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Cellular communication mediated by messenger molecules plays an important role in the progression of cancer. Herein, pH-sensitive zeolitic imidazolate framework-8 (ZIF-8) loaded with PtCl2(OH)2(NH3)2 [i.e., Pt(IV)] bimetallic nanoplatforms were developed for prostate cancer therapy by interfering inositol-1, 4, 5-trisphosphate (IP3)-mediated cellular communication. As an important messenger in cells, the function of IP3 was found to be efficiently interfered with by the Pt(IV)-binding inositol unit. This finding effect of Pt(IV) is totally different from its traditional function as a prodrug of cis-platinum for chemotherapy. The decreased IP3 signal further downregulated the cytoplasmic Ca2+ concentration and downstream signal transduction to inhibit proliferation and invasion of tumor cells. Meanwhile, Zn2+ released from ZIF-8 under an acidic tumor microenvironment decreased adenosine triphosphate biosynthesis, which could further limit the cellular communication. Such a proposed strategy of interfering cellular communication has demonstrated its feasibility in this study, which may provide new perspectives for cancer therapy.
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Antineoplásicos , Neoplasias de la Próstata , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Masculino , Antineoplásicos/farmacología , Antineoplásicos/química , Comunicación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Inositol 1,4,5-Trifosfato/metabolismo , Inositol 1,4,5-Trifosfato/química , Concentración de Iones de Hidrógeno , Imidazoles/química , Imidazoles/farmacología , Zinc/química , Zinc/farmacologíaRESUMEN
BACKGROUND: Cancer-associated fibroblasts (CAFs) are heterogeneous and can influence the progression of prostate cancer in multiple ways; however, their capacity to present and process antigens in PRAD has not been investigated. In this study, antigen presentation and process-related CAFs (APPCAFs) were identified using bioinformatics, and the clinical implications of APPCAF-related signatures in PRAD were investigated. METHODS: SMART technology was used to sequence the transcriptome of primary CAFs isolated from patients undergoing different treatments. Differential expression gene (DEG) screening was conducted. A CD4 + T-cell early activation assay was used to assess the activation degree of CD4 + T cells. The datasets of PRAD were obtained from The Cancer Genome Atlas (TCGA) database and NCBI Gene Expression Omnibus (GEO), and the list of 431 antigen presentation and process-related genes was obtained from the InnateDB database. Subsequently, APP-related CAFs were identified by nonnegative matrix factorization (NMF) based on a single-cell seq (scRNA) matrix. GSVA functional enrichment analyses were performed to depict the biological functions. A risk signature based on APPCAF-related genes (APPCAFRS) was developed by least absolute shrinkage and selection operator (LASSO) regression analysis, and the independence of the risk score as a prognostic factor was evaluated by univariate and multivariate Cox regression analyses. Furthermore, a biochemical recurrence-free survival (BCRFS)-related nomogram was established, and immune-related characteristics were assessed using the ssGSEA function. The immune treatment response in PRAD was further analyzed by the Tumor Immune Dysfunction and Exclusion (TIDE) tool. The expression levels of hub genes in APPCAFRS were verified in cell models. RESULTS: There were 134 upregulated and 147 downregulated genes, totaling 281 differentially expressed genes among the primary CAFs. The functions and pathways of 147 downregulated DEGs were significantly enriched in antigen processing and presentation processes, MHC class II protein complex and transport vesicle, MHC class II protein complex binding, and intestinal immune network for IgA production. Androgen withdrawal diminished the activation effect of CAFs on T cells. NMF clustering of CAFs was performed by APPRGs, and pseudotime analysis yielded the antigen presentation and process-related CAF subtype CTSK + MRC2 + CAF-C1. CTSK + MRC2 + CAF-C1 cells exhibited ligandâreceptor connections with epithelial cells and T cells. Additionally, we found a strong association between CTSK + MRC2 + CAF-C1 cells and inflammatory CAFs. Through differential gene expression analysis of the CTSK + MRC2 + CAF-C1 and NoneAPP-CAF-C2 subgroups, 55 significant DEGs were identified, namely, APPCAFRGs. Based on the expression profiles of APPCAFRGs, we divided the TCGA-PRAD cohort into two clusters using NMF consistent cluster analysis, with the genetic coefficient serving as the evaluation index. Four APPCAFRGs, THBS2, DPT, COL5A1, and MARCKS, were used to develop a prognostic signature capable of predicting BCR occurrence in PRAD patients. Subsequently, a nomogram with stability and accuracy in predicting BCR was constructed based on Gleason grade (p = n.s.), PSA (p < 0.001), T stage (p < 0.05), and risk score (p < 0.01). The analysis of immune infiltration showed a positive correlation between the abundance of resting memory CD4 + T cells, M1 macrophages, resting dendritic cells, and the risk score. In addition, the mRNA expression levels of THBS2, DPT, COL5A1, and MARCKS in the cell models were consistent with the results of the bioinformatics analysis. CONCLUSIONS: APPCAFRS based on four potential APPCAFRGs was developed, and their interaction with the immune microenvironment may play a crucial role in the progression to castration resistance of PRAD. This novel approach provides valuable insights into the pathogenesis of PRAD and offers unexplored targets for future research.
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Fibroblastos Asociados al Cáncer , Neoplasias de la Próstata , Masculino , Humanos , Presentación de Antígeno/genética , Análisis de Secuencia de ARN , Algoritmos , Pronóstico , Microambiente TumoralRESUMEN
OBJECTIVE: Evaluation of clinical efficacy and safety of tobramycin/dexamethasone eye ointment in treating persistent corneal epithelial dysfunction (PED) after cataract surgery. METHODS: 26 cases diagnosed as PED after cataract surgery accept the tobramycin/dexamethasone ophthalmic ointment and intense pulse light treatment in the Xiamen University of Xiamen eye center between September 2016 and April 2022 were retrospectively analyzed, mainly including clinical manifestations, characteristics of morphological changes imaged by in vivo confocal microscopy, meibomian glands infrared photography, lipid layer thickness (LLT), management and therapeutic effects. RESULTS: There were 26 eyes, include 8(35%) males and 15(65%) females with an average age of 69.6 ± 5.2 years(50 to 78 years). The mean hospitalization time was (18.4 ± 7.5) days after cataract surgery. Twenty patients had meibomian gland dysfunction. Infrared photography revealed varying loss in the meibomian glands, with a mean score of 3.8 ± 1.2 for gland loss. The mean LLT was 61.6 ± 8.4 nm. After treatment, 20 patients were cured, and 3 received amniotic membrane transplantation. After treatment, the uncorrected visual acuity (UCVA) and best-corrected vision activity (BCVA) improved (P < 0.001), and there was no significant difference in intraocular pressure (IOP) before and after treatment (P > 0.05). CONCLUSIONS: The early manifestation of PED after surgery is punctate staining of the corneal epithelium. Tobramycin and dexamethasone eye ointment bandages have a good repair effect. The meibomian gland massage combined with intense pulse light treatment can effectively shorten the course of the disease.
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Dexametasona , Epitelio Corneal , Glucocorticoides , Tobramicina , Agudeza Visual , Humanos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Estudios Retrospectivos , Epitelio Corneal/patología , Agudeza Visual/fisiología , Tobramicina/uso terapéutico , Glucocorticoides/uso terapéutico , Extracción de Catarata/efectos adversos , Enfermedades de la Córnea/etiología , Enfermedades de la Córnea/terapia , Enfermedades de la Córnea/diagnóstico , Enfermedades de la Córnea/fisiopatología , Antibacterianos/uso terapéutico , Microscopía Confocal , Complicaciones Posoperatorias , PomadasRESUMEN
Early exposure to dibutyl phthalate (DBP) can cause hypospadias in newborn foetuses. However, the underlying molecular mechanism is not well defined. Aberrant angiogenesis is associated with various dysplasias including urogenital deficits. In vivo and in vitro angiogenesis assays showed reduced angiogenesis in the hypospadias group and DBP exposed group. RNA-sequencing analysis of DBP-treated HUVECs revealed decreased expression of transforming growth factor beta 1-induced transcript 1 (TGFB1I1) and a significantly enriched angiogenesis-associated pathway. Further experiments revealed that decreased TGFB1I1 expression was associated with disrupted tube formation and migration, which resulted in decreased angiogenesis. Functional assays revealed that the overexpression of TGFB1I1 promoted tube formation and migration of HUVECs in the DBP-treated group. Moreover, we showed that the transcription factor AR was regulated by TGFB1I1 through inhibiting its translocation from the cytoplasm to the nucleus. Together, our results identified TGFB1I1 as a component of aberrant angiogenesis in hypospadias rats and its interaction with AR might be a potential target for hypospadias development.
