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BACKGROUND: Patients with spinal cord injury have a relatively high risk for bladder cancer and often complicated with bladder cancer in advanced stages, and the degree of aggressiveness of malignancy is high. Most of the literature is based on disease clinical features while, our study reviews the clinical characteristics and molecular mechanisms of spinal cord injury patients with bladder cancer, so that it might help clinicians better recognize and manage these patients. METHOD: We searched PubMed, Web of Science and Embase, using retrieval type like ("Neurogenic Lower Urinary Tract Dysfunction" OR "Spinal cord injury" OR "Spinal Cord Trauma") AND ("bladder cancer" OR "bladder neoplasm" OR "bladder carcinoma" OR "Urinary Bladder Neoplasms" OR "Bladder Tumor"). In Web of Science, the retrieval type was searched as "Topic", and in PubMed and Embase, as "All Field". The methodological quality of eligible studies and their risk of bias were assessed using the Newcastle-Ottawa scale. This article is registered in PROSPERO with the CBD number: CRD42024508514. RESULT: In WOS, we searched 219 related papers, in PubMed, 122 and in Embase, 363. Thus, a total of 254 articles were included after passing the screening, within a time range between 1960 and 2023. A comprehensive analysis of the data showed that the mortality and incidence rates of bladder cancer in spinal cord injury patients were higher than that of the general population, and the most frequent pathological type was squamous cell carcinoma. In parallel to long-term urinary tract infection and indwelling catheterization, the role of molecules such as NO, MiR 1949 and Rb 1. was found to be crucial pathogenetically. CONCLUSION: This review highlights the risk of bladder cancer in SCI patients, comprehensively addressing the clinical characteristics and related molecular mechanisms. However, given that there are few studies on the molecular mechanisms of bladder cancer in spinal cord injury, further research is needed to expand the understanding of the disease.
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Traumatismos de la Médula Espinal , Neoplasias de la Vejiga Urinaria , Traumatismos de la Médula Espinal/complicaciones , Humanos , Neoplasias de la Vejiga Urinaria/complicacionesRESUMEN
The binding of programmed death-1 (PD-1) on the surface of T cells and PD-1 ligand 1 (PD-L1) on tumor cells can prevent the immune-killing effect of T cells on tumor cells and promote the immune escape of tumor cells. Therefore, immune checkpoint blockade targeting PD-1/PD-L1 is a reliable tumor therapy with remarkable efficacy. However, the main challenges of this therapy are low response rate and acquired resistance, so that the outcomes of this therapy are usually unsatisfactory. This review begins with the description of biological structure of the PD-1/PD-L1 immune checkpoint and its role in a variety of cells. Subsequently, the therapeutic effects of immune checkpoint blockers (PD-1 / PD-L1 inhibitors) in various tumors were introduced and analyzed, and the reasons affecting the function of PD-1/PD-L1 were systematically analyzed. Then, we focused on analyzing, sorting out and introducing the possible underlying mechanisms of primary and acquired resistance to PD-1/PD-L1 blockade including abnormal expression of PD-1/PD-L1 and some factors, immune-related pathways, tumor immune microenvironment, and T cell dysfunction and others. Finally, promising therapeutic strategies to sensitize the resistant patients with PD-1/PD-L1 blockade treatment were described. This review is aimed at providing guidance for the treatment of various tumors, and highlighting the drug resistance mechanisms to offer directions for future tumor treatment and improvement of patient prognosis.
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Resistencia a Antineoplásicos , Neoplasias , Receptor de Muerte Celular Programada 1 , Humanos , Antígeno B7-H1 , Resistencia a Medicamentos , Inmunoterapia , Microambiente TumoralRESUMEN
OBJECTIVE: To compare the safety of transurethral plasma resection of the prostate (TuPkRP) in the treatment of advanced PCa (APC)-related acute urinary retention (AUR) with that in the treatment of BPH-related AUR and investigate the oncologic characteristics of the PCa patient after TuPkRP. METHODS: In this retrospective study, we first compared the baseline data between the patients with APC-related AUR (group A, n = 32) and those with BPH-related AUR (group B, n = 45) as well as their surgical parameters, such as the operation time, pre- and post-operative hemoglobin levels, IPSS at 3 months after TuPkRP and length of postoperative hospital stay. Then, we observed possible TuPkRP-induced tumor progression by comparing the oncologic parameters, such as the PSA level and ECT-manifested bone metastasis, between the APC-AUR patients treated by androgen-deprivation therapy (ADT) + TuPkRP and those treated by ADT only (group C, n = 24). RESULTS: There were no statistically significant differences in the baseline data between the APC-AUR and BPH-AUR patients (P > 0.05). The operation time and postoperative hospital stay were significantly longer in the APC-AUR than in the BPH-AUR group (P < 0.05), but the decreases in the hemoglobin level and IPSS at 3 months after operation showed no significant differences between the two groups of patients (P > 0.05). Besides, no statistically significant differences were observed in the oncologic parameters between the APC-AUR patients treated by ADT + TuPkRP and those by ADT only (P > 0.05). CONCLUSION: The safety of TuPkRP was not significantly lower and the rates of postoperative complications and adverse events were not significantly higher in the patients with APC-related AUR than in those with BPH-related AUR. And this surgical strategy did not significantly improve the progression of APC.
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Hiperplasia Prostática , Neoplasias de la Próstata , Resección Transuretral de la Próstata , Retención Urinaria , Masculino , Humanos , Próstata/patología , Neoplasias de la Próstata/complicaciones , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/cirugía , Hiperplasia Prostática/patología , Estudios Retrospectivos , Retención Urinaria/etiología , Antagonistas de Andrógenos , Resección Transuretral de la Próstata/efectos adversos , Hemoglobinas , Resultado del TratamientoRESUMEN
PURPOSE: The overall response of cisplatin-based chemotherapy in bladder urothelial carcinoma (BUC) remains unsatisfactory due to the complex pathological subtypes, genomic difference, and drug resistance. The genes that associated with cisplatin resistance remain unclear. Herein, we aimed to identify the cisplatin resistance associated genes in BUC. EXPERIMENTAL DESIGN: The cytotoxicity of cisplatin was evaluated in six bladder cancer cell lines to compare their responses to cisplatin. The T24 cancer cells exhibited the lowest sensitivity to cisplatin and was therefore selected to explore the mechanisms of drug resistance. We performed genome-wide CRISPR screening in T24 cancer cells in vitro, and identified that the gene heterogeneous nuclear ribonucleoprotein U (HNRNPU) was the top candidate gene related to cisplatin resistance. Epigenetic and transcriptional profiles of HNRNPU-depleted cells after cisplatin treatment were analyzed to investigate the relationship between HNRNPU and cisplatin resistance. In vivo experiments were also performed to demonstrate the function of HNRNPU depletion in cisplatin sensitivity. RESULTS: Significant correlation was found between HNRNPU expression level and sensitivity to cisplatin in bladder cancer cell lines. In the high HNRNPU expressing T24 cancer cells, knockout of HNRNPU inhibited cell proliferation, invasion, and migration. In addition, loss of HNRNPU promoted apoptosis and S-phase arrest in the T24 cells treated with cisplatin. Data from The Cancer Genome Atlas (TCGA) demonstrated that HNRNPU expression was significantly higher in tumor tissues than in normal tissues. High HNRNPU level was negatively correlated with patient survival. Transcriptomic profiling analysis showed that knockout of HNRNPU enhanced cisplatin sensitivity by regulating DNA damage repair genes. Furthermore, it was found that HNRNPU regulates chemosensitivity by affecting the expression of neurofibromin 1 (NF1). CONCLUSIONS: Our study demonstrated that HNRNPU expression is associated with cisplatin sensitivity in bladder urothelial carcinoma cells. Inhibition of HNRNPU could be a potential therapy for cisplatin-resistant bladder cancer.
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Antineoplásicos , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Carcinoma de Células Transicionales/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo U , Humanos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: There is a lack of biomarkers for distinguishing non-obstructive azoospermia (NOA) patients with successful sperm retrieval (Sp+) from those with failed sperm retrieval (Sp-). This study aimed to determine the potential of extracellular vesicles tRNA-derived small RNA (tsRNA) as a novel non-invasive biomarker for successful sperm retrieval by microdissection testicular sperm extraction (mTESE). METHODS: The study included 18 patients with NOA with successful sperm retrieval (Sp+) and 23 patients with NOA with failed sperm retrieval (Sp-), 15 obstructive azoospermia (OA) patients, 5 idiopathic oligospermia (IO) patients, and 12 healthy people. Seminal plasma extracellular vesicles tsRNA levels were used in a two-stage case-control study (screened by tsRNA sequencing on Illumina NextSeq instrument and validated by qRT-PCR). The bioinformatic analysis was performed to determine the role of tsRNA in the pathogenesis of non-obstructive azoospermia. RESULTS: Two tsRNAs (tRF-Val-AAC-010: AUC = 0.96, specificity = 80%, sensitivity = 95%; tRF-Pro-AGG-003: AUC = 0.96, specificity = 87%, sensitivity = 95%) were found to have high predictive accuracy for distinguishing the origin of azoospermia. In addition, the extracellular vesicles tRF-Val-AAC-010 resulted in high predictive ability (AUC = 0.89, sensitivity = 72%, specificity = 91%, P < 0.0001) in predicting the presence of sperm in non-obstructive azoospermia undergoing mTESE. Finally, bioinformatic analysis revealed that tRF-Val-AAC-010 were involved in spermatogenesis. CONCLUSIONS: This study identified that the extracellular vesicles tRF-Val-AAC-010 and tRF-Pro-AGG-003 are biomarkers for the diagnosis of non-obstructive azoospermia, and that tRF-Val-AAC-010 as a potential non-invasive biomarker for predicting the presence of sperm in non-obstructive azoospermia testicular tissue.
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Azoospermia , Vesículas Extracelulares , Azoospermia/diagnóstico , Azoospermia/genética , Estudios de Casos y Controles , Vesículas Extracelulares/patología , Humanos , Masculino , Microdisección , Estudios Retrospectivos , Semen , Recuperación de la Esperma , Espermatozoides/patología , Testículo/patologíaRESUMEN
Muscle-invasive bladder carcinoma (MIBC) accounts for 25% of newly diagnosed bladder carcinomas (BCs) and presents a high risk of progression and metastasis. This study aimed to identify reliable biomarkers associated with muscle invasion and prognosis to identify potential therapeutic targets for MIBC. Four gene datasets were downloaded from the Gene Expression Omnibus, and the integrated differentially expressed genes (DEGs) were then subjected to gene ontology (GO) terms and pathway enrichment analyses. Correlation analysis between the expression of the top-ranking DEGs and pathological T stages was performed to identify the genes associated with early muscle invasion. The corresponding prognostic values were evaluated, and co-expressed genes mined in the cBioPortal database were loaded into ClueGo in Cytoscape for pathway enrichment analysis. Using data mining from the STRING and TCGA databases, protein-protein interaction and competitive endogenous RNA networks were constructed. In total, 645 integrated DEGs were identified and these were mainly enriched in 26 pathways, including cell cycle, bladder cancer, DNA replication, and PPAR signaling pathway. S100A7 expression was significantly increased from the T2 stage and showed significantly worse overall survival and disease-specific survival in patients with BC. In total, 144 genes co-expressed with S100A7 in BC were significantly enriched in the IL-17 pathway. S100A7 was predicted to directly interact with LYZ, which potentially shows competitive binding with hsa-mir-140 to affect the expression of six lncRNAs in MIBC. In conclusion, high S100A7 expression was predicted to be associated with early muscle invasion and poor survival in patients with BC.
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Biomarcadores de Tumor/genética , Regulación Neoplásica de la Expresión Génica , Proteína A7 de Unión a Calcio de la Familia S100/genética , Neoplasias de la Vejiga Urinaria/genética , Vejiga Urinaria/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Biología Computacional , Bases de Datos Genéticas , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Mapas de Interacción de Proteínas , Proteína A7 de Unión a Calcio de la Familia S100/metabolismo , Análisis de Supervivencia , Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urological malignancies, but the pathogenesis and prognosis of ccRCC remain obscure, which need to be better understand. METHODS: Differentially expressed genes were identified and function enrichment analyses were performed using three publicly available ccRCC gene expression profiles downloaded from the Gene Expression Omnibus database. The protein-protein interaction and the competing endogenous RNA (ceRNA) networks were visualized by Cytoscape. Multivariate Cox analysis was used to predict an optimal risk mode, and the survival analysis was performed with the Kaplan-Meier curve and log-rank test. Protein expression data were downloaded from Clinical Proteomic Tumor Analysis Consortium database and Human Protein Atlas database, and the clinical information as well as the corresponding lncRNA and miRNA expression data were obtained via The Cancer Genome Atlas database. The co-expressed genes and potential function of candidate genes were explored using data exacted from the Cancer Cell Line Encyclopedia database. RESULTS: Of the 1044 differentially expressed genes shared across the three datasets, 461 were upregulated, and 583 were downregulated, which significantly enriched in multiple immunoregulatory-related biological process and tumor-associated pathways, such as HIF-1, PI3K-AKT, P53 and Rap1 signaling pathways. In the most significant module, 36 hub genes were identified and were predominantly enriched in inflammatory response and immune and biotic stimulus pathways. Survival analysis and validation of the hub genes at the mRNA and protein expression levels suggested that these genes, particularly complement component 3 (C3) and fibronectin 1 (FN1), were primarily responsible for ccRCC tumorigenesis and progression. Increased expression of C3 or FN1 was also associated with advanced clinical stage, high pathological grade, and poor survival in patients with ccRCC. Univariate and multivariate Cox regression analysis qualified the expression levels of the two genes as candidate biomarkers for predicting poor survival. FN1 was potentially regulated by miR-429, miR-216b and miR-217, and constructed a bridge to C3 and C3AR1 in the ceRNA network, indicating a critical position of FN1. CONCLUSIONS: The biomarkers C3 and FN1 could provide theoretical support for the development of a novel prognostic tool to advance ccRCC diagnosis and targeted therapy.
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Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/genética , Fibronectinas/metabolismo , Neoplasias Renales/genética , Carcinoma de Células Renales/mortalidad , Progresión de la Enfermedad , Humanos , Neoplasias Renales/mortalidad , Análisis de SupervivenciaRESUMEN
To investigate the antitumor mechanism of MAP30 in human bladder cell line (T24) and its potential toxic effects in mice. In this study, the biological behavior of MAP30's influence on bladder cell was investigated to reveal the antitumor mechanism and role of MAP30 in bladder cancer. MAP30 gene sequence optimized by gene synthesis codon was inserted into the prokaryotic expression vector pET-28a to produce a large amount of target protein in Escherichia coli. The protein product was obtained after purification. Membrane hydration method was used to prepare MAP30 liposome in order to enhance its membrane permeability. The effects of MAP30 on the viability, apoptosis and migration of T24 cell were assessed using 3(4,5dimethylthiazol2yl)2,5diphenyl2Htetrazolium bromide (MTT), flow cytometric and TUNEL assays, respectively. Mice were transfected with bladder cancer cells for 48 h. The expressions of apoptotic and non-apoptotic proteins were determined using Western blotting. Changes in tumor volume and occurrence of metastasis were assessed using luciferase assay. After 7 days, liver and kidney were excised for histological examination. The levels of reactive oxygen species (ROS), malondialdehyde (MDA), and reduced glutathione (GSH), and activities of catalase and glutathione peroxidase (GPx) were determined in serum or homogenate using enzyme-linked immunosorbent assay (ELISA). The yield of MAP30 after purification was significantly increased. The results of MTT assay showed that MAP30 significantly and concentration-dependently inhibited the proliferation and migration of T24 cells (p < 0.05). The prepared liposomes had uniform hydrated particle size of 132.6 nm, with encapsulation efficiency of 78 %. The inhibitory effect of MAP30 liposome on T24 cells was significantly higher than that of MAP30, and MAP30 significantly increased the number of apoptotic cells (p < 0.05). Western blotting showed that MAP30 significantly promoted the expression of caspase 3 (p < 0.05), but did not significantly affect the expressions of bcl-2 and bax (p > 0.05). It also significantly down-regulated the expressions of NF-kB, JNK and MMP2 (p < 0.05). Tumor formation was significantly inhibited, and tumor volume reduced in bladder cancer-bearing mice after treatment with MAP30 (p < 0.05). Histological examination showed that MAP30 induced mild histological changes in the liver and kidney of mice, and significantly increased the level of MDA at day 1 (p < 0.05). It also significantly and time-dependently increased ROS, but reduced GSH levels and activities of catalase and GPx (p < 0.05). However, MAP30 had no significant effect on DNA (p > 0.05). The apoptotic effect of MAP30 in T24 cells is mediated via activation of caspase-3 signaling pathway. The protein produces mild histological changes in the liver and kidney of mice, but has no significant effect on DNA.
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Antineoplásicos/uso terapéutico , Proteínas Inactivadoras de Ribosomas Tipo 2/toxicidad , Proteínas Inactivadoras de Ribosomas Tipo 2/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Liposomas , Masculino , Ratones , Proteínas Inactivadoras de Ribosomas Tipo 2/aislamiento & purificación , Carga Tumoral/efectos de los fármacosRESUMEN
For the treatment of ejaculatory duct obstruction, transurethral seminal vesiculoscopy (TSV) is the most common method, but the success rate is much lower than studies that have reported. So we developed a new ultrasound-guided seminal vesicle radiography (UGSVR) combining CT three-dimensional reconstruction (CT-TR) technique to improve the success rate of TSV. Between June 2018 and November 2019, 32 patients were enrolled and randomly assigned to two groups: experimental group (UGSvR combining CT-TR) and control group (standard evaluation). Baseline information, including age, smoking history and body mass index (BMI), was compared preoperatively. Surgical parameters included success rates (SR), surgical time (ST), catheter days (CD), length of hospital stays (HS) and complications were compared between groups. There were no statistically significant differences in baseline data between the two groups (all p > .05). There were no significant differences in the CD, HS and complications between the two groups (all p > .05), but the differences in ST and SR were statistically significant (p < .05). In conclusion, this new technique of UGSvR combining CT-TR was achieving a satisfactory increase in the success rate of TSV, while not increasing the incidence of complications, compared to normal evaluation before TSV operation.
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Imagenología Tridimensional , Vesículas Seminales , Humanos , Masculino , Radiografía , Vesículas Seminales/diagnóstico por imagen , Vesículas Seminales/cirugía , Tomografía Computarizada por Rayos X , Ultrasonografía IntervencionalRESUMEN
BACKGROUND: This study aimed to determine whether the enhancer of the rudimentary homolog (ERH) gene regulates cell migration and invasion in human bladder urothelial carcinoma (BUC) T24 cells and the underlying mechanism. METHODS: First, we knocked down ERH in BUC T24 and 5637 cells by shRNA and then used wound healing cell scratch migration assays, transwell cell migration assays, transwell cell invasion chamber experiments and nude mouse tail vein transfer assays to determine the migration and invasion ability after ERH was knocked down. Moreover, we used gene expression profiling chip analysis and further functional experiments to explore the possible mechanism through which ERH knockdown downregulated metastasis ability in T24 cells. RESULTS: Wound healing cell scratch migration assays, transwell cell migration assays, transwell cell invasion chamber experiments and nude mouse tail vein transfer assays all showed that the metastasis ability was significantly inhibited in human BUC T24 and 5637 cells with ERH knockdown. A gene expression profiling chip analysis in T24 cells showed that the MYC gene may be an important downstream target of the ERH gene, and the functional experiments showed that MYC is a functional target of ERH in BUC T24 cells. CONCLUSION: ERH knockdown could inhibit the metastasis of BUC T24 cells in vitro and in vivo. This study further explored the mechanism of the ERH gene in the metastasis of the T24 human bladder cancer cell line and found that ERH may regulate MYC gene expression. The results of this research provide a basis for the clinical application of ERH as a potential target for BUC treatment.
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Proteínas de Ciclo Celular/fisiología , Movimiento Celular/fisiología , Perfilación de la Expresión Génica/métodos , Factores de Transcripción/fisiología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Animales , Proteínas de Ciclo Celular/deficiencia , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen/métodos , Humanos , Ratones , Ratones Desnudos , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
OBJECTIVE: To study the expression of long nonîcoding RNA (lncRNA) H19 in human prostate cancer tissue and its effect on the glycometabolism and growth of human prostate cancer cells. METHODS: Realîtime quantitative RTîPCR (qRTîPCR) was employed to detect the expression of lncRNA H19 in human prostate tissues from 20 patients with prostate cancer (10 cases of highîGleason score prostate cancer ï¼»HGPCï¼½ and 10 cases of lowîGleason score prostate cancer ï¼»LGPCï¼½) and another 5 with benign prostatic hyperplasia (BPH). After transfection of H19 siRNA into the DU145 and PCî3 prostate cancer cells, the growth of the cells and the H19 expression in the cells were determined by MTT and qRTîPCR respectively, and the changes in the glycometabolism of the prostate cancer cells were analyzed by measuring the contents of glucose and lactate in the culture medium. Nonîtransfected and transfected negative vectors were used as blank and negative controls respectively. RESULTS: The relative expression of H19 was significantly increased in both the HGPC and LGPC tissues (0.725±0.385 and 2.086±0.542) as compared with that in the BPH tissue (0.210±0.068) (P< 0.01), even higher in the HGPC than in the LGPC tissue (P< 0.01). After transfection of H19 siRNA, the expressions of H19 were remarkably decreased in the DU145 and PCî3 prostate cancer cells in comparison with those in the blank control and negative control groups (P< 0.01), and so were the proliferation of and the glucose and lactate levels in the DU145 and PCî3 cells (P< 0.01).
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Proliferación Celular , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Glucosa/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Hiperplasia Prostática/metabolismo , ARN Largo no Codificante/genética , ARN Interferente Pequeño , TransfecciónRESUMEN
Erectile dysfunction (ED) is a common clinical condition that mainly affects men aged over 40 years. Various causes contribute to the progression of ED, including pelvic nerve injury, diabetes, metabolic syndrome, age, Peyronie's disease, smoking, and psychological disorders. Current treatments for ED are limited to symptom relief and do not address the root cause. Stem cells, with their powerful ability to proliferate and differentiate, are a promising approach for the treatment of male ED and are gradually gaining widespread attention. Current uses for treating ED have been studied primarily in experimental animals, with most studies observing improvements in erectile quality as well as improvements in erectile tissue. However, research on stem cell therapy for human ED is still limited. This article summarizes the recent literature on basic stem cell research on ED, including cavernous nerve injury, aging, diabetes, and sclerosing penile disease, and describes mechanisms of action and therapeutic effects of various stem cell therapies in experimental animals. Stem cells are also believed to interact with host tissue in a paracrine manner, and improved function can be supported through both implantation and paracrine factors. To date, stem cells have shown some preliminary promising results in animal and human models of ED.
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Disfunción Eréctil , Trasplante de Células Madre , Humanos , Disfunción Eréctil/terapia , Masculino , Trasplante de Células Madre/métodos , Animales , Células MadreRESUMEN
BACKGROUND: Both apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) inhibition and melatonin suppress prostate cancer (PCa) growth. OBJECTIVE: This study evaluated the therapeutic efficiency of self-assembled and prostate-specific membrane antigen (PSMA)-targeted nanocarrier loading 125I radioactive particles and encapsulating siRNA targeting APE1 (siAPE1) and melatonin for PCa. METHODS: The linear polyarginine R12 polypeptide was prepared using Fmoc-Arg-Pbf-OH. The PSMA-targeted polymer was synthesized by conjugating azide-modified R12 peptide to PSMA monoclonal antibody (mAb). Before experiments, the PSMA-R12 nanocarrier was installed with melatonin and siAPE1, which were subsequently labeled by 125I radioactive particles. In vitro biocompatibility and cytotoxicity of nanocomposites were examined in LNCaP cells and in vivo biodistribution and pharmacokinetics were determined using PCa tumor-bearing mice. RESULTS: PSMA-R12 nanocarrier was ~120 nm in size and was increased to ~150 nm by melatonin encapsulation. PSMA-R12 nanoparticles had efficient loading capacities of siAPE1, melatonin, and 125I particles. The co-delivery of melatonin and siAPE1 by PSMA-R12-125I showed synergistic effects on suppressing LNCaP cell proliferation and Bcl-2 expression and promoting cell apoptosis and caspase-3 expression. Pharmacokinetics analysis showed that Mel@PSMA-R12-125I particles had high uptake activity in the liver, spleen, kidney, intestine, and tumor, and were accumulated in the tumor sites within the first 8 h p.i., but was rapidly cleared from all the tested organs at 24 h p.i. Administration of nanoparticles to PCa tumors in vivo showed that Mel@PSMA-R12- 125I/siAPE1 had high efficiency in suppressing PCa tumor growth. CONCLUSION: The PSMA-targeted nanocarrier encapsulating siAPE1 and melatonin is a promising therapeutic strategy for PCa and can provide a theoretical basis for patent applications.
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Antígenos de Superficie , Glutamato Carboxipeptidasa II , Radioisótopos de Yodo , Melatonina , Nanopartículas , Neoplasias de la Próstata , Masculino , Animales , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Humanos , Radioisótopos de Yodo/administración & dosificación , Melatonina/farmacología , Melatonina/administración & dosificación , Línea Celular Tumoral , Nanopartículas/química , Ratones , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Distribución Tisular , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Ratones Endogámicos BALB C , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacologíaRESUMEN
With the advancement of RNA sequencing technology, there has been a drive to uncover and elucidate the pivotal role of A-to-I RNA editing events in tumorigenesis. However, A-to-I miRNA editing events have been clearly identified in bladder cancer, the molecular mechanisms underlying their role in bladder cancer remain unclear. In our investigation, we observed a notable under-expression of edited miR-154-p13-5p in bladder cancer (BC) tissues, in contrast to normal counterparts. Remarkably, heightened expression levels of edited miR-154-p13-5p correlated with improved survival outcomes. To assess the impact of modified miR-154-p13-5p, we conducted a string of cell phenotype assays through transfection of the corresponding miRNAs or siRNAs. The results unequivocally demonstrate that edited miR-154-p13-5p exerts a substantial inhibitory influence on proliferation, migration, and induces apoptosis by specifically targeting LIX1L in bladder cancer. Moreover, we observed that the editing of miR-154-p13-5p or LIX1L-siRNAs inhibits the expression of LIX1L, thereby suppressing EMT-related proteins and cell cycle protein CDK2. Simultaneously, an upregulation in the expression levels of Caspase-3 and Cleaved Caspase-3 were also detected. Our research findings suggest that the upregulation of edited miR-154-p13-5p could potentially enhance the prognosis of bladder cancer, thereby presenting molecular biology-based therapeutic strategies.
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Bladder cancer, the most common malignant tumor in the urinary system, exhibits significantly up-regulated expression of P3H4, which is associated with pathological factors. The objective of this study was to elucidate the underlying mechanism of P3H4 in bladder cancer. Initially, we analyzed P3H4 gene expression using the TCGA database and evaluated P3H4 levels in clinical samples and various bladder cell lines. P3H4 was found to be markedly overexpressed in bladder cancer samples. Subsequently, bladder cancer cells were transfected with shRNA targeting P3H4 (sh-P3H4), sh-METTL3, and P3H4 overexpression vectors (P3H4 OE). Viability, migration, and invasion of bladder cancer cells were assessed using CCK-8, wound healing, and transwell assays. Western blot analysis was performed to determine the levels of EMT-associated proteins, while RNA stability assays determined the half-life of P3H4. Knockdown of P3H4 resulted in inhibition of bladder cancer cell proliferation, migration, invasion, and EMT progression. Mechanistically, METTL3 was found to regulate the mRNA stability of P3H4 in bladder cancer. Moreover, overexpression of P3H4 reversed the inhibitory effects of METTL3 knockdown on bladder cancer cell behaviors. Stable cell lines were established by infecting EJ cells with lentiviral vectors containing sh-METTL3 or P3H4 OE. These cells were then implanted into the skin of BALB/c nude mice, and IHC analysis was used to analyze the expression levels of EMT-associated proteins. In vivo studies demonstrated that inhibition of METTL3 suppressed bladder cancer growth and EMT through P3H4. In conclusion, our findings suggest that METTL3 regulates the proliferation, metastasis, and EMT progression of bladder cancer through P3H4, highlighting its potential as a therapeutic target.
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Neoplasias de la Vejiga Urinaria , Animales , Ratones , Línea Celular Tumoral , Ratones Desnudos , Proliferación Celular/genética , Neoplasias de la Vejiga Urinaria/patología , Movimiento Celular/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
We aimed to build a deep learning-based pathomics model to predict the early recurrence of non-muscle-infiltrating bladder cancer (NMIBC) in this work. A total of 147 patients from Xuzhou Central Hospital were enrolled as the training cohort, and 63 patients from Suqian Affiliated Hospital of Xuzhou Medical University were enrolled as the test cohort. Based on two consecutive phases of patch level prediction and WSI-level predictione, we built a pathomics model, with the initial model developed in the training cohort and subjected to transfer learning, and then the test cohort was validated for generalization. The features extracted from the visualization model were used for model interpretation. After migration learning, the area under the receiver operating characteristic curve for the deep learning-based pathomics model in the test cohort was 0.860 (95% CI 0.752-0.969), with good agreement between the migration training cohort and the test cohort in predicting recurrence, and the predicted values matched well with the observed values, with p values of 0.667766 and 0.140233 for the Hosmer-Lemeshow test, respectively. The good clinical application was observed using a decision curve analysis method. We developed a deep learning-based pathomics model showed promising performance in predicting recurrence within one year in NMIBC patients. Including 10 state prediction NMIBC recurrence group pathology features be visualized, which may be used to facilitate personalized management of NMIBC patients to avoid ineffective or unnecessary treatment for the benefit of patients.
Asunto(s)
Aprendizaje Profundo , Recurrencia Local de Neoplasia , Neoplasias Vesicales sin Invasión Muscular , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Neoplasias Vesicales sin Invasión Muscular/patología , Curva ROC , Medición de Riesgo/métodosRESUMEN
We recently engineered an oncolytic adenovirus (PPE3-SEA) that expresses the superantigen, Staphylococcus enterotoxin A (SEA), and that has enhanced tumor specificity because the telomerase reverse transcriptase and hypoxia-inducible factor promoters regulate expression of E1A and E1B genes, respectively. Here, we evaluated the PPE3-SEA adenovirus anti-tumor activity against MB49 mouse bladder cancer cell proliferation in vitro and in vivo. PPE3-SEA infection of murine MB49 cells in vitro induced cytopathic effects, and significant expression of SEA mRNA and protein, as measured by RT-PCR and western blot, respectively. Subcutaneous MB29 bladder tumors were established in syngeneic C57BL/6 mice. After 10 days, tumors were injected with either oncolytic virus or PBS. Tumor dimensions were measured on days 1, 3, 5, 7, 9, and 11 post-treatment and tumor volumes were calculated. One of eight PPE3-SEA-treated mice had no tumor by day 9. PPE3-SEA treated group had significantly lower mean tumor volume beginning on day 5 post-treatment (p < 0.01), more fibrous tissue in the tumor, and increased presence of infiltrating CD3+ T cells than those of the control group. Gross appearance and histologic sections from the livers and kidneys of the PPE3-SEA-treated group were similar to those of the control group. In conclusion, oncolytic adenoviruses can provide a novel delivery vehicle for SEA to tumor sites, and PPE3-SEA warrants further study as a potential anti-tumor agent for bladder cancer.
Asunto(s)
Adenoviridae/genética , Enterotoxinas/biosíntesis , Virus Oncolíticos/genética , Superantígenos/biosíntesis , Neoplasias de la Vejiga Urinaria/terapia , Animales , Proteínas Bacterianas/biosíntesis , Proteínas Bacterianas/genética , Complejo CD3/metabolismo , Línea Celular Tumoral , Forma de la Célula , Supervivencia Celular , Enterotoxinas/genética , Enterotoxinas/inmunología , Femenino , Expresión Génica , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Viroterapia Oncolítica , Superantígenos/genética , Superantígenos/inmunología , Linfocitos T/inmunología , Carga Tumoral , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of tadalafil monotherapy for lower urinary tract symptoms secondary to benign prostatic hyperplasia (LUTS/BPH). METHODS: A comprehensive search was done to identify randomized controlled trials comparing the efficacy and safety of tadalafil for LUTS/BPH with placebos. Meta-analytical techniques were applied to evaluate the differences in the study results. RESULTS: Eight studies were identified and analyzed. Compared with placebo, tadalafil was associated with significant improvements in the International Prostate Symptom Score (IPSS) (mean difference = -2.19, p < 0.00001) and the International Index of Erectile Function (IIEF) score (mean difference = +4.66, p < 0.00001), despite the concomitant presence of erectile dysfunction. Significant differences were also observed in the IPSS irritative and obstructive subscores, IPSS quality of life index and BPH impact index. After pooling four doses (2.5, 5, 10 and 20 mg), tadalafil failed to produce a significant outcome in maximal urinary flow rate (Qmax) (mean difference = +0.26 ml/s, p = 0.14), but 5 mg of tadalafil significantly improved Qmax (mean difference = +0.63 ml/s, p = 0.04). No significant difference was detected in the incidence of serious adverse events (risk ratio = 1.00, p = 1.00) after tadalafil treatment. CONCLUSIONS: Tadalafil showed good efficacy and safety for improving LUTS and erectile dysfunction in men with BPH, and 5 mg of tadalafil significantly improved Qmax.
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Carbolinas/uso terapéutico , Hiperplasia Prostática/tratamiento farmacológico , Sistema Urinario/efectos de los fármacos , Enfermedades Urológicas/tratamiento farmacológico , Disfunción Eréctil/tratamiento farmacológico , Humanos , Masculino , Seguridad del Paciente , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Hiperplasia Prostática/patología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Riesgo , Tadalafilo , Resultado del Tratamiento , Agentes Urológicos/uso terapéuticoRESUMEN
OBJECTIVE: To observe the therapeutic effect of Si-Ni-San (SNS) on interstitial cystitis/bladder pain syndrome (IC/BPS) in rats, and explore the possible regulatory mechanism of SNS on IC/BPS combined with transcriptome analysis. METHODS: An IC/BPS model of Sprague-Dawley (SD) rats was established with cyclophosphamide (CYP), and the SNS was extracted for treatment. The rats were divided into 4 groups (n = 10 in each group): Control group (blank), cyclophosphamide group (CYP group, CYP injection + normal saline gavage), lower-dose SNS group (LSNS group, CYP injection + 6 g/kg SNS gavage), and higher-dose SNS group (HSNS group, CYP injection + 12 g/kg SNS gavage). Urination, pain, and histological changes were observed in the rats after the experiment, and Western blotting (WB) and transcriptome analysis were performed on bladder tissues. RESULTS: Compared with the CYP group, the urination, pain and inflammation symptoms of the IC/BPS model rats in the SNS treatment groups (LSNS and HSNS) were significantly improved (p < 0.05). WB results showed that the expressions of inflammation-related proteins interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the SNS treatment groups were significantly decreased compared with those in the CYP group. Transcriptome results showed that SNS can affect the expression of inflammation-related genes and inflammatory signaling pathways. CONCLUSIONS: SNS can significantly alleviate the symptoms of inflammation and pain in IC/BPS rats, and its mechanism may be related to the down-regulation of inflammatory factors IL-6 and TNF-α through messenger RNA (mRNA) and long non-coding RNA (LncRNA) pathways.
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Cistitis Intersticial , Ratas , Animales , Cistitis Intersticial/tratamiento farmacológico , Cistitis Intersticial/metabolismo , Cistitis Intersticial/patología , Interleucina-6/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéutico , Ratas Sprague-Dawley , Inflamación/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , DolorRESUMEN
On March 23, 2022, the U.S. Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan), also known as 177Lu-PSMA-617, for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) who have highly expressed prostate-specific membrane antigen (PSMA) and have at least one metastatic lesion. It is the first FDA-approved targeted radioligand therapy for eligible men with PSMA-positive mCRPC. Lutetium Lu 177 vipivotide tetraxetan is a radioligand that strongly binds to PSMA, making it ideal for treating cancers of the prostate by targeted radiation, resulting in DNA damage and cell death. PSMA is overexpressed in cancer cells while being lowly expressed in normal tissues, which makes it an ideal theranostic target. As precision medicine advances, this is a thrilling turning point for highly individualized treatments. This review aims to summarize the pharmacology and clinical studies of the novel drug lutetium Lu 177 vipivotide tetraxetan for the treatment of mCRPC, emphasizing its mechanism of action, pharmacokinetics and safety.