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Albeit N1-Methyladenosine (m1A) RNA modification represents an important regulator of RNA metabolism, the role of m1A modification in carcinogenesis remains enigmatic. Herein, we found that histone lactylation enhances ALKBH3 expression and simultaneously attenuates the formation of tumor-suppressive promyelocytic leukemia protein (PML) condensates by removing the m1A methylation of SP100A, promoting the malignant transformation of cancers. First, ALKBH3 is specifically upregulated in high-risk ocular melanoma due to excessive histone lactylation levels, referring to m1A hypomethylation status. Moreover, the multiomics analysis subsequently identified that SP100A, a core component for PML bodies, serves as a downstream candidate target for ALKBH3. Therapeutically, the silencing of ALKBH3 exhibits efficient therapeutic efficacy in melanoma both in vitro and in vivo, which could be reversed by the depletion of SP100A. Mechanistically, we found that YTHDF1 is responsible for recognition of the m1A methylated SP100A transcript, which increases its RNA stability and translational efficacy. Conclusively, we initially demonstrated that m1A modification is necessary for tumor suppressor gene expression, expanding the current understandings of dynamic m1A function during tumor progression. In addition, our results indicate that lactylation-driven ALKBH3 is essential for the formation of PML nuclear condensates, which bridges our knowledge of m1A modification, metabolic reprogramming, and phase-separation events.
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Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato , Antígenos Nucleares , Autoantígenos , Neoplasias Oculares , Histonas , Melanoma , Humanos , Homólogo AlkB 3 da Dioxigenase Dependente de alfa-Cetoglutarato/metabolismo , Desmetilação , Metilação de DNA , Histonas/genética , Histonas/metabolismo , Proteína da Leucemia Promielocítica/genética , Proteína da Leucemia Promielocítica/metabolismo , RNA/metabolismo , Fatores de Transcrição/metabolismo , Antígenos Nucleares/metabolismo , Autoantígenos/metabolismo , Neoplasias Oculares/metabolismoRESUMO
Antibiotics are among the most used weapons in fighting microbial infections and have greatly improved the quality of human life. However, bacteria can eventually evolve to exhibit antibiotic resistance to almost all prescribed antibiotic drugs. Photodynamic therapy (PDT) develops little antibiotic resistance and has become a promising strategy in fighting bacterial infection. To augment the killing effect of PDT, the conventional strategy is introducing excess ROS in various ways, such as applying high light doses, high photosensitizer concentrations, and exogenous oxygen. In this study, we report a metallacage-based PDT strategy that minimizes the use of ROS by jointly using gallium-metal organic framework rods to inhibit the production of bacterial endogenous NO, amplify ROS stress, and enhance the killing effect. The augmented bactericidal effect was demonstrated both in vitro and in vivo. This proposed enhanced PDT strategy will provide a new option for bacterial ablation.
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Fotoquimioterapia , Humanos , Espécies Reativas de Oxigênio/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , BactériasRESUMO
Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.
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Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics.
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Diabetes Mellitus Tipo 2 , Insulinas , Metformina , Neoplasias , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Glicemia , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Insulinas/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
OBJECTIVE: To report cerebrospinal fluid leak as an uncommon but noteworthy delayed complication after endoscopic orbital surgeries and to describe its incidence, mechanism, prevention, diagnosis, and management. METHODS: Case series of 3 patients who underwent endoscopic orbital surgery in the Department of Ophthalmology, Shanghai Ninth People's Hospital affiliated to Shanghai JiaoTong University School of Medicine from January 2003 to December 2020. A review of the literature was also conducted. RESULTS: Three cases of delayed cerebrospinal fluid leaks occurred 10 years, 3 months, and 4 months after endoscopic orbital surgeries, respectively, were reviewed and reported. Two patients developed cerebrospinal fluid leaks after surgical repair of orbital blowout fractures with titanium mesh and porous polyethylene (Medpor), respectively, and 1 patient developed cerebrospinal fluid leak after transantral optic canal decompression. In the first case, head computed tomography (CT) cisternography and magnetic resonance imaging confirmed the site of the leak that required surgical repair. In the second case, a coronal CT showed that the implanted titanium mesh was tightly against the cribriform plate, which might cause defect of skull base and dura. In the third case, orbital CT identified a dehiscence on the sphenoidal wall as the leak site, which was repaired in a secondary endoscopic surgery. CONCLUSIONS: A cerebrospinal fluid leak, as an uncommon but noteworthy complication, can occur as delayed as 10 more years after surgery. For patients with specific anatomic characteristics, such as Kero type III, surgeons should perform meticulous preoperative evaluation and intraoperative procedures to prevent this complication.
