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Erdafitinib is a novel fibroblast growth factor receptor (FGFR) inhibitor that has shown great therapeutic promise for solid tumor patients with FGFR3 alterations, especially in urothelial carcinoma. However, the mechanisms of resistance to FGFR inhibitors remain poorly understood. In this study, we found Erdafitinib could kill cells by inducing incomplete autophagy and increasing intracellular reactive oxygen species levels. We have established an Erdafitinib-resistant cell line, RT-112-RS. whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis performed on Erdafitinib-resistant RT-112-RS cells and parental RT-112 cells introduced P4HA2 as a linchpin to Erdafitinib resistance. The gain and loss of function study provided evidence for P4HA2 conferring such resistance in RT-112 cells. Furthermore, P4HA2 could stabilize the HIF-1α protein which then activated downstream target genes to reduce reactive oxygen species levels in bladder cancer. In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , Línea Celular Tumoral , Pirazoles/farmacología , Especies Reactivas de Oxígeno , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/genética , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Presently, the majority of investigations primarily evaluate the association between lipid profiles and asthma. However, few investigations explore the connection between lipids and mortality related to the disease. This study aims to explore the association of serum lipids with all-cause mortality within asthmatic adults. METHODS: The investigation included 3233 eligible patients with asthma from the NHANES (2011-2018). The potential associations were explored using three Cox proportional hazards models, restricted cubic splines (RCS), threshold effect models, and CoxBoost models. In addition, subgroup analyses were conducted to investigate these associations within distinct populations. RESULTS: After controlling all covariables, the Cox proportional hazards model proved a 17% decrease in the probability of death for each increased unit of low-density lipoprotein-cholesterol (LDL-C) (mmol/L). Yet, there was no association seen between blood high-density lipoprotein cholesterol (HDL-C), total cholesterol, or triglyceride and all-cause mortality in asthmatics. The application of RCS and threshold effect models verified an inverse and linear association of LDL-C with all-cause mortality. According to the results from the CoxBoost model, LDL-C exhibited the most substantial impact on the follow-up status of asthmatics among the serum lipids. CONCLUSION: Our investigation concluded that in American asthmatic populations, LDL-C levels were inversely and linearly correlated with mortality. However, no independent relationship was found between triglycerides, total cholesterol, or HDL-C and mortality.
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Asma , HDL-Colesterol , LDL-Colesterol , Modelos de Riesgos Proporcionales , Triglicéridos , Humanos , Asma/sangre , Asma/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Adulto , LDL-Colesterol/sangre , HDL-Colesterol/sangre , Triglicéridos/sangre , Estudios de Cohortes , Lípidos/sangre , Anciano , Factores de RiesgoRESUMEN
BACKGROUND: Prostatic cancer (PCa) is one of the most common malignant tumors in men worldwide. Emerging evidence indicates significance of hypoxia and immunity in PCa invasion and metastasis. This study aimed to develop a hypoxia- and immune-related gene risk signature and explore the molecular mechanisms to formulate a better prognostic tool for PCa patients. METHODS: The hypoxia and immune scores of all PCa patients in The Cancer Genome Atlas (TCGA) dataset were calculated via the maximally selected rank statistics method and the ESTIMATE algorithm. From common genes identified overlapping hypoxia- and immune-related differentially expressed genes (DE-HRGs and DE-IRGs), a hypoxia- and immune-related gene risk signature was developed utilizing univariate and multivariate Cox regression analyses, and validated in the Memorial Sloan Kettering Cancer Centre (MSKCC) database. The immune cell infiltration level of PCa samples were evaluated with ssGSEA algorithm. Differential expression of prognostic genes was evidenced by immunohistochemistry and western blot (WB) in paired PCa samples. Expression levels of these genes and their variations under regular and hypoxic conditions were examined in cell lines. The functional effects of the prognostic gene on PCa cells were examined by wound healing and transwell assays. RESULTS: A hypoxia- and immune-related gene risk signature constructed by ISG15 and ZFP36 displays significant predictive potency, with higher risk score representing worse survival. A nomogram based on independent prognostic factors including the risk score and Gleason score exhibited excellent clinical value in the survival prediction of PCa. Infiltration levels of eosinophils, neutrophils, Tcm, Tem, TFH, Th1 cells, and Th17 cells were significantly lower in the high-risk group. Conversely, aDC, pDC, T helper cells, and Tregs were significantly higher. Additionally, the two prognostic genes were closely correlated with the tumor-infiltrating immune cell subset in PCa progression. RT-qPCR and WB presented higher and lower expression of ISG15 and ZFP36 in PCa cells, respectively. They were correspondingly increased and decreased in PCa cells under hypoxic conditions. Wound healing and transwell assays showed that over-expression of ISG15 promoted the migration and invasion of PCa cells. CONCLUSION: Our study identified a novel hypoxia- and immune-related gene signature, contributing a new perspective to the treatment of PCa.
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Citocinas , Neoplasias de la Próstata , Tristetraprolina , Ubiquitinas , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Biología Computacional/métodos , Citocinas/genética , Citocinas/inmunología , Perfilación de la Expresión Génica , Humanos , Hipoxia/genética , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Tristetraprolina/genética , Tristetraprolina/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismoRESUMEN
OBJECTIVE: To investigate the correlation of the anterior lobe thickness of the prostate (ALTP) with bladder outlet obstruction (BOO), and evaluate the effect of ALTP on the clinical progression of BPH. METHODS: This retrospective study included 159 cases of BPH. We obtained the clinical indicators of the patients, including ALTP, prostate volume (PV), postvoid residual urine (PVR), maximum urinary flow rate (Qmax), BOO index (BOOI) and IPSS, and analyzed the correlations of ALTP with IPSS, PV, Qmax, age, PVR and BOOI. Using the ROC curve and cut-off point of ALTP, we compared the clinical indicators between the small and large ALTP groups, and analyzed the correlation between ALTP and the clinical progression of BPH. RESULTS: IPSS was not significantly correlated with ALTP (P > 0.05), nor was ALTP with PV and Qmax (P > 0.05). The area under the ROC curve was 0.742 (95% CI: 0.656ï¼0.828) and the cut-off point of ALTP was 0.65 cm. Statistically significant differences were observed in PV, Qmax, IPSS and the rate of surgery between the small ALTP (<0.65 cm) and large ALTP (≥0.65 cm) groups (P < 0.05). CONCLUSION: ALTP is not proportional to PV or to IPSS. ALTP ≥ 0.65 cm increases the incidence of BOO, and may be a risk factor for the clinical progression of BPH.
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Hiperplasia Prostática , Obstrucción del Cuello de la Vejiga Urinaria , Retención Urinaria , Masculino , Humanos , Hiperplasia Prostática/complicaciones , Próstata , Estudios Retrospectivos , Obstrucción del Cuello de la Vejiga Urinaria/etiología , Progresión de la EnfermedadRESUMEN
BACKGROUND: Nitric oxide (NO) has been shown to be important in sperm function, and the concentration of NO appears to determine these effects. Studies have demonstrated both positive and negative effects of NO on sperm function, but have not been able to provide a clear link between NO concentration and the extent of exposure to NO. To study the relationship between nitric oxide and sperm capacitation in vitro, and to provide a theoretical basis for the use of NO-related preparations in improving sperm motility for in vitro fertilization, we investigated the effects of NO concentration and time duration at these concentrations on in vitro sperm capacitation in both normal and abnormal sperm groups. We manipulated NO concentrations and the time duration of these concentrations using sodium nitroprusside (an NO donor) and NG-monomethyl-L-argenine (an NO synthase inhibitor). RESULTS: Compared to the normal sperm group, the abnormal sperm group had a longer basal time to reach the appropriate concentration of NO (p < 0.001), and the duration of time at this concentration was longer for the abnormal sperm group (p < 0.001). Both the basal time and the duration of time were significantly correlated with sperm viability and percentage of progressive sperm (p < 0.001). The experimental group had a significantly higher percentage of progressive sperm than the control group (p < 0.001). CONCLUSIONS: We hypothesize that there is a certain regularity to both NO concentration and its duration of time in regards to sperm capacitation, and that an adequate duration of time at the appropriate NO concentration is beneficial to sperm motility.
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Óxido Nítrico/farmacología , Capacitación Espermática/efectos de los fármacos , Motilidad Espermática/efectos de los fármacos , Adulto , Supervivencia Celular , Fertilización In Vitro/métodos , Humanos , Técnicas In Vitro , Masculino , Óxido Nítrico/análisis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroprusiato/farmacología , Factores de Tiempo , omega-N-Metilarginina/farmacologíaRESUMEN
The generation of radiological results from image data represents a pivotal aspect of medical image analysis. The latest iteration of ChatGPT-4, a large multimodal model that integrates both text and image inputs, including dermatoscopy images, histology images, and X-ray images, has attracted considerable attention in the field of radiology. To further investigate the performance of ChatGPT-4 in medical image recognition, we examined the ability of ChatGPT-4 to recognize credible osteosarcoma X-ray images. The results demonstrated that ChatGPT-4 can more accurately diagnose bone with or without significant space-occupying lesions but has a limited ability to differentiate between malignant lesions in bone compared to adjacent normal tissue. Thus far, the current capabilities of ChatGPT-4 are insufficient to make a reliable imaging diagnosis of osteosarcoma. Therefore, users should be aware of the limitations of this technology.
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Background: Presently, numerous studies have indicated that protein consumption and levels of blood albumin serve as important biomarkers for a range of respiratory illnesses. However, there have been few investigations into the correlation between protein consumption, serum albumin, and asthma. Methods: Our analysis incorporated 2509 asthmatics from the 2011-2018 NHANES dataset. The investigation employed three linear regression models and XGBoost model to investigate the potential link between protein intake, serum albumin levels, and blood eosinophil counts (BEOC) in patients with asthma. The trend test, generalized additive model (GAM), and threshold effect model were utilized to validate this correlation. As well, we undertook stratified analyses to look at the correlation of serum albumin with BEOC among distinct populations. Results: In the univariable regression model, which did not account for any covariates, we observed a positive correlation between protein intake and BEOC. However, univariable and multivariable regression analyses all suggested a negative connection of serum albumin with BEOC in asthma populations. In Model C, which took into account all possible factors, BEOC dropped by 2.82 cells/uL for every unit increase in serum albumin (g/L). Additionally, the GAM and threshold effect model validated that serum albumin and BEOC showed an inverted U-shaped correlation. Conclusion: Our investigation discovered there was no independent link between asthmatics' protein intake and BEOC. However, we observed an inverted U-shaped relationship between serum albumin levels and BEOC, suggesting a possible relationship between the overall nutritional status of asthmatics and immune system changes. Our findings provide new directions for future research in the field of asthma management and therapy.
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Asma , Eosinófilos , Humanos , Asma/sangre , Asma/inmunología , Eosinófilos/inmunología , Masculino , Femenino , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Recuento de Leucocitos , Estados Unidos/epidemiología , Proteínas en la Dieta/administración & dosificación , Encuestas Nutricionales , Albúmina Sérica/análisis , Albúmina Sérica Humana/análisis , Anciano , Adulto JovenRESUMEN
Background: Kidney cancer is a prevalent malignancy with an increasing incidence worldwide. Blood cell indices and inflammation-related markers have shown huge potential as biomarkers for predicting cancer incidences, but that is not clear in kidney cancer. Our study aims to investigate the correlations of blood cell indices and inflammation-related markers with kidney cancer risk. Methods: We performed a population-based cohort prospective analysis using data from the UK Biobank. A total of 466,994 participants, free of kidney cancer at baseline, were included in the analysis. The hazard ratios (HRs) and 95% confidence intervals (CIs) for kidney cancer risk were calculated using Cox proportional hazards regression models. Restricted cubic spline models were used to investigate nonlinear longitudinal associations. Stratified analyses were used to identify high-risk populations. The results were validated through sensitivity analyses. Results: During a mean follow-up of 12.4 years, 1,710 of 466,994 participants developed kidney cancer. The Cox regression models showed that 13 blood cell indices and four inflammation-related markers were associated with kidney cancer incidence. The restricted cubic spline models showed non-linear relationships with kidney cancer. Finally, combined with stratified and sensitivity analyses, we found that the mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), platelet distribution width (PDW), systemic immune-inflammation index (SII), and product of platelet count and neutrophil count (PPN) were related to enhanced kidney cancer risk with stable results. Conclusion: Our findings identified that three blood cell indices (MCHC, RDW, and PDW) and two inflammation-related markers (SII and PPN) were independent risk factors for the incidence of kidney cancer. These indexes may serve as potential predictors for kidney cancer and aid in the development of targeted screening strategies for at-risk individuals.
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Glycyl-tRNA synthetase (GARS1) is differentially expressed across cancers. In this study, the value of GARS1 in the diagnosis and prognosis of various cancers was comprehensively evaluated by multiple omics integrative pan-cancer analysis and experimental verification. Through Kaplan-Meier, ROC and multiple databases, we explored GARS1 expression and prognostic and diagnostic patterns across cancers. The GARS1 relative reaction network was identified in PPI, GO, KEGG, methylation models and the genetic mutation atlas. Further research on the GARS1 value in bladder urothelial carcinoma (BLCA) was conducted by regression and nomogram models. We further analyzed the correlation between GARS1 and immune markers and cells in BLCA. Finally, in vitro experiments were used to validate GARS1 the oncogenic function of GARS1 in BLCA. We found that GARS1 was highly expressed across cancers, especially in BLCA. GARS1 expression was correlated with poor survival and had high diagnostic value in most tumor types. GARS1 is significantly associated with tRNA-related pathways whose mutation sites are mainly located on tRNA synthetase. In addition, Upregulation of GARS1 was connected with immune cell infiltration and five key MMR genes. M2 macrophages, TAMs, Th1 and T-cell exhaustion, and marker sets associated with GARS1 expression indicated specific immune infiltration in BLCA. Finally, in vitro experiments validated that GARS1 expression promotes BLCA cell proliferation and metastasis and inhibits apoptosis. Overall, GARS1 can be a novel prognostic and immunological biomarker through multiple omics integrative pan-cancer analysis. The expression of GARS1 in BLCA was positively correlated with specific immune infiltration, indicating that GARS1 might be related to the tumor immune microenvironment.
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Biomarcadores de Tumor , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Biomarcadores de Tumor/genética , Pronóstico , Línea Celular Tumoral , Proliferación Celular/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/genéticaRESUMEN
Background: To develop a model for the accurate prediction of calculous obstructive pyonephrosis prior to percutaneous nephrolithotomy (PNL), leading to early local anaesthesia microchannel nephrostomy for drainage of pyonephrosis. Methods: By comparing the differences in baseline clinical indicators between the pyonephrosis group and nonpyonephrosis groups, independent risk factors were screened out, and a diagnostic alignment diagram model for predicting calculus obstructive pyonephrosis before PNL was established. Results: Multivariate regression analysis showed that preoperative blood neutrophil count (Neu), serum creatinine level (Scr), serum albumin level (Alb), urine nitrite (UN), hydronephrosis density (HD) and fever history within one month (HFWOM) were independent risk factors for calculous obstructive pyonephrosis. The AUC value of the receiver operating characteristic (ROC) curve was 0.929. The calibration curves showed that the predictive model was well corrected and that the predictive model had strong consistency. Decision analysis curves showed good clinical efficacy of the model. Conclusion: The alignment diagram model accurately predicts patients with preoperative calculous obstructive pyonephrosis in the PNL and provides an evidence-based basis for early renal microchannel nephrostomy.
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Background: Increasing evidence emphasizes the potential relationship between diabetes and OAB (overactive bladder). However, large population epidemiology is still lacking. Methods: This cross-sectional study included six cycle NHANES surveys, with a total of 23863 participants. Logistic regression models were constructed to analyze the association between diabetes mellitus, diabetes-related markers, and inflammatory biomarkers with OAB. Restricted cubic splines were used to analyze the non-linear associations. Mediating analysis was performed to test the effect of inflammatory biomarkers on the relationship between diabetes-related markers and OAB. Finally, machine learning models were applied to predict the relative importance and construct the best-fit model. Results: Diabetes mellitus participants' OAB prevalence increased by 77% compared with non-diabetes. As the quartiles of diabetes-related markers increased, the odds of OAB monotonically increased in three models (all p for trend < 0.001). Glycohemoglobin exhibited a linear association with OAB (p for nonlinearity > 0.05). White blood cells significantly mediated the associations between diabetes-related markers (glycohemoglobin, fasting glucose, and insulin) with OAB, and the proportions were 7.23%, 8.08%, and 17.74%, respectively (all p < 0.0001). Neutrophils partly mediated the correlation between (glycohemoglobin, fasting glucose, and insulin) and OAB at 6.58%, 9.64%, and 17.93%, respectively (all p < 0.0001). Machine learning of the XGBoost model constructs the best fit model, and XGBoost predicts glycohemoglobin is the most important indicator on OAB. Conclusion: Our research revealed diabetes mellitus and diabetes-related markers were remarkably associated with OAB, and systemic inflammation was an important mediator of this association.
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Biomarcadores , Diabetes Mellitus , Inflamación , Vejiga Urinaria Hiperactiva , Humanos , Vejiga Urinaria Hiperactiva/epidemiología , Vejiga Urinaria Hiperactiva/sangre , Femenino , Estudios Transversales , Masculino , Inflamación/sangre , Persona de Mediana Edad , Adulto , Biomarcadores/sangre , Diabetes Mellitus/epidemiología , Diabetes Mellitus/sangre , Encuestas Nutricionales , Anciano , Aprendizaje Automático , Glucemia/metabolismo , Glucemia/análisis , PrevalenciaRESUMEN
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
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Proteínas de Homeodominio , Neoplasias Hepáticas , Neoplasias de la Próstata , Proteínas Supresoras de Tumor , Masculino , Humanos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Animales , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Ratones , Metabolismo de los Lípidos/efectos de los fármacos , Plasticidad de la Célula/efectos de los fármacos , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/tratamiento farmacológico , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/patología , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/tratamiento farmacológico , Carcinoma Neuroendocrino/secundarioRESUMEN
The purpose of this study is to evaluate whether the periprostatic adipose tissue thickness (PPATT) is an independent prognostic factor for prostate cancer patients after laparoscopic radical prostatectomy (LRP). This retrospective cohort study included consecutive prostate cancer patients who underwent LRP treatment at Wuhan Union Hospital from June 2, 2016, to September 7, 2023. PPATT was defined as the thickness of periprostatic fat and was obtained by measuring the shortest vertical distance from the pubic symphysis to the prostate on the midsagittal T2-weighted MR images. Subcutaneous adipose tissue thickness (SATT) was obtained by measuring the shortest vertical distance from the pubic symphysis to the skin at the same slice with PPATT. The primary outcome of the study was biochemical recurrence (BCR), and the secondary outcome was overall survival (OS). Multivariable Cox regression analysis was used to identify independent prognostic factors for prostate cancer survival and prognosis. Based on the optimal cutoff value, 162 patients were divided into a low PPATT/SATT group (n = 82) and a high PPATT/SATT group (n = 80). During the entire follow-up period (median 23.5 months), 26 patients in the high PPATT/SATT group experienced BCR (32.5%), compared to 18 in the low PPATT/SATT group (22.0%). Kaplan-Meier curve analysis indicated that the interval to BCR was significantly shorter in the high PPATT/SATT group (P = 0.037). Multivariable Cox regression analysis revealed that an increase in the PPATT/SATT ratio was associated with BCR (hazard ratio: 1.90, 95% CI, 1.03-3.51; P = 0.040). The PPATT/SATT ratio is a significant independent risk factor for BCR after LRP for prostate cancer patients.
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Imagen por Resonancia Magnética , Próstata , Prostatectomía , Neoplasias de la Próstata , Grasa Subcutánea , Humanos , Masculino , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Persona de Mediana Edad , Anciano , Grasa Subcutánea/diagnóstico por imagen , Grasa Subcutánea/patología , Imagen por Resonancia Magnética/métodos , Factores de Riesgo , Estudios Retrospectivos , Próstata/patología , Próstata/cirugía , Próstata/diagnóstico por imagen , Pronóstico , Recurrencia Local de Neoplasia/diagnóstico por imagen , Recurrencia Local de Neoplasia/patologíaRESUMEN
The development of resistance to cisplatin (CDDP) in bladder cancer presents a notable obstacle, with indications pointing to the substantial role of circular RNAs (circRNAs) in this resistance. Nevertheless, the precise mechanisms through which circRNAs govern resistance are not yet fully understood. Our findings demonstrate that circUGGT2 is significantly upregulated in bladder cancer, facilitating cancer cell migration and invasion. Additionally, our analysis of eighty patient outcomes revealed a negative correlation between circUGGT2 expression levels and prognosis. Using circRNA pull-down assays, mass spectrometry analyses, and RNA Immunoprecipitation (RIP), it was shown that circUGGT2 interacts with the KU heterodimer, consisting of KU70 and KU80. Both KU70 and KU80 are critical components of the non-homologous end joining (NHEJ) pathway, which plays a role in CDDP resistance. Flow cytometry was utilized in this study to illustrate the impact of circUGGT2 on the sensitivity of bladder cancer cell lines to CDDP through its interaction with KU70 and KU80. Additionally, a reduction in the levels of DNA repair factors associated with the NHEJ pathway, such as KU70, KU80, DNA-PKcs, and XRCC4, was observed in chromatin of bladder cancer cells following circUGGT2 knockdown post-CDDP treatment, while the levels of DNA repair factors in total cellular proteins remained constant. Thus, the promotion of CDDP resistance by circUGGT2 is attributed to its facilitation of repair factor recruitment to DNA breaks via interaction with the KU heterodimer. Furthermore, our study demonstrated that knockdown of circUGGT2 resulted in reduced levels of γH2AX, a marker of DNA damage response, in CDDP-treated bladder cancer cells, implicating circUGGT2 in the NHEJ pathway for DNA repair.
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Cisplatino , Reparación del ADN por Unión de Extremidades , Resistencia a Antineoplásicos , Autoantígeno Ku , ARN Circular , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/genética , ARN Circular/metabolismo , ARN Circular/genética , Línea Celular Tumoral , Autoantígeno Ku/metabolismo , Autoantígeno Ku/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Progresión de la EnfermedadRESUMEN
There is growing evidence suggesting that exposure to volatile organic compounds (VOCs) can pose significant health risks, including interference with the function of the reproductive system. However, there has been a lack of research focused on the impact of common environmental VOCs on the levels of sex hormones in the general female population. In this study, we conducted a cross-sectional analysis utilizing the database of the National Health and Nutrition Examination Survey (NHANES, 2013-2016). A total of 2633 participants were included in this study. The Pearson correlation model revealed the potential of co-exposure or co-toxicity between benzene and 2,5-dimethylfuran. According to GLM models, we discovered a significant positive association between blood levels of 2,5-dimethylfuran and benzene with testosterone levels in women. Subgroup analysis further identified that the women with underweight and healthy weight might be the high-risk subgroup. Bayesian kernel machine regression (BKMR) was applied to further assess the univariate and bivariate exposure-response relationships between multiple VOCs. Our research systemically formulated the possible relationship between exposure to VOCs and female sex hormones, indicating the role of VOCs as a risk factor for endocrine disruption, especially benzene and 2,5-dimethylfuran. These findings have important implications for public health and call for further investigation.
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Contaminantes Atmosféricos , Compuestos Orgánicos Volátiles , Humanos , Femenino , Compuestos Orgánicos Volátiles/análisis , Estudios Transversales , Exposición a Riesgos Ambientales/análisis , Encuestas Nutricionales , Benceno/análisis , Contaminantes Atmosféricos/análisis , Teorema de Bayes , Hormonas Esteroides Gonadales/análisisRESUMEN
Background: A series of novel inflammation-related indexes has been confirmed to be efficient indicators of human immune and inflammatory status, with great potential as predictors for a variety of diseases. However, the association between inflammation-related indexes and sex hormones in the general population remained uncertain. Methods: We incorporated data from the NHANES 2013-2016 survey of American adults. On the basis of distribution and comparison analysis, we chose to undertake separate analyses of men and women (including premenopausal and postmenopausal groups). Multivariable weighted linear regression models, eXtreme Gradient Boosting (XGBoost) models, generalized linear analysis, stratified models, logistic regression models and sensitivity analysis were utilized to assess the relationships between inflammation-related indexes and sex hormones. Results: Total 9372 participants out of 20146 were fitted into our research. We conducted separate gender analysis due to different distribution. Multivariable weighted linear regression indicated every component of the inflammation-related index was negatively correlated with at least one component of the male hormone indexes. However, SII, NLR, PPN, and NC were associated positively with female estradiol. XGBoost identify SII, PLR and NLR were the critical indexes on sex hormones. Inflammation-related indexes was associated with Testosterone deficiency in male and postmenstrual group and associated with Excessive Estradiol in premenstrual group. Finally, the subgroup analysis revealed that the association between sex hormones and inflammatory indicators was prominent in American adults over the age of 60 or those with BMI (>28 kg/m2). Conclusion: In all, inflammation-related indexes act as independent risks associated with sex hormone alterations and metabolic disorder in both genders. Using multiple models, we revealed the relative importance of inflammation-related indexes. Subgroup analysis also identified the high-risk population. More prospective and experimental research should be conducted to validate the results.
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Hormonas Esteroides Gonadales , Inflamación , Humanos , Femenino , Adulto , Masculino , Encuestas Nutricionales , Estudios Transversales , Estudios Prospectivos , EstradiolRESUMEN
Recent research has shown that ferroptosis, the iron-dependent accumulation of lipid peroxides that leads to cell death, suppresses cancer metastasis. However, the role of ferroptosis in prostate cancer metastasis has not been completely elucidated. In the current study, we identified the essential role of serum/glucocorticoid regulated kinase 2 (SGK2) in promoting prostate cancer metastasis by inhibiting ferroptosis. We found that the expression of SGK2 was higher in metastatic prostate cancer and predicted poor clinical outcomes. SGK2 knockdown inhibited the metastatic capacity of prostate cancer cells in vivo and in vitro, while SGK2 overexpression inhibited ferroptosis and facilitated prostate cancer metastasis by phosphorylating the Thr-24 and Ser-319 sites of forkhead box O1 (FOXO1). This process induced the translocation of FOXO1 from the nucleus to the cytoplasm, relieving the inhibitory effect of FOXO1 on glutathione peroxidase 4 (GPX4). These findings delineated a novel role of SGK2 in ferroptosis regulation of prostate cancer metastasis, identifying a new key pathway driving prostate cancer metastasis and potentially providing new treatment strategies for metastatic prostate cancer.
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Ferroptosis , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Neoplasias de la Próstata , Proteínas Serina-Treonina Quinasas , Humanos , