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1.
NPJ Syst Biol Appl ; 10(1): 75, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013872

RESUMO

Mathematical models of biochemical reaction networks are an important and emerging tool for the study of cell signaling networks involved in disease processes. One promising potential application of such mathematical models is the study of how disease-causing mutations promote the signaling phenotype that contributes to the disease. It is commonly assumed that one must have a thorough characterization of the network readily available for mathematical modeling to be useful, but we hypothesized that mathematical modeling could be useful when there is incomplete knowledge and that it could be a tool for discovery that opens new areas for further exploration. In the present study, we first develop a mechanistic mathematical model of a G-protein coupled receptor signaling network that is mutated in almost all cases of uveal melanoma and use model-driven explorations to uncover and explore multiple new areas for investigating this disease. Modeling the two major, mutually-exclusive, oncogenic mutations (Gαq/11 and CysLT2R) revealed the potential for previously unknown qualitative differences between seemingly interchangeable disease-promoting mutations, and our experiments confirmed oncogenic CysLT2R was impaired at activating the FAK/YAP/TAZ pathway relative to Gαq/11. This led us to hypothesize that CYSLTR2 mutations in UM must co-occur with other mutations to activate FAK/YAP/TAZ signaling, and our bioinformatic analysis uncovers a role for co-occurring mutations involving the plexin/semaphorin pathway, which has been shown capable of activating this pathway. Overall, this work highlights the power of mechanism-based computational systems biology as a discovery tool that can leverage available information to open new research areas.


Assuntos
Mutação , Receptores Acoplados a Proteínas G , Transdução de Sinais , Humanos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Mutação/genética , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo , Biologia de Sistemas/métodos , Modelos Biológicos , Melanoma/genética , Melanoma/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo
2.
Vestn Oftalmol ; 140(3): 5-10, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38962973

RESUMO

MicroRNAs (miRNAs) are short non-coding RNAs (18-25 nucleotides in length) that are important participants in the regulation of gene expression. In 2003, their active role in oncogenesis was demonstrated. In 2008, the first report on the isolation of miRNAs from uveal melanoma (UM) tissue was published. Four years later (2012), the presence of miRNAs in the plasma of patients with this category was shown. To date, changes in the expression level of 100 miRNAs in the plasma of cancer patients (with cancer of various localizations) out of the 2654 miRNAs described in mirbase.org have been proven. In the plasma of patients with UM, changes in the expression of only 13 miRNAs have been confirmed. As a rule, studies were conducted in patients at the stage of hematogenous metastasis of UM. PURPOSE: This study analyzed the expression pattern of miRNA-223 and miRNA-126 in patients with localized choroidal melanoma (CM) taking into account biometric parameters in the absence of metastases. MATERIAL AND METHODS: Blood plasma of 84 patients with M0N0 CM aged 35-86 years (mean age 63.4±1.2 years) was investigated. The basis for the diagnosis of CM was the results of ophthalmological examination, optical coherence tomography, and ultrasound scanning. In all cases, the absence of metastases was proven (using computed tomography or magnetic resonance imaging). Control - plasma of 28 volunteers (mean age 62.9±1.42 years, age range 45-78 years), who did not have tumoral, autoimmune, or chronic inflammatory processes. The expression levels of miRNAs circulating in blood plasma were determined by real-time polymerase chain reaction. RESULTS: An increase in the expression levels of miRNA-223 and miRNA-126 in the plasma of all 84 patients with CM was confirmed compared to the control group. Features of the miRNA expression pattern that emerged with changes in the tumor's quantitative parameters were identified. CONCLUSION: Evaluation of the levels of miRNA-223 and miRNA-126 in the blood plasma of patients with CM can be used in clinical practice to clarify the diagnosis of CM, as well as to predict the development of hematogenous metastases.


Assuntos
Biomarcadores Tumorais , Neoplasias da Coroide , Regulação Neoplásica da Expressão Gênica , Melanoma , MicroRNAs , Humanos , Melanoma/genética , Melanoma/diagnóstico , Neoplasias da Coroide/genética , Neoplasias da Coroide/diagnóstico , Pessoa de Meia-Idade , Masculino , Feminino , MicroRNAs/genética , MicroRNAs/sangue , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Epigênese Genética , Idoso , Neoplasias Uveais/genética , Neoplasias Uveais/diagnóstico
3.
J Transl Med ; 22(1): 605, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951874

RESUMO

BACKGROUND: Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM. METHODS: By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects. RESULTS: UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment. CONCLUSION: This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.