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Vazamento de Líquido Cefalorraquidiano , Titânio , Humanos , China , Vazamento de Líquido Cefalorraquidiano/etiologia , Endoscopia/métodos , Base do Crânio/cirurgia , Estudos RetrospectivosRESUMO
Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common and deadly eye cancer in adults. Both UM and CM originate from melanocytes and exhibit an aggressive growth pattern with high rates of metastasis and mortality. The integral membrane glycoprotein beta-secretase 2 (BACE2), an enzyme that cleaves amyloid precursor protein into amyloid beta peptide, has been reported to play a vital role in vertebrate pigmentation and metastatic melanoma. However, the role of BACE2 in ocular melanoma remains unclear. In this study, we showed that BACE2 was significantly upregulated in ocular melanoma, and inhibition of BACE2 significantly impaired tumor progression both in vitro and in vivo. Notably, we identified that transmembrane protein 38B (TMEM38B), whose expression was highly dependent on BACE2, modulated calcium release from endoplasmic reticulum (ER). Inhibition of the BACE2/TMEM38B axis could trigger exhaustion of intracellular calcium release and inhibit tumor progression. We further demonstrated that BACE2 presented an increased level of N6-methyladenosine (m6A) RNA methylation, which led to the upregulation of BACE2 mRNA. To our knowledge, this study provides a novel pattern of BACE2-mediated intracellular calcium release in ocular melanoma progression, and our findings suggest that m6A/BACE2/TMEM38b could be a potential therapeutic axis for ocular melanoma.
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Secretases da Proteína Precursora do Amiloide/genética , Ácido Aspártico Endopeptidases/genética , Cálcio/metabolismo , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Melanoma/metabolismo , RNA/genética , Neoplasias Uveais/genética , Neoplasias Uveais/metabolismo , Adenosina/análogos & derivados , Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/metabolismo , Epigênese Genética , Perfilação da Expressão Gênica , Humanos , Canais Iônicos/genética , Canais Iônicos/metabolismo , Melanoma/mortalidade , Melanoma/patologia , Metilação , RNA/metabolismo , Interferência de RNA , Neoplasias Uveais/mortalidade , Neoplasias Uveais/patologiaRESUMO
ABSTRACT: The aim of the study was to report a novel forkhead box L2 (FOXL2) missense mutation in a Chinese blepharophimosis/ ptosis/epicanthus inversus syndrome family. Three generations of the Chinese family with blepharophimosis/ptosis/epicanthus inversus syndrome were enrolled in this study. Blood samples from patients of this family were collected and then analyzed by whole-exome sequencing. Confocal microscopy was performed to detect the subcellular location of FOXL2. Transactivation studies were performed and verified with real time polymerase chain reaction. A novel mutation (c.1068G>C) located in the downstream of deoxyribonucleic acid-binding forkhead domain was identified. Confocal photos showed the novel mutation did not disturb FOXL2 function, and the mutant protein could still transactivate steroidogenic acute regulatory protein, a key regulator of primary ovarian failure (POF). Our study revealed a novel missense mutation (c.1068G>C) and expanded the spectrum of FOXL2 gene mutations.