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Dibutil Ftalato , Hipospadias , Masculino , Humanos , Femenino , Ratas , Animales , Dibutil Ftalato/toxicidad , Exposición Materna , Hipospadias/inducido químicamente , Hipospadias/metabolismo , Plastificantes/toxicidad , Angiogénesis , Ratas Sprague-DawleyRESUMEN
Di-n-butyl phthalate (DBP) is a plasticizer commonly used in industrial production and is present in our daily life. It has been confirmed that DBP causes genitourinary malformations, especially hypospadias. However, the research of hypospadias mainly focusses on the genital tubercle in previous studies. In this study, we found DBP could affect the exocrine function of the vascular endothelium which disturb the development of genital nodules and induced hypospadias. We used cytokine array to find that vascular endothelium-derived NAP-2 may be a major abnormal secreted cytokine with biological functions. The transcriptomic sequencing analysis showed that abnormal activation of the RhoA/ROCK signaling pathway was the main reason for increased NAP-2 secretion. The expression levels of epithelial-mesenchymal transition (EMT) biomarkers and NAP-2 in hypospadias animal models were detected with Immunohistochemistry, Western blot, Immunofluorescence, and ELISA methods. The expression levels of NAP-2, RhoA/ROCK signaling pathway related proteins, reactive oxygen species (ROS) levels in HUVEC cells, EMT biomarkers and migration capacity of urothelial cells cocultured with HUVEC were measured with ELISA, flow cytometry, Western blot or Transwell assay for further cell experiments. The results showed that DBP leaded to NAP-2 oversecretion from vascular endothelium mainly rely on the activation of RhoA/ROCK signaling pathway and ROS accumulation. The RhoA/ROCK inhibitor fasudil could partially decrease ROS production, and both fasudil and N-acetyl-L-cysteine (NAC) could decrease NAP-2 secretion. Meanwhile, the oversecretion of NAP-2 from HUVEC in coculture system promoted EMT and migration capacity of urothelial cells, and TGF-ß inhibitor LY219761 could block the aberrant activation of EMT process. Therefore, it could be concluded that DBP increase NAP-2 secretion from vascular endothelium by RhoA/ROCK/ROS pathway, and further promote EMT in urothelial cells through TGF-ß pathway. This study provided a novel direction for studying the occurrence of hypospadias and may provide a hypospadias predictive marker in the future.
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Dibutil Ftalato , Hipospadias , Masculino , Humanos , Femenino , Ratas , Animales , Hipospadias/metabolismo , Ratas Sprague-Dawley , Transición Epitelial-Mesenquimal , Especies Reactivas de Oxígeno , Endotelio Vascular/metabolismo , Exposición Materna , Factor de Crecimiento Transformador beta , CitocinasRESUMEN
BACKGROUND: Bladder cancer (BC) is one of the most common malignancies of the genitourinary system. Animal models offer an important tool to explore tumour initiation, progression, and therapeutic mechanisms. Our aim is to construct an optimized orthotopic BC model which is predictable, reproducible, and convenient. METHODS: The optimized orthotopic BC model was constructed in male C57BL/6 mice utilizing microsyringes to inoculate them with a murine BC cell line (MB49). Anesthetised mice were inoculated with an MB49 cell suspension (10 µL) at approximately 5 × 106/mL. The whole process of modelling was observed and monitored every 3 days for 21 days utilizing HE staining and transabdominal ultrasonography (TUS). RESULTS: In this study, the model showed excellent success rates for tumour formation (96.67%) and metastatic rate (89.66%). Compared to the control group (sham operation), mice in the modelling group had serous cachexia, visible haematuresis and weight loss (all P < 0.05). The lungs, liver, ureter and kidneys were found to have tumour metastasis. Moreover, the average survival time (19.73 ± 1.69 d) of modelling mice was significantly shorter than that of the control mice (P < 0.05), which remained alive. CONCLUSION: Our study established a method using microsyringes to inject murine BC cells into the bladder wall, creating a stable transplantable BC model in mice.