Assuntos
Movimento Celular , Senescência Celular , Células Endoteliais , Fator 4 Semelhante a Kruppel , Neoplasias Hepáticas , Melanoma , Análise de Célula Única , Neoplasias Uveais , Humanos , Neoplasias Uveais/patologia , Neoplasias Uveais/genética , Melanoma/patologia , Melanoma/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Linhagem Celular Tumoral , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Regulação Neoplásica da Expressão Gênica , Feminino , Masculino
4.
Hereditas ; 161(1): 22, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987843

RESUMO

BACKGROUND: Uveal melanoma (UVM) stands as the predominant type of primary intraocular malignancy among adults. The clinical significance of N7-methylguanosine (m7G), a prevalent RNA modifications, in UVM remains unclear. METHODS: Primary information from 80 UVM patients were analyzed as the training set, incorporating clinical information, mutation annotations and mRNA expression obtained from The Cancer Genome Atlas (TCGA) website. The validation set was carried out using Gene Expression Omnibus (GEO) database GSE22138 and GSE84976. Kaplan-Meier and Cox regression of univariate analyses were subjected to identify m7G-related regulators as prognostic genes. RESULT: A prognostic risk model comprising EIF4E2, NUDT16, SNUPN and WDR4 was established through Cox regression of LASSO. Evaluation of the model's predictability for UVM patients' prognosis by Receiver Operating Characteristic (ROC) curves in the training set, demonstrated excellent performance Area Under the Curve (AUC) > 0.75. The high-risk prognosis within the TCGA cohort exhibit a notable worse outcome. Additionally, an independent correlation between the risk score and overall survival (OS) among UVM patients were identified. External validation of this model was carried out using the validation sets (GSE22138 and GSE84976). Immune-related analysis revealed that patients with high score of m7G-related risk model exhibited elevated level of immune infiltration and immune checkpoint gene expression. CONCLUSION: We have developed a risk prediction model based on four m7G-related regulators, facilitating effective estimate UVM patients' survival by clinicians. Our findings shed novel light on essential role of m7G-related regulators in UVM and suggest potential novel targets for the diagnosis, prognosis and therapy of UVM.


Assuntos
Guanosina , Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/genética , Neoplasias Uveais/mortalidade , Melanoma/genética , Prognóstico , Guanosina/análogos & derivados , Feminino , Masculino , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Curva ROC , Estimativa de Kaplan-Meier
5.
Hum Vaccin Immunother ; 20(1): 2374647, 2024 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-39004419

RESUMO

Patients with metastatic uveal melanoma (mUM) have a poor prognosis, and few appropriate medications are available. Tebentafusp is approved by the Food and Drug Administration for mUM recently. However, the real efficacy and safety of tebentafusp are still unclear. We searched PubMed, Embase, and Cochrane Library from inception to March 20, 2024. The research was reported based on the preferred reporting items for systematic reviews and meta-analysis guidelines. We used random effects models to aggregate data on the response rates and adverse events of tebentafusp therapy. Six studies met the inclusion criteria with a total sample of 589 participants. The pooled objective response rate was 0.08 (95% CI: 0.05-0.12), and pooled disease control rate was 0.51 (95% CI: 0.44-0.57). The overall incidence was 0.99 (95% CI: 0.95-1.00) for any grade adverse events, 0.50 (95% CI: 0.41-0.59) for grade 3-4 adverse events, and 0.01 (95% CI: 0-0.03) for discontinuation due to adverse events. Tebentafusp exhibits promising treatment outcomes for mUM patients. Although accompanied with a common occurrence of adverse events, which can typically be managed and controlled. Future research is necessary for substantiating these findings and refining guidelines for management of mUM.