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Blefarofimose , Proteína Forkhead Box L2 , Anormalidades da Pele , Anormalidades Urogenitais , Blefarofimose/diagnóstico , Blefarofimose/genética , China , Proteína Forkhead Box L2/genética , Humanos , Mutação de Sentido Incorreto , Linhagem , Anormalidades da Pele/diagnóstico , Anormalidades da Pele/genética , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/genéticaRESUMO
Retinoblastoma (Rb) is the most common primary intraocular childhood malignancy and one of the main causes of blindness in children. In China, most tumors are diagnosed at an advanced stage and have relatively poor outcomes compared to developed countries. Here, we aimed to update the clinical manifestations and RB transcriptional corepressor 1 (RB1) mutation spectrum in Chinese Rb patients. Medical charts of 184 eyes in 145 Chinese Rb patients belonging to unrelated families were reviewed. Genomic DNA was isolated from peripheral blood of the patients and their parents. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in the RB1 gene was performed. In addition, multiplex ligation-dependent probe amplification (MLPA) was done to detect gross aberrations. Germline RB1 mutations were observed in 37.2% (54/145) of Rb patients. RB1-mutated patients presented with earlier age of diagnosis (p = 0.019), with a significantly larger proportion of bilateral cases (p = <0.001) and secondary malignancies (p = 0.027) relative to those without RB1 mutations. For ocular clinical presentations, RB1-mutated retinoblastomas presented with a larger proportion of ectropion uveae (p = 0.017) and iris neovascularization (p = 0.001). These RB1 mutations comprised of 13 (24.1%) nonsense mutation, 13 (24.1%) splicing mutations, 11 (20.4%) frameshift deletions, 11 (20.4%) gross mutations, 3 (5.6%) missense mutations, 2 (3.7%) promoter mutations and 1 (1.9%) non-frameshift deletion. In addition, 8 novel RB1 mutations were identified. These germline RB1 mutations were not related to age at diagnosis or laterality. Here, we provide a comprehensive spectrum of RB1 germline mutations in Chinese Rb patients and describe correlations between RB1 mutations and clinical presentations. Our study also provides new evidence that will inform management and genetic counselling of Rb patients and families.
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Povo Asiático/genética , Mutação em Linhagem Germinativa/genética , Mutação , Neoplasias da Retina/genética , Proteínas de Ligação a Retinoblastoma/genética , Retinoblastoma/genética , Ubiquitina-Proteína Ligases/genética , Criança , Pré-Escolar , China/epidemiologia , Análise Mutacional de DNA , Feminino , Genes do Retinoblastoma , Humanos , Lactente , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase Multiplex , Neoplasias da Retina/diagnóstico , Retinoblastoma/diagnóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Thyroid eye disease (TED) is a debilitating autoimmune orbital disease that is often a result of Graves' disease. Dysthyroid optic neuropathy (DON) is a rare but sight-threatening manifestation of TED with therapeutic challenges that can potentially lead to visual loss. CASE PRESENTATION: A 74-year-old man experienced active TED with extremely severe redness and swelling of the conjunctiva, loss of visual acuity and exacerbation of disfiguring proptosis. Computed tomography revealed the involvement of extraocular muscles resulting in optic nerve compression. He was in poor general condition and was intolerant to steroids. To achieve the optimal operating conditions for orbital decompression surgery, the patient was initially treated with orbital radiotherapy. The patient responded well, with improvements in clinical activity score and visual acuity. CONCLUSION: This case demonstrates a rare and severe case of DON with therapeutic challenges. To date, no cases has been reported of a patient with such severe and unusual ocular manifestations. Early awareness of the occurrence of optic nerve compression and prompt treatment are important to prevent irreversible outcomes. Orbital radiotherapy should be considered as a useful surgery-delaying alternative for DON, especially in patients who have contraindications to steroids.
