate the role of long noncoding RNA(lncR NA)SNHG15 and its potential pathways in uveal melanoma(UM).METHODS:The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patie...AIM:To evaluate the role of long noncoding RNA(lncR NA)SNHG15 and its potential pathways in uveal melanoma(UM).METHODS:The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patients with UM were obtained from the Cancer Genome Atlas(TCGA)database and further analyzed.The SPSS 24.0 statistical software package was used for statistical analyses.To investigate the potential function of SNHG15 in UM,we conducted in-depth research on Gene Set Enrichment Analysis(GSEA).RESULTS:The univariate analysis revealed that the age,tumor diameter,pathological type,extrascleral extension,cancer status,and high expression of SNHG15 were statistical risk factors for death from all causes.The multivariate analysis suggested that the mR NA expression level of SNHG15 was an independent risk factor for death from all causes,as was age and pathological type.KaplanMeier survival analysis confirmed that UM patients with high SNHG15 expression might have a poor prognosis.In addition,SNHG15 was significantly differentially expressed in the different groups of tumor pathologic stage,metastasis and living status.Besides,the logistic regression analysis indicated that high SNHG15 expression group in UM was significantly associated with cancer status,pathologic stage,metastasis,and living status.Moreover,the GSEA indicated the potential pathways regulated by SNHG15 in UM.CONCLUSION:Our research suggests that SNHG15 may play a vital role as a potential marker in UM that predicts poor prognosis.Besides,GSEA indicates the underlying signaling pathways enriched differentially in SNHG15 high expression phenotype.展开更多
AIM: To examine the genetic profile of primary uveal melanoma(UM) as compared to UM in immune escape.·METHODS: Dendritic cells(DC) loaded with lysates of UM cells of high metastatic potential were used to stimula...AIM: To examine the genetic profile of primary uveal melanoma(UM) as compared to UM in immune escape.·METHODS: Dendritic cells(DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate cytotoxic T-lymphocytes(CTLs). When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction(q RT-PCR),and analyzed the correlation of these expressions and patients' survival.· RESULTS: Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2.. The expression of these genes in the relapsed UM was significantly greater than those in primary UM.UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression.· CONCLUSION: Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells.展开更多
AIM: To investigate the clinical characteristics of idiopathic uveal effusion syndrome(IUES) and to identify effective surgical modalities for its treatment.METHODS: This retrospective analysis included clinical data ...AIM: To investigate the clinical characteristics of idiopathic uveal effusion syndrome(IUES) and to identify effective surgical modalities for its treatment.METHODS: This retrospective analysis included clinical data of 33 eyes from 26 patients with IUES at Beijing Tongren Hospital. Records of eye examinations, ocular ultrasound, ocular ultrasound biomicroscopy(UBM), and follow-up surgical treatment were reviewed and analyzed.RESULTS: Of 26 patients, 17(65.4%) were male and 9(34.6%) were female. The average age of disease onset was 46.8 y(range: 22-64 y). Seven patients(26.9%) showed retinal detachment in both eyes at presentation. B-ultrasound showed the presence of retinal detachment in one eye or both eyes. All patients had binocular ciliary leakage and detachment. Eyes with retinal detachment underwent four-quadrantic partial-thickness sclerectomy and sclerostomy. Subretinal fluid resolution was achieved within 6 mo. Recurrence was observed in three eyes and was resolved with re-operation.CONCLUSION: Ophthalmic ultrasound and UBM, among others, can be helpful in the diagnosis of IUES. Sclerectomy and sclerostomy are surgical modalities that can successfully treat the disease. Some patients may experience recurrence after surgery;reoperation remains safe and effective for them. Long-term follow-up is essential in such settings.展开更多
Background:Uveal melanoma is the most prevalent intraocular malignancy.In preceding decades,many studies have been published on uveal melanoma.However,so far,uveal melanoma-related bibliometric studies have not been r...Background:Uveal melanoma is the most prevalent intraocular malignancy.In preceding decades,many studies have been published on uveal melanoma.However,so far,uveal melanoma-related bibliometric studies have not been reported.Methods:Uveal melanoma-related articles and reviews published between 2005 and 2019 were retrieved in the Web of Science Core Collection on March 15,2020.Three bibliometric tools(HistCite,VOSviewer,and CiteSpace)were employed to conduct the current study.Results:A total of 3,404 publications related to uveal melanoma were identified,involving 3015 articles(88.57%)and 389 reviews(11.43%)with 65,429 co-cited references in 9 languages,which were published by 2,875 institutions in 66 countries/regions.The United States contributed to most publications(n=1427,41.92%),and the Thomas Jefferson University was involved in most of the studies(n=160,5.56%).Investigative Ophthalmology&Visual Science published the majority of the papers(n=175,5.14%),whereas Ophthalmology received the most co-citations(n=7050).Shields CL owned the most publications and co-citations(n=122 and 2151,respectively).Gene and molecular biology aspects,prevalence,the main prognosis factor,and treatment were the intellectual foundations of uveal melanoma research.In the field of uveal melanoma,emerging hotspots of uveal melanoma include epidemiologic characteristics,prognosis factors,mechanisms of uveal melanoma development,the use of novel predictive tools,and clinical applications of novel targeted drugs.Conclusion:This first bibliometric study focused on the integral tendency of the past 15 years,identified landmark items,and revealed current research hotspots in the field of uveal melanoma,which will provide references for clinicians and researchers,as well as an example of visualization analysis to explore research hotspots in other fields.展开更多
Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug deliv...Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment.Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore,certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.展开更多
AIM: To detect how BRCA-associated protein 1(BAP1) regulates cell migration in uveal melanoma(UM) cells. METHODS: Wound healing and transwell assays were performed to detect UM cell migration abilities. Protein chip, ...AIM: To detect how BRCA-associated protein 1(BAP1) regulates cell migration in uveal melanoma(UM) cells. METHODS: Wound healing and transwell assays were performed to detect UM cell migration abilities. Protein chip, immunoprecipitations and surface plasmon resonance analyses were applied to identify BAP1 protein partners. Western blot and calpain activity assays were used to test the expression and function of calpastatin(CAST). RESULTS: CAST protein was confirmed as a new BAP1 protein partner, and loss of BAP1 reduced the expression and function of CAST in UM cells. The overexpression of CAST rescued the cell migration phenotype caused by BAP1 loss.CONCLUSION: BAP1 interacts with CAST in UM cells, and CAST and its subsequent calpain pathway may mediate BAP1-related cell migration regulation.展开更多
AIM:To construct an immune-related prognostic signature(IPS)that can distinguish and predict prognosis in uveal melanoma(UM).METHODS:The transcriptomic data and clinicopathological information of 80 UM patients were e...AIM:To construct an immune-related prognostic signature(IPS)that can distinguish and predict prognosis in uveal melanoma(UM).METHODS:The transcriptomic data and clinicopathological information of 80 UM patients were extracted from the TCGA database.These patients were randomly assigned to a training and a testing set.RESULTS:Lasso Cox analysis was performed for the prognostic immune-related genes to develop an IPS for UM in the training set.The signature was validated in both the testing set and entire cohort.We confirmed the prognostic value of our IPS in distinct subgroups and found its association with the T stage and basal diameter of the tumor.Tumor Immune Estimation Resource database analysis revealed that the IPS was negatively correlated with the infiltration of neutrophils and dendritic cells,but positively correlated with the infiltration level of CD8+T cells.In addition,we demonstrated that immune checkpoints containing PD-1,CTLA-4,IDO,and TIGIT were moderately associated with the IPS.CONCLUSION:This is the first study to develop and validate an immune-related signature with the ability of predicting prognosis for UM patients.Further studies are needed to validate its prediction accuracy.展开更多
AIM: To find new biomarkers for uveal melanoma(UM) by analyzing the serum peptidome profile. METHODS: Proteomic spectra in patients with UM before and after operation were analyzed and compared with those of healthy c...AIM: To find new biomarkers for uveal melanoma(UM) by analyzing the serum peptidome profile. METHODS: Proteomic spectra in patients with UM before and after operation were analyzed and compared with those of healthy controls. Magnetic affinity beads were used to capture serum peptides and matrix-assisted laser desorption/ionization time-of-flight(MALDI-TOF) mass spectrometer were used to compile serum peptide profiles. RESULTS: A panel of 49 peptides were differentially expressed between UM patients and controls, of which 33 peptides were of higher intensities in patient group and 16 peptides were of higher intensities in control group. Based on combined use of these potential markers, peptides with mean molecular masses of 1467 and 9289.0 Da provide high sensitivity(83.3%), specificity(100%) and accuracy rate(93.0%) together to differentiate melanoma patients from healthy controls. At the time point of 6mo postoperatively, the levels of many peptides differentially expressed before surgery showed no more statistical difference between the patients and the control group. Fibrinogen α-chain precursors were identified as potential UM markers.CONCLUSION: We have shown that a convenient and fast proteomic technique, affinity bead separation and MALDITOF analysis combined with bioinformatic software, facilitates the identification of novel biomarkers for UM.展开更多
AIM: To measure the concentration of vascular endothelial growth factor-A(VEGF-A), and placental growth factor(PLGF) in aqueous humor of uveal melanoma patients before and after Iodine-125 plaque therapy(IPT), determi...AIM: To measure the concentration of vascular endothelial growth factor-A(VEGF-A), and placental growth factor(PLGF) in aqueous humor of uveal melanoma patients before and after Iodine-125 plaque therapy(IPT), determine the postoperative fluctuation and evaluate associated factors in vivo.METHODS: Participants were 18 Chinese patients with uveal melanoma who were elected to IPT. Undiluted aqueous humor samples were collected at Iodine plaque implant and removal time, then stored immediately at-80℃ until assayed. The concentration of VEGF-A, PLGF and other 7 cytokines comprising interleukin-2(IL-2), IL-8, IL-10, interferon(IFN)-γ, programmed death(PD)-1, transforming growth factor(TGF)-β1 and insulin-like growth factor(IGF)-1 in aqueous humor was measured using Raybiotech immunoassay kit, a high throughput strategy. The VEGF-A and PLGF levels were compared across preoperation and postoperation subgroups, as well as those of other 7 interleukins. Correlation and grouped analyses were conducted to determine the independent effects of clinical parameters and other cytokines on VEGF-A and PLGF concentration or fluctuation. This study set a self-control design.RESULTS: VEGF-A(P=0.038) and PLGF(P=0.026) were the only two increased cytokines after IPT. Preoperative and postoperative level of VEGF-A and PLGF(r=0.575, P=0.013;r=0.987, P<0.001) correlated with each other significantly. Level of VEGF-A(r=0.626, P=0.005;r=0.588, P=0.01) and PLGF(r=0.616, P=0.007;r=0.588, P=0.01) had positive correlation with tumor thickness consistently. Elevated VEGF-A or PLGF level were strong predictive factors of each other(P=0.007, OR=60.0). The elevated VEGF-A group showed a higher postoperative level of IFN-γ(P=0.005), IL-2(P<0.001) and IL-10(P=0.004) in aqueous humor. When the elevated PLGF group got similar results that a higher postoperative level of IFN-γ(P=0.007), IL-2(P<0.001) and IL-10(P=0.013) in aqueous humor. CONCLUSION: This study reveals that VEGF-A and PLGF in aqueous humor significantly increased with tumor thickness and radiation process in uveal melanoma patients. VEGF-A and PLGF may be crucial in uveal melanoma genesis and radiotherapy reactions. Immune mediators comprised IFN-γ, IL-2 and IL-10 could play roles in the link between inflammation and angiogenesis in uveal melanoma when exposed to radiotherapy.展开更多
文摘Uveal melanoma(UM)is the most common primary intraocular cancer in adults.The incidence in Europe and the United States is 6-7 per million population per year.Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection,up to 50%of UM patients develop metastases that usually involve the liver and are fatal within 1 year.To date,chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM,which is still characterized by poor prognosis.No standard therapeutic approaches for its prevention or treatment have been established.The application of immunotherapy agents,such as immune checkpoint inhibitors that are effective in cutaneous melanoma,has shown limited effects in the treatment of ocular disease.This is due to UM’s distinct genetics,natural history,and complex interaction with the immune system.Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations,UMs are usually triggered by a mutation in GNAQ or GNA11.As a result,more effective immunotherapeutic approaches,such as cancer vaccines,adoptive cell transfer,and other new molecules are currently being studied.In this review,we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.
基金supported by grants from Shanghai Key Clinical Specialty,Shanghai Eye Disease Research Center(Grant No.:2022Zz01003 to Xianqun Fan)the National Key Research and Development Plan(Grant No.:2018YFC1106100 to Xianqun Fan)+1 种基金the National Natural Science Foundation of China(Grant Nos.:12275178 to Shengfang Ge and 82103240 to Peiwei Chai)Innovative Research Team of High-level Local Universities in Shanghai(Grant Nos.:SHSMU-ZDCX20210902 to Renbing Jia and SHSMUZDCX20210900 to Xianqun Fan),the Science and Technology Commission of Shanghai(Grant No.:19JC1410200 to Xianqun Fan),and Cross-disciplinary Research Fund of Shanghai Ninth People's Hospital,Shanghai Jiao Tong university School of Medicine(Grant No.:JYJC202210 to Ai Zhuang).
文摘Uveal melanoma(UM)is the most frequent and life-threatening ocular malignancy in adults.Aberrant histone methylation contributes to the abnormal transcriptome during oncogenesis.However,a comprehensive understanding of histone methylation patterns and their therapeutic potential in UM remains enigmatic.Herein,using a systematic epi-drug screening and a high-throughput transcriptome profiling of histone methylation modifiers,we observed that disruptor of telomeric silencing-1-like(DOT1L),a methyltransferase of histone H3 lysine 79(H3K79),was activated in UM,especially in the high-risk group.Concordantly,a systematic epi-drug library screening revealed that DOT1L inhibitors exhibited salient tumor-selective inhibitory effects on UM cells,both in vitro and in vivo.Combining Cleavage Under Targets and Tagmentation(CUT&Tag),RNA sequencing(RNA-seq),and bioinformatics analysis,we identified that DOT1L facilitated H3K79 methylation of nicotinate phosphoribosyltransferase(NAPRT)and epigenetically activated its expression.Importantly,NAPRT served as an oncogenic accelerator by enhancing nicotinamide adenine dinucleotide(NAD^(+))synthesis.Therapeutically,DOT1L inhibition epigenetically silenced NAPRT expression through the diminishment of dimethylation of H3K79(H3K79me2)in the NAPRT promoter,thereby inhibiting the malignant behaviors of UM.Conclusively,our findings delineated an integrated picture of the histone methylation landscape in UM and unveiled a novel DOT1L/NAPRT oncogenic mechanism that bridges transcriptional addiction and metabolic reprogramming.
基金Supported by National Natural Science Foundation of China(No.82141128)The Capital Health Research and Development of Special(No.2020-1-2052)+4 种基金Beijing Natural Science Foundation(No.7204245)Science&Technology Project of Beijing Municipal Science&Technology Commission(No.Z201100005520045,No.Z181100001818003)Scientific Research Common Program of Beijing Municipal Commission of Education(No.KM202010025018)Beijing Municipal Administration of Hospitals’Youth Programme(No.QML20190202)Beijing Dongcheng District Outstanding Talents Cultivating Plan(No.2018)。
文摘Chemotherapy remains an important approach for the treatment of liver metastases from uveal melanoma(UM).Compared with systemic chemotherapy,regional chemotherapy has similar efficacy and fewer systemic adverse effects.Regional chemotherapy for UM liver metastases includes hepatic ar ter y infusion(HAI),transarterial chemoembolization(TACE),and isolated hepatic perfusion(IHP).In this review,we aim to examine the efficacy of regional chemotherapy and compare HAI,TACE,and IHP in terms of overall survival(OS).The three approaches showed no obvious difference in OS results.
文摘Background: Uveal melanoma (UVM) is the most common primary intraocular tumor in adults. However, identification of the effective biomarker for the diagnosis and treatment of UVM remains to be explored. Calcium and integrin-binding protein 1 (CIB1) is emerging as an important factor in tumor progression. Purpose: To determine the contribution of CIB1 in the diagnosis of UVM. Method: Immunohistochemical staining is used to detect the CIB1 expression level, while Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and UALCAN online tools were used to analyze patient survival and CIB1 correlation genes in UVM. Integrative analysis using STRING and GeneMANIA predicted the correlated genes with CIB1 in UVM. Results: CIB1 expression level in UVM was significantly enhanced when compared with that in paracancerous tissues. A higher CIB1 expression level resulted in a significantly worse disease-free survival as well as overall survival. Moreover, the survival probability of patients was associated with body weight and gender of the patients with UVM. The correlated genes with CIB1 in UVM, and the similarity of the genes in UVM expression and survival heatmap were verified. Furthermore, Gene ontology enrichment analysis revealed that CIB1 and its correlated genes are significantly enriched in ITGA2B-ITGB3-CIB1 complex, regulation of intracellular protein transport and regulation of ion transport. Conclusions: Our novel findings suggested that CIB1 might be a potential diagnostic predictor for UVM, and might contribute to the potential strategy for UVM treatment by targeting CIB1.
基金supported by Beijing Municipal Administration of Hospitals’ Ascent Plan(No.DFL20150201)the National Natural Science Foundation of China(No.81570891)+2 种基金Beijing Natural Science Foundation(No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(No.2014-2-003)The Capital Health Research and Development of Special(No.2016-1-2051)
文摘Objective: The present study aimed to investigate circular RNA(circRNA) expression in uveal melanoma(UM).Methods: First,we used microarray to compare the expression profiles of circRNA in five UM samples and five normal uvea tissues.Next,bioinformatics analyses,including gene ontology(GO) analysis and pathway analysis,were applied to study these differentially expressed circRNAs to predict pathogenic pathways that may be involved.Quantitative real-time polymerase chain reaction(qRT-PCR) in 20 UM samples and 20 normal uvea samples was used to confirm the circRNA expression profiles obtained from the microarray data.Finally,we analyzed the interaction between validated circRNAs and their potential cancer-associated miRNA targets.Results: In total,50,579 circRNAs [fold change(FC) ≥2.0; P<0.05],including 20,654 up-regulated and 29,925 down-regulated circRNAs,were identified as differentially expressed between UM tissues and normal uvea tissues.We used qRT-PCR to verify seven dysregulated circRNAs indicated by the microarray data,including hsa_circ_0119873,hsa_circ_0128533,hsa_circ_0047924,hsa_circ_0103232,hsa-circRNA10628-6,hsa_circ_0032148 and hsa_circ_0133460,which may be promising candidates to study future molecular mechanisms.Conclusions: This study explored,for the first time,the abnormal expression of circRNAs in UM and described the expression profile of circRNAs,providing a new potential target for the mechanism of UM and future treatment of UM.
基金Supported by the National Natural Science Foundation of China (No.81570891 No.81272981)+3 种基金Beijing Natural Science Foundation (No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau (No.2014-2-003)the Capital Health Research and Development of Special (No.2016-1-2051)Hospitals’ Ascent Plan (No.DFL20150201)
文摘AIM: To reveal the insight mechanism of liver metastasis in uveal melanoma, we investigated cell functions of microR NA-21 in three different uveal melanoma cell lines and analyze the relationship of target gene p53 and its downstream targets.METHODS: Quantitative reverse transcription polymerase chain reaction(qR T-PCR) was used to detect microR NA-21 expression in normal uveal tissue and uveal melanoma cell lines. Lenti-virus expression system was used to construct OCM-1, MuM-2 B and M619 cell line with stable overexpression and inhibition of microR NA-21. In vitro cell function tests such as cell proliferation, cell apoptosis, cell circle and abilities of migration and invasion were examined by MTT, Brd U assay, flow cytometry, transwell assay and Matrigel invasion assay respectively. The target gene was predicted by bioinformatics and confirmed by using a dual luciferase reporter assay. The expression of p53 and its suspected downstream targets LIM and SH3 protein 1(LASP1) and glutathione S transferase pi(GST-Pi) were determined by qR T-PCR in mR NA level and Western blotting analysis in protein level. Finally, the effect of microR NA-21 in a xenograft tumor model was assessed in four-week-old BALB/c nude mice. RESULTS: Compared to normal uveal melanoma, expressions of micro RNA-21 were significantly higher in uveal melanoma cell lines. Overexpression of microR NA-21 promoted proliferation, migration, and invasion of OCM-1, M619 and MuM-2 B cells, while inhibition of microR NA-21 reveal opposite effects. Wild type p53 was identified as a target gene of micro RNA-21-3 p, and proved by dual luciferase reporter assay. Up-regulated micro RNA-21 inhibited the expression of wild type p53 gene, and the increased expression of LASP1 in mR NA level and protein level, while down-regulated microR NA-21 presented opposite way. However, GST-pi showed the potential pattern as expected, but relative mR NA level showed no statistically significant difference in OCM-1 cells. Furthermore, the mR NA expression of GST-pi was decreased in microR NA-21 overexpressing Mu M-2 B, and increased in M619 cells with inhibition of microR NA-21. In vivo, inhibition of microR NA-21 reduced tumor growth with statistically significant difference.CONCLUSION: These findings provide novel insight into molecular etiology of microR NA-21 in uveal melanoma cell lines, and suggest that microR NA-21 might be a potential candidate for the diagnosis and prognostic factor of human uveal melanoma.
基金Supported by the Health Special Project of Jilin Province Department of Finance (No.3D5177883429)
文摘AIM: To explore the effect of parthenolide(PTL) on human uveal melanoma(UM) cells(C918 and SP6.5 cells) and its molecular mechanism. METHODS: Carboxyfluorescein succinimidyl amino ester(CFSE) assays and cell counting kit-8(CCK-8) were performed to detect the cell viability. Flow cytometry was used to analyze cell cycle and apoptosis. Quantitative realtime polymerase chain reaction(qRT-PCR) and Western blot assays were performed to measure proliferation-related and apoptosis-related factors.RESULTS: Firstly, PTL decreased the viability of C918 and SP6.5 cells in a dose-dependent manner, and the effect of PTL on C918 cells was stronger than on SP6.5;however, it did not affect normal cells. Secondly, PTL increased the proportion of cell number at cell cycle G1 phase in C918 cells, and decreased the proportion of cell number at S phase, but the proportion did not change at G2 phase. In addition, PTL induced the apoptosis of C918 cells, and decreased the expressions of Cyclin D1, B-cell lymphoma-2(Bcl-2) and B-cell lymphoma-extra large(Bcl-XL). Also, PTL increased Cyclin inhibition protein 1(P21), Bcl-2-associated X protein(Bax), Cysteinyl aspartate specific proteinas-3(Caspase-3) and Caspase-9 expression. However, the expression of Caspase-8 was not changed. CONCLUSION: PTL inhibites proliferation and induces apoptosis in UM cells by arresting G1 phase and regulating mitochondrial pathway, however, it does not affect normal cells.
基金Supported by National Natural Science Foundation of China(No.81570891)Beijing Natural Science Foundation(No.7204245+6 种基金No.7151003)Scientific Research Common Program of Beijing Municipal Commission of Education(No.KM202010025018)Beijing Municipal Administration of Hospitals’Youth Programme(No.QMS20190202)Beijing Municipal Administration of Hospitals,Ascent Plan(No.DFL20150201)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(2014-2-003)The Capital Health Research and Development of Special(2016-1-2051)Beijing Dongcheng District Outstanding Talents Cultivating Plan(2018)。
文摘AIM:To investigate the role of microRNA-145(miRNA-145)and microRNA-205(miRNA-205)in proliferation and invasion of uveal melanoma(UM)cells.METHODS:The expression level of miRNA-145 and miR NA-205 from samples of UM patients were determined by real-time polymerase chain reaction(RT-PCR).The growth and invasion inhibitory effects were observed by the transfection of UM cells with miRNA-145 and miRNA-205.Several epithelial-to-mesenchymal transition(EMT)-related proteins were screened by Western blotting.UM clinical samples from The Cancer Genome Atlas(TCGA)were applied to search for potential protein interaction.Pearson’s correlation analysis was applied to estimate co-expression between genes.Dual-luciferase reporter assay was used to verify the binding sites on target protein for miRNA-145 and miRNA-205.RESULTS:The expression levels of miRNA-145 and miRNA-205 in the samples from patients with UM were significantly lower than those in the normal tissue samples.Significant growth and invasion inhibitory effects were observed in human UM cells with miRNA-145 and miR NA-205 overexpression.The miRNA-145 and miRNA-205 could decrease the expression level of cell division control protein 42(CDC42).After database searching and sequence alignment,we identified that Neuropilin 1(NRP1)had binding sites for both miRNA-145 and miRNA-205.CONCLUSION:The miRNA-145 and miRNA-205 can reduce the proliferation,migration and invasion of UM cells by targeting the mRNA of its upstream protein NRP1 to down-regulate the expression level of CDC42.
基金supported by a grant from the Chinese Key Project for Infectious Diseases(2008ZX10002-025)
文摘BACKGROUND:Metastatic liver melanoma is a rare event in the Chinese population with extremely poor prognosis.Any treatment that controls a metastatic hepatic lesion potentially prolongs survival.This study aimed to evaluate the survival of patients with isolated liver metastases from uveal melanoma treated with partial hepatectomy or non-surgical management and to find the best therapeutic modality for these patients.METHODS:From January 1996 to September 2008,eight patients with liver metastases secondary to uveal melanoma were admitted to our hospital.Five patients underwent partial hepatectomy and 3 received other treatments(TACE,RFA,PEI).Their medical records were reviewed and overall survival was analyzed.RESULTS:The patients comprised 3 men and 5 women,with a median age of 44 years.Six patients presented with liver metastases at the time the primary tumor was diagnosed.The interval from the diagnosis of uveal melanoma to liver metastasis in the remaining 2 patients was 9.5 and 32.5 months,respectively.The median survival after the treatment of liver metastasis was 11.5 and 7.5 months in the surgical and nonsurgical groups,respectively.There was no procedure-related mortality in the whole study cohort.CONCLUSIONS:Partial hepatectomy or other therapies were safe and feasible for isolated liver metastases from uveal mela-noma.Aggressive treatment with multidisciplinary modalities may result in prolonged survival.
基金Supported by the Key Science and Technology Program of Shaanxi Province,China(No.2015SF146)
文摘AIM:To evaluate the morphological changes in anterior segment in Chinese patients with uveal effusion(UE)after the attack of acute primary angle-closure(APAC)using ultrasound biomicroscopy(UBM),and to assess the clinical course and prognosis of the disease.METHODS:In a retrospective case series,26 eyes in 26 consecutive patients diagnosed with UE after the treatment of intraocular pressure(IOP)-lowering medication for the attack of APAC were enrolled. The unaffected fellow eyes served as controls. The morphological changes were observed by ultrasonography,slit lamp microscopy and gonioscopy. UBM was used to assess the degree and extent of effusion based on the analysis of parameters associated with UE.RESULTS:The mean IOP was 9.2(SD 2.1)mm Hg at the diagnosis of UE after IOP-lowering medication,while 14.1(SD,2.6)mm Hg in the fellow eyes(P=0.000). The anterior chamber depth(ACD)(P=0.000),angle opening distance at 500 μm(AOD500)(P<0.01)and anterior chamber angle(ACA)(P<0.05)were decreased significantly,while ciliary body thickness(CBT)(P<0.05)increased significantly in UE eyes. UE grade analysis showed 7 eyes in grade 1,9 eyes in grade 2,and 10 eyes in grade 3. Quadrant scores were performed of 4 eyes in 1 quadrant,3 eyes in 3 quadrants,and 19 eyes in 4 quadrants. There was the positive correlation between grade and quadrant score(R=0.644,P=0.000). The effusion on all eyes were recovered after medication,which mean IOP was 13.9(SD,2.8)mm Hg.CONCLUSION:UE is a frequent complication in Chinese patients after the attack of APAC,partially associated with hypotony. The severity of UE is correlation with height of effusion,extent of detachment,and shallower ACD.
基金Supported by Shanghai Key Laboratory of Fundus Diseases,2017(No.01030)Luzhou Southwest Medical University,Municipal Department Level(No.2017LZXNYD-J01)。
文摘AIM:To investigate the role of tumor microenvironment(TME)-related long non-coding RNA(lncRNA)in uveal melanoma(UM),probable prognostic signature and potential small molecule drugs using bioinformatics analysis.METHODS:UM expression profile data were downloaded from the Cancer Genome Atlas(TCGA)and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration.The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis(ss GSEA)method,and the immune cell infiltration of a single specimen was evaluated.Finally,the specimens were divided into high and low infiltration groups.The differential expression between the two groups was analyzed using the R package‘edge R’.Univariate,multivariate and Least Absolute Shrinkage and Selection Operator(LASSO)Cox regression analyses were performed to explore the prognostic value of TMErelated lncRNAs.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes(KEGG)functional analyses were also performed.The Connectivity Map(CMap)data set was used to screen molecular drugs that may treat UM.RESULTS:A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups.Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis.Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements.Among 269 differentially expressed lncRNAs,69 were up-regulated and 200 were down-regulated.Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age,TNM stage,tumor base diameter,and low and high risk indices had significant prognostic value.We screened the potential small-molecule drugs for UM,including W-13,AH-6809 and Imatinib.CONCLUSION:The prognostic markers identified in this study are reliable biomarkers of UM.This study expands our current understanding of the role of TME-related lncRNAs in UM genesis,which may lay the foundations for future treatment of this disease.
基金Supported by the National Natural Science Foundation of China(No.81970835,No.81800867)。
文摘AIM:To evaluate the role of long noncoding RNA(lncR NA)SNHG15 and its potential pathways in uveal melanoma(UM).METHODS:The SNHG15 mRNA expression level and corresponding clinicopathological characteristics of 80 patients with UM were obtained from the Cancer Genome Atlas(TCGA)database and further analyzed.The SPSS 24.0 statistical software package was used for statistical analyses.To investigate the potential function of SNHG15 in UM,we conducted in-depth research on Gene Set Enrichment Analysis(GSEA).RESULTS:The univariate analysis revealed that the age,tumor diameter,pathological type,extrascleral extension,cancer status,and high expression of SNHG15 were statistical risk factors for death from all causes.The multivariate analysis suggested that the mR NA expression level of SNHG15 was an independent risk factor for death from all causes,as was age and pathological type.KaplanMeier survival analysis confirmed that UM patients with high SNHG15 expression might have a poor prognosis.In addition,SNHG15 was significantly differentially expressed in the different groups of tumor pathologic stage,metastasis and living status.Besides,the logistic regression analysis indicated that high SNHG15 expression group in UM was significantly associated with cancer status,pathologic stage,metastasis,and living status.Moreover,the GSEA indicated the potential pathways regulated by SNHG15 in UM.CONCLUSION:Our research suggests that SNHG15 may play a vital role as a potential marker in UM that predicts poor prognosis.Besides,GSEA indicates the underlying signaling pathways enriched differentially in SNHG15 high expression phenotype.
基金Supported by National Natural Science Foundation of China(No.81570891No.81272981)+4 种基金the Beijing Municipal Administration of Hospitals'Ascent Plan(No.DFL20150201)Science&Technology Project of Beijing Municipal Science&Technology Commission(No.Z151100001615052)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(No.ZYLX201307)Beijing Natural Science Foundation(No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(No.2014-2-003)
文摘AIM: To examine the genetic profile of primary uveal melanoma(UM) as compared to UM in immune escape.·METHODS: Dendritic cells(DC) loaded with lysates of UM cells of high metastatic potential were used to stimulate cytotoxic T-lymphocytes(CTLs). When CTLs co-cultured with the UM cells, most UM cells could be eliminated. Survival UM cells grew slowly and were considered to be survival variants and examined by a microarray analysis. These differential genes were analyzed further with Venn Diagrams and functions related to immune escape. We additionally examined transcriptional changes of manually selected survival variants of UM cells and of clinical UM samples by quantitative real-time polymerase chain reaction(q RT-PCR),and analyzed the correlation of these expressions and patients' survival.· RESULTS: Gene expression analyses revealed a marked up-regulation of SLAMF7 and CCL22 and a significant down-regulation of KRT10, FXYD3 and ABCC2.. The expression of these genes in the relapsed UM was significantly greater than those in primary UM.UM patients with overexpression of these genes had a shorter survival period as compared with those of their underexpression.· CONCLUSION: Gene expression, in particular of SLAMF7, CCL22, KRT10, FXYD3 and ABCC2, differed between primary UM cells and survival variants of UM cells.
文摘AIM: To investigate the clinical characteristics of idiopathic uveal effusion syndrome(IUES) and to identify effective surgical modalities for its treatment.METHODS: This retrospective analysis included clinical data of 33 eyes from 26 patients with IUES at Beijing Tongren Hospital. Records of eye examinations, ocular ultrasound, ocular ultrasound biomicroscopy(UBM), and follow-up surgical treatment were reviewed and analyzed.RESULTS: Of 26 patients, 17(65.4%) were male and 9(34.6%) were female. The average age of disease onset was 46.8 y(range: 22-64 y). Seven patients(26.9%) showed retinal detachment in both eyes at presentation. B-ultrasound showed the presence of retinal detachment in one eye or both eyes. All patients had binocular ciliary leakage and detachment. Eyes with retinal detachment underwent four-quadrantic partial-thickness sclerectomy and sclerostomy. Subretinal fluid resolution was achieved within 6 mo. Recurrence was observed in three eyes and was resolved with re-operation.CONCLUSION: Ophthalmic ultrasound and UBM, among others, can be helpful in the diagnosis of IUES. Sclerectomy and sclerostomy are surgical modalities that can successfully treat the disease. Some patients may experience recurrence after surgery;reoperation remains safe and effective for them. Long-term follow-up is essential in such settings.
文摘Background:Uveal melanoma is the most prevalent intraocular malignancy.In preceding decades,many studies have been published on uveal melanoma.However,so far,uveal melanoma-related bibliometric studies have not been reported.Methods:Uveal melanoma-related articles and reviews published between 2005 and 2019 were retrieved in the Web of Science Core Collection on March 15,2020.Three bibliometric tools(HistCite,VOSviewer,and CiteSpace)were employed to conduct the current study.Results:A total of 3,404 publications related to uveal melanoma were identified,involving 3015 articles(88.57%)and 389 reviews(11.43%)with 65,429 co-cited references in 9 languages,which were published by 2,875 institutions in 66 countries/regions.The United States contributed to most publications(n=1427,41.92%),and the Thomas Jefferson University was involved in most of the studies(n=160,5.56%).Investigative Ophthalmology&Visual Science published the majority of the papers(n=175,5.14%),whereas Ophthalmology received the most co-citations(n=7050).Shields CL owned the most publications and co-citations(n=122 and 2151,respectively).Gene and molecular biology aspects,prevalence,the main prognosis factor,and treatment were the intellectual foundations of uveal melanoma research.In the field of uveal melanoma,emerging hotspots of uveal melanoma include epidemiologic characteristics,prognosis factors,mechanisms of uveal melanoma development,the use of novel predictive tools,and clinical applications of novel targeted drugs.Conclusion:This first bibliometric study focused on the integral tendency of the past 15 years,identified landmark items,and revealed current research hotspots in the field of uveal melanoma,which will provide references for clinicians and researchers,as well as an example of visualization analysis to explore research hotspots in other fields.
基金Supported by the National Natural Science Foundation of China(No.81201808,No.81502544)the American Fight For Sight Postdoctoral Award+2 种基金Central South University Lieying grantEmory University Melanoma Prevention and Research Discovery Fundan unrestricted grant from Research to Prevent Blindness,Inc
文摘Rapid advances in nanomedicine have significantly changed many aspects of nanoparticle application to the eye including areas of diagnosis, imaging and more importantly drug delivery. The nanoparticle-based drug delivery systems has provided a solution to various drug solubility-related problems in ophthalmology treatment.Nanostructured compounds could be used to achieve local ocular delivery with minimal unwanted systematic side effects produced by taking advantage of the phagocyte system. In addition, the in vivo control release by nanomaterials encapsulated drugs provides prolong exposure of the compound in the body. Furthermore,certain nanoparticles can overcome important body barriers including the blood-retinal barrier as well as the corneal-retinal barrier of the eye for effective delivery of the drug. In summary, the nanotechnology based drug delivery system may serve as an important tool for uveal melanoma treatment.
基金Supported by the Science and Technology Commission of Shanghai (No.14411961800)
文摘AIM: To detect how BRCA-associated protein 1(BAP1) regulates cell migration in uveal melanoma(UM) cells. METHODS: Wound healing and transwell assays were performed to detect UM cell migration abilities. Protein chip, immunoprecipitations and surface plasmon resonance analyses were applied to identify BAP1 protein partners. Western blot and calpain activity assays were used to test the expression and function of calpastatin(CAST). RESULTS: CAST protein was confirmed as a new BAP1 protein partner, and loss of BAP1 reduced the expression and function of CAST in UM cells. The overexpression of CAST rescued the cell migration phenotype caused by BAP1 loss.CONCLUSION: BAP1 interacts with CAST in UM cells, and CAST and its subsequent calpain pathway may mediate BAP1-related cell migration regulation.
文摘AIM:To construct an immune-related prognostic signature(IPS)that can distinguish and predict prognosis in uveal melanoma(UM).METHODS:The transcriptomic data and clinicopathological information of 80 UM patients were extracted from the TCGA database.These patients were randomly assigned to a training and a testing set.RESULTS:Lasso Cox analysis was performed for the prognostic immune-related genes to develop an IPS for UM in the training set.The signature was validated in both the testing set and entire cohort.We confirmed the prognostic value of our IPS in distinct subgroups and found its association with the T stage and basal diameter of the tumor.Tumor Immune Estimation Resource database analysis revealed that the IPS was negatively correlated with the infiltration of neutrophils and dendritic cells,but positively correlated with the infiltration level of CD8+T cells.In addition,we demonstrated that immune checkpoints containing PD-1,CTLA-4,IDO,and TIGIT were moderately associated with the IPS.CONCLUSION:This is the first study to develop and validate an immune-related signature with the ability of predicting prognosis for UM patients.Further studies are needed to validate its prediction accuracy.
基金Supported by the National Natural Science Foundation of China(No.81570891No.81272981)+2 种基金the Beijing Natural Science Foundation(No.7151003)Advanced Health Care Professionals Development Project of Beijing Municipal Health Bureau(No.2014-2-003)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(No.ZYLX201307)
文摘AIM: To find new biomarkers for uveal melanoma(UM) by analyzing the serum peptidome profile. METHODS: Proteomic spectra in patients with UM before and after operation were analyzed and compared with those of healthy controls. Magnetic affinity beads were used to capture serum peptides and matrix-assisted laser desorption/ionization time-of-flight(MALDI-TOF) mass spectrometer were used to compile serum peptide profiles. RESULTS: A panel of 49 peptides were differentially expressed between UM patients and controls, of which 33 peptides were of higher intensities in patient group and 16 peptides were of higher intensities in control group. Based on combined use of these potential markers, peptides with mean molecular masses of 1467 and 9289.0 Da provide high sensitivity(83.3%), specificity(100%) and accuracy rate(93.0%) together to differentiate melanoma patients from healthy controls. At the time point of 6mo postoperatively, the levels of many peptides differentially expressed before surgery showed no more statistical difference between the patients and the control group. Fibrinogen α-chain precursors were identified as potential UM markers.CONCLUSION: We have shown that a convenient and fast proteomic technique, affinity bead separation and MALDITOF analysis combined with bioinformatic software, facilitates the identification of novel biomarkers for UM.
基金Supported by National Natural Science Foundation of China(No.81570891)Beijing Natural Science Foundation(No.7151003)。
文摘AIM: To measure the concentration of vascular endothelial growth factor-A(VEGF-A), and placental growth factor(PLGF) in aqueous humor of uveal melanoma patients before and after Iodine-125 plaque therapy(IPT), determine the postoperative fluctuation and evaluate associated factors in vivo.METHODS: Participants were 18 Chinese patients with uveal melanoma who were elected to IPT. Undiluted aqueous humor samples were collected at Iodine plaque implant and removal time, then stored immediately at-80℃ until assayed. The concentration of VEGF-A, PLGF and other 7 cytokines comprising interleukin-2(IL-2), IL-8, IL-10, interferon(IFN)-γ, programmed death(PD)-1, transforming growth factor(TGF)-β1 and insulin-like growth factor(IGF)-1 in aqueous humor was measured using Raybiotech immunoassay kit, a high throughput strategy. The VEGF-A and PLGF levels were compared across preoperation and postoperation subgroups, as well as those of other 7 interleukins. Correlation and grouped analyses were conducted to determine the independent effects of clinical parameters and other cytokines on VEGF-A and PLGF concentration or fluctuation. This study set a self-control design.RESULTS: VEGF-A(P=0.038) and PLGF(P=0.026) were the only two increased cytokines after IPT. Preoperative and postoperative level of VEGF-A and PLGF(r=0.575, P=0.013;r=0.987, P<0.001) correlated with each other significantly. Level of VEGF-A(r=0.626, P=0.005;r=0.588, P=0.01) and PLGF(r=0.616, P=0.007;r=0.588, P=0.01) had positive correlation with tumor thickness consistently. Elevated VEGF-A or PLGF level were strong predictive factors of each other(P=0.007, OR=60.0). The elevated VEGF-A group showed a higher postoperative level of IFN-γ(P=0.005), IL-2(P<0.001) and IL-10(P=0.004) in aqueous humor. When the elevated PLGF group got similar results that a higher postoperative level of IFN-γ(P=0.007), IL-2(P<0.001) and IL-10(P=0.013) in aqueous humor. CONCLUSION: This study reveals that VEGF-A and PLGF in aqueous humor significantly increased with tumor thickness and radiation process in uveal melanoma patients. VEGF-A and PLGF may be crucial in uveal melanoma genesis and radiotherapy reactions. Immune mediators comprised IFN-γ, IL-2 and IL-10 could play roles in the link between inflammation and angiogenesis in uveal melanoma when exposed to radiotherapy.