Assuntos
Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/tratamento farmacológico , Melanoma/tratamento farmacológico , Resultado do Tratamento , Metástase Neoplásica , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico
6.
Invest Ophthalmol Vis Sci ; 65(8): 3, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38953846

RESUMO

Purpose: To investigate the correlation between apparent diffusion coefficient (ADC) histograms and high-risk clinicopathologic features related to uveal melanoma (UM) prognosis. Methods: This retrospective study included 53 patients with UM who underwent diffusion-weighted imaging (DWI) between August 2015 and March 2024. Axial DWI was performed with a single-shot spin-echo echo-planar imaging sequence. ADC histogram parameters of ADCmean, ADC50%, interquartile range (IQR), skewness, kurtosis, and entropy were obtained from DWI. The relationships between histogram parameters and high-risk clinicopathological characteristics including tumor size, preoperative retinal detachment, histological subtypes, Ki-67 index, and chromosome status, were analyzed by Spearman correlation analysis, Mann-Whitney U test, or Kruskal-Wallis test. Results: A total of 53 patients (mean ± SD age, 55 ± 15 years; 22 men) were evaluated. The largest basal diameter (LBD) was correlated with kurtosis (r = 0.311, P = 0.024). Tumor prominence (TP) was correlated with entropy (r = 0.581, P < 0.001) and kurtosis (r = 0.273, P = 0.048). Additionally, significant correlations were identified between the Ki-67 index and ADCmean (r = -0.444, P = 0.005), ADC50% (r = -0.487, P = 0.002), and skewness (r = 0.394, P = 0.014). Finally, entropy was correlated with monosomy 3 (r = 0.541, P = 0.017). Conclusions: The ADC histograms provided valuable insights into high-risk clinicopathologic features of UM and hold promise in the early prediction of UM prognosis.


Assuntos
Imagem de Difusão por Ressonância Magnética , Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/patologia , Neoplasias Uveais/genética , Masculino , Feminino , Pessoa de Meia-Idade , Melanoma/patologia , Estudos Retrospectivos , Prognóstico , Imagem de Difusão por Ressonância Magnética/métodos , Adulto , Idoso , Imagem Ecoplanar/métodos
7.
Front Immunol ; 15: 1427348, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38966635

RESUMO

Uveal melanoma (UM) is a highly aggressive and fatal tumor in the eye, and due the special biology of UM, immunotherapy showed little effect in UM patients. To improve the efficacy of immunotherapy for UM patients is of great clinical importance. Single-cell RNA sequencing(scRNA-seq) provides a critical perspective for deciphering the complexity of intratumor heterogeneity and tumor microenvironment(TME). Combing the bioinformatics analysis, scRNA-seq could help to find prognosis-related molecular indicators, develop new therapeutic targets especially for immunotherapy, and finally to guide the clinical treatment options.


Assuntos
Imunoterapia , Melanoma , Análise de Célula Única , Microambiente Tumoral , Neoplasias Uveais , Humanos , Neoplasias Uveais/genética , Neoplasias Uveais/terapia , Neoplasias Uveais/imunologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Melanoma/terapia , Melanoma/genética , Melanoma/imunologia , Análise de Célula Única/métodos , Imunoterapia/métodos , Análise de Sequência de RNA , Biomarcadores Tumorais/genética , Heterogeneidade Genética , Animais , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica
8.
Invest Ophthalmol Vis Sci ; 65(8): 11, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38967943

RESUMO

Purpose: Ocular melanoma is a common primary malignant ocular tumor in adults with limited effective treatments. Epigenetic regulation plays an important role in tumor development. The switching/sucrose nonfermentation (SWI/SNF) chromatin remodeling complex and bromodomain and extraterminal domain family proteins are epigenetic regulators involved in several cancers. We aimed to screen a candidate small molecule inhibitor targeting these regulators and investigate its effect and mechanism in ocular melanoma. Methods: We observed phenotypes caused by knockdown of the corresponding gene and synergistic effects with BRD inhibitor treatment and SWI/SNF complex knockdown. The effect of JQ-1 on ocular melanoma cell cycle and apoptosis was analyzed with flow cytometry. Via RNA sequencing, we also explored the mechanism of BRD4. Results: The best tumor inhibitory effect was observed for the BRD4 inhibitor (JQ-1), although there were no statistically obvious changes in the shBRD4 and shBRD9 groups. Interestingly, the inhibitory effect of JQ-1 was decrease in the shBRD4 group. JQ-1 inhibits the growth of melanoma in various cell lines and in tumor-bearing mice. We found 17 of these 28 common differentially expressed genes were downregulated after MEL270 and MEL290 cells treated with JQ-1. Four of these 17 genes, TP53I11, SH2D5, SEMA5A, and MDGA1, were positively correlated with BRD4. In TCGA database, low expression of TP53I11, SH2D5, SEMA5A, and MDGA1 improved the overall survival rate of patients. Furthermore, the disease-free survival rate was increased in the groups with low expression of TP53I11, SH2D5, and SEMA5A. Conclusions: JQ-1 may act downstream of BRD4 and suppress ocular melanoma growth by inducing G1 cell cycle arrest.


Assuntos
Apoptose , Azepinas , Pontos de Checagem do Ciclo Celular , Proteínas de Ciclo Celular , Melanoma , Fatores de Transcrição , Triazóis , Animais , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Camundongos , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Azepinas/farmacologia , Triazóis/farmacologia , Triazóis/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Neoplasias Uveais/metabolismo , Citometria de Fluxo , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Proteínas que Contêm Bromodomínio
9.
Cancer Genomics Proteomics ; 21(4): 350-360, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38944422

RESUMO

BACKGROUND/AIM: Uveal melanoma is an ocular malignancy whose prognosis severely worsens following metastasis. In order to improve the understanding of molecular physiology of metastatic uveal melanoma, we identified genes and pathways implicated in metastatic vs non-metastatic uveal melanoma. PATIENTS AND METHODS: A previously published dataset from Gene Expression Omnibus (GEO) was used to identify differentially expressed genes between metastatic and non-metastatic samples as well as to conduct pathway and perturbagen analyses using Gene Set Enrichment Analysis (GSEA), EnrichR, and iLINCS. RESULTS: In male metastatic uveal melanoma samples, the gene LOC401052 is significantly down-regulated and FHDC1 is significantly up-regulated compared to non-metastatic male samples. In female samples, no significant differently expressed genes were found. Additionally, we identified many significant up-regulated immune response pathways in male metastatic uveal melanoma, including "T cell activation in immune response". In contrast, many top up-regulated female pathways involve iron metabolism, including "heme biosynthetic process". iLINCS perturbagen analysis identified that both male and female samples have similar discordant activity with growth factor receptors, but only female samples have discordant activity with progesterone receptor agonists. CONCLUSION: Our results from analyzing genes, pathways, and perturbagens demonstrate differences in metastatic processes between sexes.


Assuntos
Perfilação da Expressão Gênica , Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Neoplasias Uveais/metabolismo , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Feminino , Masculino , Metástase Neoplásica , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Fatores Sexuais
10.
Cesk Slov Oftalmol ; 80(Ahead of print): 1-6, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38925897

RESUMO

AIM: To demonstrate a rare case of ciliary body leiomyoma in our patient Case report: A 72-year-old female reported to our clinic for a preventive examination, upon which we found a dome-shaped grey-brownish mass on the retinal periphery. After completing gonioscopic and ultrasound examinations, we referred the patient to a specialist facility. Due to a finding of suspicious malignant melanoma, we completed the MRI scan and recommended enucleation of the eyeball. A histopathological examination showed a leiomyoma of the ciliary body. CONCLUSION: The aim of this case report is to demonstrate the difficulty of intraocular leiomyoma diagnosis. Only immunohistochemical examination differentiated the tumor from malignant melanoma and determined the diagnosis of ciliary body leiomyoma. Perhaps because of the extreme rarity of this type of tumor, we often neglect to consider a diagnosis of leiomyoma.


Assuntos
Corpo Ciliar , Leiomioma , Neoplasias Uveais , Humanos , Leiomioma/patologia , Leiomioma/diagnóstico por imagem , Leiomioma/diagnóstico , Leiomioma/cirurgia , Feminino , Corpo Ciliar/patologia , Corpo Ciliar/diagnóstico por imagem , Idoso , Neoplasias Uveais/patologia , Neoplasias Uveais/diagnóstico por imagem , Neoplasias Uveais/diagnóstico , Neoplasias Uveais/cirurgia , Melanoma/patologia , Melanoma/diagnóstico por imagem , Melanoma/diagnóstico , Melanoma/cirurgia , Diagnóstico Diferencial
11.
Cells ; 13(12)2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38920653

RESUMO

Uveal melanoma (UM), a distinct subtype of melanoma, presents unique challenges in its clinical management due to its complex molecular landscape and tendency for liver metastasis. This review highlights recent advancements in understanding the molecular pathogenesis, genetic alterations, and immune microenvironment of UM, with a focus on pivotal genes, such as GNAQ/11, BAP1, and CYSLTR2, and delves into the distinctive genetic and chromosomal classifications of UM, emphasizing the role of mutations and chromosomal rearrangements in disease progression and metastatic risk. Novel diagnostic biomarkers, including circulating tumor cells, DNA and extracellular vesicles, are discussed, offering potential non-invasive approaches for early detection and monitoring. It also explores emerging prognostic markers and their implications for patient stratification and personalized treatment strategies. Therapeutic approaches, including histone deacetylase inhibitors, MAPK pathway inhibitors, and emerging trends and concepts like CAR T-cell therapy, are evaluated for their efficacy in UM treatment. This review identifies challenges in UM research, such as the limited treatment options for metastatic UM and the need for improved prognostic tools, and suggests future directions, including the discovery of novel therapeutic targets, immunotherapeutic strategies, and advanced drug delivery systems. The review concludes by emphasizing the importance of continued research and innovation in addressing the unique challenges of UM to improve patient outcomes and develop more effective treatment strategies.


Assuntos
Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/genética , Neoplasias Uveais/terapia , Neoplasias Uveais/patologia , Neoplasias Uveais/diagnóstico , Melanoma/genética , Melanoma/terapia , Melanoma/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Microambiente Tumoral/genética , Mutação/genética
12.
Front Immunol ; 15: 1395225, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38915414

RESUMO

Introduction: Despite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable. Methods: In this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57). Results: In the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively). Conclusions: This data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens.


Assuntos
Inibidores de Checkpoint Imunológico , Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/mortalidade , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/imunologia , Neoplasias Uveais/patologia , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/imunologia , Masculino , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Metástase Neoplásica
13.
Curr Treat Options Oncol ; 25(7): 932-951, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38869695

RESUMO

OPINION STATEMENT: Uveal melanoma is the most common primary ocular tumor in adults. With the evidence demonstrating that episcleral plaque brachytherapy (EPB) has similar survival rates as enucleation in the Collaborative Ocular Melanoma Study (COMS), eye-sparing treatments have come to the fore today. External radiotherapy techniques (proton beam radiotherapy and stereotactic radiosurgery/fractionated stereotactic radiosurgery) are an important treatment option for globe-sparing treatments. There are no prospective randomized trials comparing these techniques; however, retrospective series, meta-analyses, and reviews indicate that these EPB and external radiotherapy techniques are equal. With this review, we aimed to examine the external radiotherapy techniques used in the treatment of uveal melanoma in detail with reference to the current literature.


Assuntos
Braquiterapia , Gerenciamento Clínico , Melanoma , Radiocirurgia , Neoplasias Uveais , Neoplasias Uveais/radioterapia , Neoplasias Uveais/mortalidade , Humanos , Melanoma/radioterapia , Melanoma/mortalidade , Braquiterapia/métodos , Radiocirurgia/métodos , Resultado do Tratamento , Terapia com Prótons/métodos
14.
Front Immunol ; 15: 1383125, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38903495

RESUMO

Background: Screening for gene mutations has become routine clinical practice across numerous tumor entities, including melanoma. BAP1 gene mutations have been identified in various tumor types and acknowledged as a critical event in metastatic uveal melanoma, but their role in non-uveal melanoma remains inadequately characterized. Methods: A retrospective analysis of all melanomas sequenced in our department from 2014-2022 (n=2650) was conducted to identify BAP1 mutated samples. Assessment of clinical and genetic characteristics was performed as well as correlations with treatment outcome. Results: BAP1 mutations were identified in 129 cases and distributed across the entire gene without any apparent hot spots. Inactivating BAP1 mutations were more prevalent in uveal (55%) compared to non-uveal (17%) melanomas. Non-uveal BAP1 mutated melanomas frequently exhibited UV-signature mutations and had a significantly higher mutation load than uveal melanomas. GNAQ and GNA11 mutations were common in uveal melanomas, while MAP-Kinase mutations were frequent in non-uveal melanomas with NF1, BRAF V600 and NRAS Q61 mutations occurring in decreasing frequency, consistent with a strong UV association. Survival outcomes did not differ among non-uveal melanoma patients based on whether they received targeted or immune checkpoint therapy, or if their tumors harbored inactivating BAP1 mutations. Conclusion: In contrast to uveal melanomas, where BAP1 mutations serve as a significant prognostic indicator of an unfavorable outcome, BAP1 mutations in non-uveal melanomas are primarily considered passenger mutations and do not appear to be relevant from a prognostic or therapeutic perspective.


Assuntos
Melanoma , Mutação , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Neoplasias Uveais , Humanos , Ubiquitina Tiolesterase/genética , Melanoma/genética , Melanoma/mortalidade , Melanoma/terapia , Neoplasias Uveais/genética , Neoplasias Uveais/mortalidade , Neoplasias Uveais/terapia , Masculino , Proteínas Supressoras de Tumor/genética , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Prognóstico
16.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892225

RESUMO

Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis in multiple cancer types; however, sEVs in the aqueous humor (AH) of uveal melanoma (UM) patients have never previously been profiled. In this study, we used single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically the tetraspanin co-expression patterns of CD9, CD63, and CD81. sEVs were analyzed from paired pre- and post-treatment (brachytherapy, a form of radiation) AH samples collected from 19 UM patients. In post-brachytherapy samples, two subpopulations, CD63/81+ and CD9/63/81+ sEVs, were significantly increased. These trends existed even when stratified by tumor location and GEP class 1 and class 2 (albeit not significant for GEP class 2). In this initial report of single vesicle profiling of sEVs in the AH of UM patients, we demonstrated that sEVs can be detected in the AH. We further identified two subpopulations that were increased post-brachytherapy, which may suggest radiation-induced release of these particles, potentially from tumor cells. Further study of the cargo carried by these sEV subpopulations may uncover important biomarkers and insights into tumorigenesis for UM.


Assuntos
Humor Aquoso , Braquiterapia , Vesículas Extracelulares , Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/radioterapia , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia , Vesículas Extracelulares/metabolismo , Melanoma/radioterapia , Melanoma/metabolismo , Melanoma/patologia , Humor Aquoso/metabolismo , Humor Aquoso/efeitos da radiação , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/metabolismo , Adulto , Idoso de 80 Anos ou mais
17.
Invest Ophthalmol Vis Sci ; 65(6): 7, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38833258

RESUMO

Purpose: The purpose of this study was to analyze the extent of DNA breaks in primary uveal melanoma (UM) with regard to radiotherapy dose delivery (single-dose versus fractionated) and monosomy 3 status. Methods: A total of 54 patients with UM were included. Stereotactic radiotherapy (SRT) was performed in 23 patients, with 8 undergoing single-dose SRT (sdSRT) treatment and 15 receiving fractionated SRT (fSRT). DNA breaks in the enucleated or endoresected tumors were visualized by a TUNEL assay and quantified by measuring the TUNEL-positive area. Protein expression was analyzed by immunohistochemistry. Co-detection of chromosome 3 with proteins was performed by immuno-fluorescent in situ hybridization. Results: The amount of DNA breaks in the total irradiated group was increased by 2.7-fold (P < 0.001) compared to non-irradiated tissue. Tumors treated with fSRT were affected more severely, showing 2.1-fold more DNA damage (P = 0.007) compared to the cases after single (high) dose irradiation (sdSRT). Monosomy 3 tumors showed less DNA breaks compared to disomy 3 samples (P = 0.004). The presence of metastases after radiotherapy correlated with monosomy 3 and less DNA breaks compared to patients with non-metastatic cancer in the combined group with fSRT and sdSRT (P < 0.05). Conclusions: Fractionated irradiation led to more DNA damage than single-dose treatment in primary UM. As tumors with monosomy 3 showed less DNA breaks than those with disomy 3, this may indicate that they are less radiosensitive, which may influence the efficacy of irradiation.


Assuntos
Cromossomos Humanos Par 3 , Dano ao DNA , Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/radioterapia , Neoplasias Uveais/genética , Melanoma/radioterapia , Melanoma/genética , Feminino , Cromossomos Humanos Par 3/genética , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Hibridização in Situ Fluorescente , Marcação In Situ das Extremidades Cortadas , Dosagem Radioterapêutica , Imuno-Histoquímica , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Relação Dose-Resposta à Radiação
18.
Sci Signal ; 17(840): eadn8376, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38861613

RESUMO

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and its upstream regulator, p70S6K1, compared with both wild-type and BAP1 reconstituted cells. In turn, expression of p70S6K1 increased S6 phosphorylation and proliferation of BAP1-deficient UM cells. Consistent with these findings, BAP1 mutant primary UM tumors expressed lower amounts of p70S6K1 target genes, and S6 phosphorylation was decreased in BAP1 mutant patient-derived xenografts (PDXs), which grew more slowly than wild-type PDXs in the liver (the main metastatic site of UM) in mice. BAP1-deficient UM cells were also more resistant to amino acid starvation, which was associated with diminished phosphorylation of S6. These studies demonstrate that BAP1 deficiency slows the proliferation of UM cells through regulation of S6 phosphorylation. These characteristics may be associated with metastasis by ensuring survival during amino acid starvation.


Assuntos
Proliferação de Células , Melanoma , Transdução de Sinais , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Neoplasias Uveais , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Mutação , Fosforilação , Proteína S6 Ribossômica/metabolismo , Proteína S6 Ribossômica/genética , Estresse Fisiológico , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo , Neoplasias Uveais/patologia , Feminino
19.
Cesk Slov Oftalmol ; 80(3): 170-174, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38886109

RESUMO

The aim of the thesis is to present the case of a patient in whom bilateral calcification of the hydrophilic intraocular lens (IOL) Lentis M+ LS-313 MF30 (Oculentis) has developed. Due to the negative effect on visual functions, explantation and replacement of the artificial lens was necessary in both eyes. Case Report: An overview of the available literature summarized the diagnostics, current examination methods and possibilities of the surgical solution of calcification of the bifocal hydrophilic lens Lentis M+ LS-313 MF30 (Oculentis). The specific solution is described in a case report of a patient in whom calcification of both lenses developed 6 years after implantation of the IOL. In 2015, the patient underwent uncomplicated cataract surgery of both eyes with the implantation of an artificial intraocular lens into the capsule. In September 2021, an 82-year-old man was examined at our outpatient clinic for deterioration of visual acuity and changes in the material of the artificial IOL which were perceptible during a clinical examination, on the recommendation of a local ophthalmologist. Blurred vision predominated. A diagnosis of intraocular lens opacification was confirmed and documented using a Scheimpflug camera (OCULUS Pentacam HR) and anterior OCT (Avanti RTVue XR Optovue,). The patient was indicated for explantation and replacement of the opacified intraocular lens in the left and subsequently in the right eye- The same type of IOL was used for reimplantation with good functional results. Conclusion: Since 2010, multifocal lens implantation has been on an upward trend worldwide. This type of MF IOL has also been used in thousands of implantations. A number of other explantations can be expected in the coming years. The optimal solution is the correct replacement of the calcified IOL with the same construction made of safer hydrophobic material.


Assuntos
Melanoma , Radiocirurgia , Humanos , Masculino , Radiocirurgia/efeitos adversos , Melanoma/radioterapia , Idoso de 80 Anos ou mais , Calcinose/cirurgia , Calcinose/diagnóstico por imagem , Neoplasias da Coroide/radioterapia , Neoplasias da Coroide/diagnóstico , Lentes Intraoculares/efeitos adversos , Lesões por Radiação/etiologia , Lesões por Radiação/diagnóstico , Lesões por Radiação/cirurgia , Neoplasias Uveais/radioterapia , Implante de Lente Intraocular/efeitos adversos
20.
Int Ophthalmol ; 44(1): 256, 2024 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-38909111

RESUMO

PURPOSE: Uveal melanoma is the most prevalent intraocular malignancy in adults, derived from uveal tract melanocytes. This study focuses on the frequency and risk of second primary malignancies in UM patients. METHODS: A PubMed search (1980-2023) identified studies on SPM incidence in UM patients. From 191 references, 14 studies were chosen, focusing on UM, SPMs, and analysing data on demographics and types of neoplasms. RESULTS: Among 31,235 UM patients in 14 studies, 4695 had 4730 SPMs (15.03% prevalence). Prostate (15%), breast (12%), and colorectal (9%) cancers were most common. Digestive system malignancies were highest (19%), with colorectal cancer leading (51%). Breast and prostate cancers were prevalent in respective systems. Lung, bladder, and non-Hodgkin's lymphoma were also notable. The study observed an increasing trend in the frequency of SPMs over time, reflecting broader trends in cancer survivorship and the growing prevalence of multiple malignancies. CONCLUSION: The study highlights a significant presence of SPMs in UM patients, with an increasing trend in frequency over time, emphasizing prostate and breast cancers. This underscores the need for focused surveillance and tailored follow-up for UM survivors, considering their higher risk of additional malignancies. Future research should further investigate SPM aetiology in UM patients.


Assuntos
Melanoma , Neoplasias Uveais , Humanos , Neoplasias Uveais/epidemiologia , Melanoma/epidemiologia , Incidência , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/patologia , Prevalência , Fatores de Risco , Segunda Neoplasia Primária/epidemiologia
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