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Neoplasias de la Vejiga Urinaria , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BL , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
In response to fighting COVID-19 pandemic, researchers in machine learning and artificial intelligence have constructed some medical knowledge graphs (KG) based on existing COVID-19 datasets, however, these KGs contain a considerable amount of semantic relations which are incomplete or missing. In this paper, we focus on the task of knowledge graph embedding (KGE), which serves an important solution to infer the missing relations. In the past, there have been a collection of knowledge graph embedding models with different scoring functions to learn entity and relation embeddings published. However, these models share the same problems of rarely taking important features of KG like attribute features, other than relation triples, into account, while dealing with the heterogeneous, complex and incomplete COVID-19 medical data. To address the above issue, we propose a graph feature collection network (GFCNet) for COVID-19 KGE task, which considers both neighbor and attribute features in KGs. The extensive experiments conducted on the COVID-19 drug KG dataset show promising results and prove the effectiveness and efficiency of our proposed model. In addition, we also explain the future directions of deepening the study on COVID-19 KGE task.
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PURPOSE: The aim of this study is to compare the long-term effects of transepithelial corneal crosslinking with two continuous cycles of iontophoresis (EI-CXL) and conventional corneal crosslinking (C-CXL) in adults with progressive keratoconus. METHODS: A retrospective analysis was conducted in adults who underwent C-CXL or EI-CXL between 2013 and 2015. Visual acuity, corneal tomography, anterior segment optical coherence tomography, in vivo corneal confocal microscopy (IVCM), and endothelial cell count (ECC) were performed preoperatively and 5 years postoperatively. RESULTS: Sixty-eight patients with a mean age of (24.3 ± 3.8) years were included, 34 for each group. After CXL, UCVA or BCVA remained stable, while the spherical diopter, cylinder diopter, spherical equivalent, and Kmax significantly decreased at 1, 2, and 3 years in both groups than baseline (P < 0.05). No significant differences were found in any refractive or tomographic parameters as well as the minimal corneal thickness between groups during follow-up. At 5 years, Kmax was slightly higher in EI-CXL group (58.16 ± 6.28) than that of C-CXL group (57.46 ± 4.98). At 3 and 5 years, the minimal corneal thickness in C-CXL group was still significantly lower than baseline (P < 0.05). IVCM demonstrated the demarcation zone at a mean depth of (302.0 ± 41.7) µm after C-CXL, and at (251.2 ± 28.1) µm after EI-CXL (P < 0.001). Keratocyte repopulation was detectable at all follow-up timepoint in both groups. Postoperative complications including progression were recorded in 6 patients (11.7%) after C-CXL and 3 patients (8.8%) after EI-CXL. ECC remained stable in both groups. CONCLUSION: EI-CXL showed approximate efficacy with C-CXL in stabilizing progressive keratoconus in adults. EI-CXL has the potential to be a preferable transepithelial protocol.
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Queratocono , Fotoquimioterapia , Adulto , Preescolar , Colágeno/uso terapéutico , Sustancia Propia , Topografía de la Córnea , Reactivos de Enlaces Cruzados/uso terapéutico , Humanos , Iontoforesis , Queratocono/diagnóstico , Queratocono/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Estudios Prospectivos , Estudios Retrospectivos , Rayos UltravioletaRESUMEN
With the development of blockchain technologies, many Ponzi schemes disguise themselves under the veil of smart contracts. The Ponzi scheme contracts cause serious financial losses, which has a bad effect on the blockchain. Existing Ponzi scheme contract detection studies have mainly focused on extracting hand-crafted features and training a machine learning classifier to detect Ponzi scheme contracts. However, the hand-crafted features cannot capture the structural and semantic feature of the source code. Therefore, in this study, we propose a Ponzi scheme contract detection method called MTCformer (Multi-channel Text Convolutional Neural Networks and Transofrmer). In order to reserve the structural information of the source code, the MTCformer first converts the Abstract Syntax Tree (AST) of the smart contract code to the specially formatted code token sequence via the Structure-Based Traversal (SBT) method. Then, the MTCformer uses multi-channel TextCNN (Text Convolutional Neural Networks) to learn local structural and semantic features from the code token sequence. Next, the MTCformer employs the Transformer to capture the long-range dependencies of code tokens. Finally, a fully connected neural network with a cost-sensitive loss function in the MTCformer is used for classification. The experimental results show that the MTCformer is superior to the state-of-the-art methods and its variants in Ponzi scheme contract detection.
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Algoritmos , Redes Neurales de la Computación , Aprendizaje Automático , SemánticaRESUMEN
The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.
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Diabetes Mellitus Experimental/inducido químicamente , Diabetes Gestacional/inducido químicamente , Dibutil Ftalato/toxicidad , Disruptores Endocrinos/toxicidad , Proteína Forkhead Box M1/metabolismo , Exposición Materna/efectos adversos , Factor de Transcripción STAT1/metabolismo , Animales , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Femenino , Proteína Forkhead Box M1/genética , Expresión Génica/efectos de los fármacos , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Fosforilación , Embarazo , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley , Factor de Transcripción STAT1/genética , Transducción de SeñalRESUMEN
The treatment and management of ocular surface diseases have shifted towards a co-treatment approach focusing on overall ocular surface homeostasis. When treating issues related to the eye, it is essential to not only focus on the damaged or disabled areas but also consider the larger picture. Meibomian gland dysfunction (MGD), Demodex infection, and blepharitis all interact at the eyelid site and can cause damage to the ocular surface to varying degrees. Palpebral lesions disrupt the balance of ocular surface homeostasis, leading to dry eye and keratitis. Traditional treatments, such as manual physical hot compress massage, have limited effectiveness due to the structure of the eyelid. However, intense pulsed light (IPL) technology uses penetrating light energy to generate heat energy, which can eliminate inflammation of capillaries or kill Demodex. Additionally, the LipiFlow thermal effect and physical compression provide a more vital and longer-lasting therapeutic effect on MGD by excluding other primary causes of ocular surface inflammation. Therefore, personalized treatment techniques based on photothermal effects may be effective. In the future, IPL and LipiFlow may potentially dismiss immune-inflammation factors causing ocular surface disease or block the delivery of systemic immune-related diseases.
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BACKGROUND: Studies have demonstrated that Sertoli cells are the direct target of Dibutyl phthalate (DBP). However, the role of neurotransmitter receptors is not elucidated. METHODS: Based on our previous studies, maternal Sprague-Dawley (SD) rats in Gestation Day (GD) 14-18 and TM4 cells exposure to 750 mg/kg/day and 100 µM DBP were regarded as treated groups. Firstly, qRT-PCR array was used to determine the different expression of neurotransmitter receptors. We examined the OX1R expression on Rats in Control and DBP groups by immunohistochemistry. Real-time PCR and Western Blot were used to detect the protein and mRNA expression levels of OX1R in vivo and in vitro. The potential downstream signaling pathways were explored by analyzing the GSE99690 cohort. In addition, we extracted Primary Sertoli Cells (PSCs) from the testis of control group. The apoptosis-related proteins, AKT signaling pathway-related proteins and mRNA expressions were detected by Western Blot and Real-time PCR in PSCs. The validity of PSCs was measured by CCK-8 assay and flow cytometric analysis was used to demonstrate the apoptotic rates of PSCs after DBP exposure. RESULTS: The Orexin receptor 1 (OX1R) was screened out by qRT-PCR array. Our results showed that DBP could significantly suppress the OX1R expression of Sertoli cells in vivo and in vitro. Functional analysis showed the AKT signaling pathway was mediated by OX1R. The highly expressed apoptosis level and impaired cell activity were observed in PSCs, which can be reversed by Orexin A. Meanwhile, the p-AKT signaling pathway were hindered after DBP exposure while rescued in DBP + Orexin-A group. CONCLUSIONS: DBP can induce Sertoli cell apoptosis through its toxicological effect by suppressing OX1R and p-AKT expression, which provide a novel insight on the role of neurotransmitter receptors.
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BACKGROUND: The aim of this study is to build a prognostic model for cutaneous melanoma (CM) using fatty acid-related genes and evaluate its capacity for predicting prognosis, identifying the tumor immune microenvironment (TIME) composition, and assessing drug sensitivity. METHODS: Through the analysis of transcriptional data from TCGA-SKCM and GTEx datasets, we screened for differentially expressed fatty acids-related genes (DEFAGs). Additionally, we employed clinical data from TCGA-SKCM and GSE65904 to identify genes associated with prognosis. Subsequently, utilizing all the identified prognosis-related fatty acid genes, we performed unsupervised clustering analysis using the ConsensusClusterPlus R package. We further validated the significant differences between subtypes through survival analysis and pathway analysis. To predict prognosis, we developed a LASSO-Cox prognostic signature. This signature's predictive ability was rigorously examined through multivariant Cox regression, survival analysis, and ROC curve analysis. Following this, we constructed a nomogram based on the aforementioned signature and evaluated its accuracy and clinical utility using calibration curves, cumulative hazard rates, and decision curve analysis. Using this signature, we stratified all cases into high- and low-risk groups and compared the differences in immune characteristics and drug treatment responsiveness between these two subgroups. Additionally, in this study, we provided preliminary confirmation of the pivotal role of CD1D in the TIME of CM. We analyzed its expression across various immune cell types and its correlation with intercellular communication using single-cell data from the GSE139249 dataset. RESULTS: In this study, a total of 84 DEFAGs were identified, among which 18 were associated with prognosis. Utilizing these 18 prognosis-related genes, all cases were categorized into three subtypes. Significant differences were observed between subtypes in terms of survival outcomes, the expression of the 18 DEFAGs, immune cell proportions, and enriched pathways. A LASSO-Cox regression analysis was performed on these 18 genes, leading to the development of a signature comprising 6 DEFAGs. Risk scores were calculated for all cases, dividing them into high-risk and low-risk groups. High-risk patients exhibited significantly poorer prognosis than low-risk patients, both in the training group (p < 0.001) and the test group (p = 0.002). Multivariate Cox regression analysis indicated that this signature could independently predict outcomes [HR = 2.03 (1.69-2.45), p < 0.001]. The area under the ROC curve for the training and test groups was 0.715 and 0.661, respectively. Combining risk scores with clinical factors including metastatic status and patient age, a nomogram was constructed, which demonstrated significant predictive power for 3 and 5 years patient outcomes. Furthermore, the high and low-risk subgroups displayed differences in the composition of various immune cells, including M1 macrophages, M0 macrophages, and CD8+ T cells. The low-risk subgroup exhibited higher StromalScore, ImmuneScore, and ESTIMATEScore (p < 0.001) and demonstrated better responsiveness to immune therapy for patients with PD1-positive and CTLA4-negative or positive expressions (p < 0.001). The signature gene CD1D was found to be mainly expressed in monocytes/macrophages and dendritic cells within the TIME. Through intercellular communication analysis, it was observed that cases with high CD1D expression exhibited significantly enhanced signal transductions from other immune cells to monocytes/macrophages, particularly the (HLA-A/B/C/E/F)-CD8A signaling from natural killer (NK) cells to monocytes/macrophages (p < 0.01). CONCLUSIONS: The prognostic signature constructed in this study, based on six fatty acid-related genes, exhibits strong capabilities in predicting patient outcomes, identifying the TIME, and assessing drug sensitivity. This signature can aid in patient risk stratification and provide guidance for clinical treatment strategies. Additionally, our research highlights the crucial role of CD1D in the CM's TIME, laying a theoretical foundation for future related studies.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/genética , Neoplasias Cutáneas/genética , Linfocitos T CD8-positivos , Nomogramas , Ácidos Grasos , Pronóstico , Microambiente Tumoral/genéticaRESUMEN
Purpose: To compare the refractive efficacy and morphological changes in the cornea following a novel biphasic higher fluence transepithelial corneal crosslinking (BI-TE-CXL) and transepithelial corneal crosslinking (TE-CXL) in adults keratoconus.Methods: Patients with progressive keratoconus who required corneal crosslinking were assigned to the BI-TE-CXL group (32 eyes, phase 1: 7.2 J/cm2 for 5 min and 20 s of pulsed-light exposure, KXL, Glaukos-Avedro; phase 2: 3.6 J/cm2 for 6 min and 40 s of continuous light exposure at the front curvature apex with a 6 mm diameter light spot, UVX-2000, IROC) or the TE-CXL group (32 eyes, uniform 7.2 J/cm2 for 5 min and 20 s of pulsed-light exposure, KXL, Glaukos-Avedro). Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), corneal fluorescein staining (CFS), corneal topography, anterior segment optical coherence tomography (AS-OCT), and in vivo corneal confocal microscopy (IVCM) were performed 3, 6, 12 and 24 months after surgery.Results: The CFS scores in the BI-TE-CXL group were significantly higher than those in the TE-CXL group on the first two days after surgery (p < 0.001). The Kmax (at 12 and 24 months) and CDVA (logMAR) were significantly lower in the BI-TE-CXL group than those in the TE-CXL group (p < 0.05). The corneal demarcation line under AS-OCT was visible in 81.3% of patients in the BI-TE-CXL group and 15.6% in the TE-CXL group. The depth of the demarcation line under IVCM was significantly deeper in the BI-TE-CXL group (248.3 ± 25.0 µm) than that of the TE-CXL group (136.5 ± 15.6 µm) in the central cornea (p < 0.001). The cross-linked collagen structures in the central cornea were still present after 12 months in the BI-TE-CXL group. No significant difference in sub-basal nerve density between the two groups (p > 0.05).Conclusions: Following BI-TE-CXL, CDVA was significantly improved, accompanied by deeper demarcation line depth and persistent crosslinked structures in the central corneal stroma.
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Queratocono , Adulto , Humanos , Queratocono/diagnóstico , Queratocono/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Riboflavina/uso terapéutico , Rayos Ultravioleta , Reactivos de Enlaces Cruzados/uso terapéutico , Córnea , Sustancia Propia , Topografía de la Córnea , Microscopía ConfocalRESUMEN
OBJECTIVE: To estimate the pterygium ocular surface state, and compare with healthy eyes and dry eyes. To investigate the inflammation due to pterygia growth by tear Lymphotoxin-alpha (LT α) test. DESIGN: Prospective, single-center study. PARTICIPANTS: 400 patients, divided into 100 pterygium group, 100 mild dry eye group, 100 moderate dry eye group, and 100 age-and sex-matched normal controls. METHODS: The non-invasive break-up time (NIBUT), tear meniscus height (TMH) test, corneal fluorescein staining (CFS), meibomian gland loss score (MGs), and lipid layer thickness (LLT) were evaluated in all patients. Pterygium status and ocular status in the pterygium group were collected. The tear LT α test was conducted in the pterygium patients group. RESULT: Pterygium can affect the ocular surface, leading to decreased tear film stability. The TMH, NIBUT, CFS, MGs, and lipid layer thickness can provide insights into this phenomenon. The presence of pterygium can change the structure and condition of the ocular surface. Tear LT α testing shows an abnormal decrease in LT α levels in pterygium patients. This indicates an immune-inflammation microenvironment that causes tissue repair deficiency. CONCLUSION: The dry eye triggered by the growth of pterygium may originate from the tear film instability due to pterygia. As an inflammatory index, LT α in the development of pterygium and the aggravation of dry eye patients can indicate that the ocular surface is in different inflammatory states. Future tear testing in LT α may be a potential indicator to assess the inflammatory status of the dry eye.
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BACKGROUND: Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. METHODS: In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. CONCLUSION: Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Inhibidores de Puntos de Control Inmunológico , Piridinas , Neoplasias del Cuello Uterino , Humanos , Femenino , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Persona de Mediana Edad , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/mortalidad , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Retratamiento , Supervivencia sin ProgresiónRESUMEN
To explore the correlation between tear LT-a, pterygium status, and dry eye indicators. We established a diagnostic model to evaluate active pterygium. A retrospective study was conducted between June 2021 and June 2023 on 172 patients, comprising 108 men and 64 women. The study analyzed LT-a and various ocular parameters in all participants. The data was collected using Excel software and analyzed using SPSS 25.0 statistical software and Medcalc. We made a nomogram diagnostic model to different diagnosed the state of pterygium. This study found that pterygium has progressive eye surface damage during the active state. There was no significant difference in dry eye indicators between the two groups. However, the concentration of LT-a in the active group was significantly lower than that in the inactive group (P < 0.001). We observed that increased pterygium grade corresponded to a worse ocular surface condition. In addition, LT-a was significantly positively correlated with disease duration, but negatively correlated with age, pterygium size, active pterygium state, and LLT value. The optimal intercept value for evaluating active pterygium in Lt-a was ≤ 0.49 dg/ml. We screened three variables for evaluating active pterygium through Single and Multiple regression analysis: LT-a grading, pterygium size, and congestion score. Finally, we made a reliable diagnostic nomogram model. Pterygium development triggers immune inflammation. Our model based on LT-a identifies active pterygium for personalized treatment options and new research directions.
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Conjuntiva/anomalías , Síndromes de Ojo Seco , Pterigion , Masculino , Humanos , Femenino , Pterigion/diagnóstico , Linfotoxina-alfa , Estudios RetrospectivosRESUMEN
PURPOSE: To clarify the ocular surface features of patients with recent history of epidemic keratoconjunctivitis (EKC) and the relation between corneal dendritic cells (DCs) and ocular discomfort. METHODS: Normal controls (NC) and dry eye (DE) patients without EKC were recruited. Patients with recent EKC history (onset >4 weeks, but <20 weeks) were recruited as EKC + DE group (with dry eye) or EKC-DE group (without dry eye). Ocular surface disease index (OSDI) questionnaire, tear film parameters including lipid layer thickness, first tear break-up time (fBUT), average tear break-up time (aBUT), tear meniscus height and Schirmer I test, meibomian gland parameters, and in vivo corneal confocal microscopy were evaluated. RESULTS: 50 subjects in the NC group, 83 patients in the DE group, 76 patients in the EKC + DE group, and 38 patients in the EKC-DE group were included. Compared with the NC, DE, and EKC-DE groups, the EKC + DE group represented higher OSDI, lid margin, and meibum score (p < 0.05). In the EKC + DE group, the tear volume (10.5 ± 3.7 mm) was significantly higher than in the DE group (8.1 ± 2.8 mm, p < 0.001). The DC density in the EKC + DE group (29.98 ± 15.38 cells/image) was significantly higher than in NC, DE, and EKC-DE groups (4.68 ± 4.05 cells/image) (p < 0.001). The DC density was positively correlated with OSDI, lid margin, and meibum score (all p < 0.01) while inversely correlated with fBUT, aBUT (all p < 0.001) in the EKC + DE group. CONCLUSIONS: Corneal DC density significantly correlates to ocular discomfort and tear film instability in patients with recent EKC history who suffer from DE without aqueous tear deficiency.
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Síndromes de Ojo Seco , Queratoconjuntivitis , Humanos , Lágrimas/metabolismo , Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/metabolismo , Córnea/metabolismo , Queratoconjuntivitis/diagnóstico , Glándulas Tarsales/metabolismo , Células DendríticasRESUMEN
Background: The residual stone fragment is a tremendous issue after ureteroscopic lithotripsy and requires urologists to evaluate the condition of patients comprehensively. Our study aimed to construct a nomogram to make a personalized prediction of postoperative residual stone rate (RSR). Methods: We implemented a retrospective cohort study in the Department of Urology, Shanghai General Hospital. A total of 277 patients undergoing ureteroscopy (URS) were enrolled in our study. Among them, 186 patients were included in the training group and the remaining 91 patients comprised the testing group. We utilized stepwise forward algorithm and logistic regression analysis to build predictive models and selected the best model based on Akaike's information criterion (AIC). The model was assessed by receiver operating characteristic (ROC) curves and the Hosmer-Lemeshow (HL) test. We also conducted decision curve analysis (DCA) to demonstrate the net benefit of the model. The independent testing group was used to validate the practicability of the nomogram. Results: The severity of hydronephrosis, stone location, the transverse diameter of stone, hypertension, and white blood cell (WBC) were found to be significant predictive variables for RSR after URS. The area under the curve (AUC) of the training group was 0.7203 and that of the testing group was 0.7280. Besides, the nomogram also presented great calibration and accepted net benefit in a wide range of probabilities. Conclusions: Our study achieved a predictive nomogram with excellent application value for urologists to assess RSR and make personalized treatment decisions.