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Descompressão Cirúrgica , Oftalmopatia de Graves/patologia , Oftalmopatia de Graves/terapia , Órbita/efeitos da radiação , Acuidade Visual , Idoso , Terapia Combinada , Humanos , Masculino , Prognóstico , Dosagem RadioterapêuticaRESUMO
BACKGROUND Eyelid retraction is the most common and often the first sign of thyroid eye disease (TED). Upper-eyelid retraction causes both functional and cosmetic problems. In order to correct the position of the upper eyelid, surgery is required. Many procedures have demonstrated good outcomes in mild and moderate cases; however, unpredictable results have been obtained in severe cases. Dryden introduced an upper-eyelid-lengthening procedure, which used scleral grafts, but outcomes were unsatisfactory. A new technique is introduced in this study as a reasonable alternative for TED-related severe upper-eyelid retraction correction. MATERIAL AND METHODS An innovative technique for levator lengthening using bovine acellular dermal matrix as a spacer graft is introduced for severe upper-eyelid retraction secondary to TED. Additionally, 2 modifications were introduced: the fibrous cords scattered on the surface of the levator aponeurosis were excised and the orbital fat pad anterior to the aponeurosis was dissected and sutured into the skin closure in a "skin-tarsus-fat-skin" fashion. RESULTS The modified levator-lengthening surgery was performed on 32 eyelids in 26 patients consisting of 21 women and 5 men (mean age, 37.8 years; age range, 19-67 years). After corrective surgery, the average upper margin reflex distance was lowered from 7.7±0.85 mm to 3.3±0.43 mm. Eighteen cases (69%) had perfect results, while 6 cases (23%) had acceptable results. CONCLUSIONS A modified levator-lengthening procedure using bovine acellular dermal matrix as a spacer graft ameliorated both the symptoms and signs of severe upper-eyelid retraction secondary to TED. This procedure is a reasonable alternative for correction of TED-related severe upper-eyelid retraction.
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Derme Acelular/metabolismo , Matriz Extracelular/metabolismo , Doenças Palpebrais/terapia , Pálpebras/patologia , Músculos/patologia , Glândula Tireoide/patologia , Adulto , Animais , Bovinos , Doenças Palpebrais/cirurgia , Pálpebras/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculos/cirurgia , Resultado do Tratamento , Adulto JovemRESUMO
The study was performed to evaluate the effectiveness and safety of porous polyethylene with embedded titanium in the repair of orbital blowout fracture. The study was designed as a prospective case series. Patients who were diagnosed with orbital blowout fracture from May 2012 to March 2013 were included in the study. A composite material of porous polyethylene and titanium mesh was used. Orbital volumes before and after surgery were measured, and the results of diplopia and ocular movement were recorded. The occurrence of diplopia was grouped and compared according to the time interval between injury and surgery. The incidence of other complications was also recorded. A total of 26 patients were involved in the study. The minimal follow-up time was 12 months. All surgeries were performed uneventfully. The orbital volume significantly decreased after the surgery, and the remission rate and the elimination rate of diplopia in 12 months were 85.7% and 47.6%, respectively. Postoperative diplopia was correlated with the time interval between injury and surgery. One patient presented with undercorrection of enophthalmos, and another patient presented with acute aggravation of diplopia and exophthalmos after surgery, which was resolved with treatment. In conclusion, porous polyethylene with embedded titanium was effective and safe in the repair of orbital blowout fracture, and studies with more subjects and longer follow-up period are recommended in future studies.
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Fraturas Orbitárias/cirurgia , Polietilenos , Telas Cirúrgicas , Adulto , Feminino , Seguimentos , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Fraturas Orbitárias/diagnóstico , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: Uveal melanoma (UM) with BAP1 inactivating mutations has a high risk of metastasis, but the mechanism behind BAP1 deficiency driving UM metastasis is unknown. METHODS: We analyzed the single-cell RNA sequencing (scRNA-Seq) data comprised primary and metastatic UM with or without BAP1 mutations (MUTs) to reveal inter- and intra-tumor heterogeneity among different groups. Then, an immune-competent mouse liver metastatic model was used to explore the role of ITGB2-ICAM1 in BAP1-associated UM metastasis. RESULTS: Cluster 1 tumor cells expressed high levels of genes linked to tumor metastasis, such as GDF15, ATF3, and CDKN1A, all of which are associated with poor prognosis. The strength of communication between terminally exhausted CD8+ T cells and GDF15hiATF3hiCDKN1Ahi tumor cells was enhanced in BAP1-mutated UM, with CellChat analysis predicting strong ITGB2-ICAM1 signaling between them. High expression of either ITGB2 or ICAM1 was a worse prognostic indicator. Using an immune-competent mouse liver metastatic model, we indicated that inhibiting either ICAM1 or ITGB2 prevented liver metastasis in the BAP1-mutated group in vivo. The inhibitors primarily inhibited hypoxia- and ECM-related pathways indicated by changes in the expression of genes such as ADAM8, CAV2, ENO1, PGK1, LOXL2, ITGA5, and VCAN. etc. CONCLUSION: This study suggested that the ITGB2-ICAM1 axis may play a crucial role for BAP1-associated UM metastasis by preserving hypoxia- and ECM- related signatures, which provide a potential strategy for preventing UM metastasis in patients with BAP1 mutation.
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Neoplasias Hepáticas , Melanoma , Mutação , Proteínas Supressoras de Tumor , Ubiquitina Tiolesterase , Neoplasias Uveais , Animais , Feminino , Humanos , Masculino , Camundongos , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Molécula 1 de Adesão Intercelular , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Mutação/genética , Transdução de Sinais/genética , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/genética , Neoplasias Uveais/patologia , Neoplasias Uveais/metabolismo , Antígenos CD18/metabolismoRESUMO
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.
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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/métodosRESUMO
Uveal melanoma (UM) is a leading intraocular malignancy with a high 5-year mortality rate, and radiotherapy is the primary approach for UM treatment. However, the elevated lactic acid, deficiency in ROS, and hypoxic tumor microenvironment have severely reduced the radiotherapy outcomes. Hence, this study devised a novel CoMnFe-layered double oxides (LDO) nanosheet with multienzyme activities for UM radiotherapy enhancement. On one hand, LDO nanozyme can catalyze hydrogen peroxide (H2O2) in the tumor microenvironment into oxygen and reactive oxygen species (ROS), significantly boosting ROS production during radiotherapy. Simultaneously, LDO efficiently scavenged lactic acid, thereby impeding the DNA and protein repair in tumor cells to synergistically enhance the effect of radiotherapy. Moreover, density functional theory (DFT) calculations decoded the transformation pathway from lactic to pyruvic acid, elucidating a previously unexplored facet of nanozyme activity. The introduction of this innovative nanomaterial paves the way for a novel, targeted, and highly effective therapeutic approach, offering new avenues for the management of UM and other cancer types.
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Ácido Láctico , Melanoma , Espécies Reativas de Oxigênio , Microambiente Tumoral , Espécies Reativas de Oxigênio/metabolismo , Humanos , Ácido Láctico/metabolismo , Melanoma/metabolismo , Melanoma/radioterapia , Microambiente Tumoral/efeitos dos fármacos , Neoplasias Uveais/metabolismo , Neoplasias Uveais/radioterapia , Neoplasias Uveais/genética , Linhagem Celular Tumoral , Nanoestruturas/uso terapêutico , Camundongos , Animais , Modelos Animais de DoençasRESUMO
Adoptive immunotherapy in the T cell landscape exhibits efficacy in cancer treatment. Over the past few decades, genetically modified T cells, particularly chimeric antigen receptor T cells, have enabled remarkable strides in the treatment of hematological malignancies. Besides, extensive exploration of multiple antigens for the treatment of solid tumors has led to clinical interest in the potential of T cells expressing the engineered T cell receptor (TCR). TCR-T cells possess the capacity to recognize intracellular antigen families and maintain the intrinsic properties of TCRs in terms of affinity to target epitopes and signal transduction. Recent research has provided critical insight into their capability and therapeutic targets for multiple refractory solid tumors, but also exposes some challenges for durable efficacy. In this review, we describe the screening and identification of available tumor antigens, and the acquisition and optimization of TCRs for TCR-T cell therapy. Furthermore, we summarize the complete flow from laboratory to clinical applications of TCR-T cells. Last, we emerge future prospects for improving therapeutic efficacy in cancer world with combination therapies or TCR-T derived products. In conclusion, this review depicts our current understanding of TCR-T cell therapy in solid neoplasms, and provides new perspectives for expanding its clinical applications and improving therapeutic efficacy.
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The application of navigation and endoscope is an area of intense interest in the surgical repair of orbital fractures. This study explored the advantages of a combined endoscopy navigation technique (ENT) for repairing large orbital floor and medial wall fractures (OFMWFs) with destruction of the inferomedial strut (IMS). Fifty-two consecutive patients with large OFMWFs with the destruction of the IMS underwent ENT-assisted surgical repair from January 2013 to February 2016. Patient demographics, causes of injury, clinical features, imaging data, and follow-up information (diplopia, ocular dysmotility, enophthalmos, infraorbital hypoesthesia, and other conditions) were collected and analyzed. Orbital volumes and implant positions were also evaluated. The median follow-up duration was 21 (range, 16-29) months. At the end of the follow-up visits, orbital reconstruction was demonstrated by orbital computed tomography. Of the 30 patients with diplopia within the 30-degree visual field of gaze, 27 (90%) reached diplopia remission. Of 40 patients, 34 (85%) achieved complete elimination of ocular dysmotility. Of 47 patients with enophthalmos of >2 mm, 43 (91%) acquired good symmetry with a mean improvement of 3.00 ± 1.00 mm. Of 33 patients, 27 (82%) recovered from infraorbital hypoesthesia. The postoperative orbital volumes of the two sides showed no significant differences (p = 0.087, paired t-test). Early surgical repair showed better outcomes of diplopia, ocular motility, and enophthalmos than late repair (p = 0.001, p = 0.007, and p = 0.000, generalized estimated equations). No patient developed surgery-related complications of visual acuity compromise, strabismus, ectropion, entropion, or lacrimal canaliculus injuries. ENT-assisted surgery appears to be safe, precise, and effective for the repair of large OFMWFs with destruction of the IMS.
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Enoftalmia , Fraturas Orbitárias , Humanos , Fraturas Orbitárias/diagnóstico por imagem , Fraturas Orbitárias/cirurgia , Fraturas Orbitárias/complicações , Enoftalmia/etiologia , Enoftalmia/cirurgia , Diplopia/etiologia , Hipestesia/complicações , Endoscopia/métodos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6-methyladenine (m6 A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in-depth understanding of the crosstalk between histone acetylation and m6 A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m6 A modifications in the regulation of tumorigenesis of ocular melanoma. METHODS: Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m6 A RNA modification level. Multi-omics assays, including RNA-sequencing, cleavage under targets and tagmentation, single-cell sequencing, methylated RNA immunoprecipitation-sequencing (meRIP-seq), and m6 A individual nucleotide resolution cross-linking and immunoprecipitation-sequencing (miCLIP-seq), were performed to reveal the mechanisms of HDACis on methyltransferase-like 14 (METTL14) and FAT tumor suppressor homolog 4 (FAT4) in ocular melanoma. Quantitative real-time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA-binding protein immunoprecipitation-qPCR, meRIP-seq, miCLIP-seq, and RNA stability assay were adopted to investigate the mechanism by which m6 A levels of FAT4 were affected. RESULTS: First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m6 A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo-histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14, thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4, a tumor suppressor, in a m6 A-YTH N6-methyladenosine RNA-binding protein 1-dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14-mediated m6 A modification in tumorigenesis. CONCLUSIONS: These results demonstrate that HDACis exert anti-cancer effects by orchestrating m6 A modification, which unveiling a "histone-RNA crosstalk" of the HDAC/METTL14/FAT4 epigenetic cascade in ocular melanoma.
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Histonas , Melanoma , Humanos , Metilação , Histonas/metabolismo , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Melanoma/genética , Carcinogênese , RNA/metabolismo , Proteínas de Ligação a RNA/genética , Metiltransferases/genética , Metiltransferases/metabolismoRESUMO
Metabolic reprogramming of amino acids has been increasingly recognized to initiate and fuel tumorigenesis and survival. Therefore, there is emerging interest in the application of amino acid metabolic strategies in antitumor therapy. Tremendous efforts have been made to develop amino acid metabolic node interventions such as amino acid antagonists and targeting amino acid transporters, key enzymes of amino acid metabolism, and common downstream pathways of amino acid metabolism. In addition to playing an essential role in sustaining tumor growth, new technologies and studies has revealed amino acid metabolic reprograming to have wide implications in the regulation of antitumor immune responses. Specifically, extensive crosstalk between amino acid metabolism and T cell immunity has been reported. Tumor cells can inhibit T cell immunity by depleting amino acids in the microenvironment through nutrient competition, and toxic metabolites of amino acids can also inhibit T cell function. In addition, amino acids can interfere with T cells by regulating glucose and lipid metabolism. This crucial crosstalk inspires the exploitation of novel strategies of immunotherapy enhancement and combination, owing to the unprecedented benefits of immunotherapy and the limited population it can benefit. Herein, we review recent findings related to the crosstalk between amino acid metabolism and T cell immunity. We also describe possible approaches to intervene in amino acid metabolic pathways by targeting various signaling nodes. Novel efforts to combine with and unleash potential immunotherapy are also discussed. Hopefully, some strategies that take the lead in the pipeline may soon be used for the common good.
Assuntos
Neoplasias , Linfócitos T , Humanos , Microambiente Tumoral , Neoplasias/patologia , Metabolismo Energético , Imunoterapia , AminoácidosRESUMO
AIMS: Adenomas of the ciliary body epithelium, including adenoma of the pigmented ciliary body epithelium (APCE) and adenoma of the non-pigmented ciliary body epithelium (ANPCE), are extremely rare, and most knowledge about them comes from sporadic case reports. The purpose of this study was to provide a comprehensive understanding of adenomas of the ciliary body epithelium and to identify the similarities and differences between APCE and ANPCE. METHODS: This study was a retrospective case series comprising data from 41 patients obtained from retrieved publications and five cases diagnosed at the Shanghai Ninth People's Hospital. The clinicopathological features, treatment and prognosis of APCE and ANPCE were compared using the non-parametric rank sum test, t-test and the χ2 test. RESULTS: The clinical and histopathological features and treatment were analogous between APCE (n=23) and ANPCE (n=23). The overall visual prognosis associated with the two tumours was good, with 63% of the patients having stable or improved vision after treatment. Enucleation was the primary cause of eventual vision loss (three in APCE vs two in ANPCE, p=0.001). Notably, iris invasion was commonly observed in patients with APCE (six in APCE vs zero in ANPCE, p=0.014), and iris invasion was associated with decreased vision eventually (p=0.003). Tumour size was irrelevant to the vision outcome (p=0.65). Metastasis or recurrence did not occur in any of the patients. CONCLUSION: In most cases, the clinicopathological features of ANPCE and APCE were similar. Iris invasion was commonly observed in patients with APCE, which was associated with poor visual prognosis.
RESUMO
Existing strategies for bone defect repair are difficult to monitor. Smart scaffold materials that can quantify the efficiency of new bone formation are important for bone regeneration and monitoring. Carbon nanotubes (CNT) have promising bioactivity and electrical conductivity. In this study, a noninvasive and intelligent monitoring scaffold was prepared for bone regeneration and monitoring by integrating carboxylated CNT into chemically cross-linked carboxymethyl chitosan hydrogel. CNT scaffold (0.5% w/v) demonstrated improved mechanical properties with good biocompatibility and electrochemical responsiveness. Cyclic voltammetry and electrochemical impedance spectroscopy of CNT scaffold responded sensitively to seed cell differentiation degree in both cellular and animal levels. Interestingly, the CNT scaffold could make up the easy deactivation shortfall of bone morphogenetic protein 2 by sustainably enhancing stem cell osteogenic differentiation and new bone tissue formation through CNT roles. This research provides new ideas for the development of noninvasive and electrochemically responsive bioactive scaffolds, marking an important step in the development of intelligent tissue engineering.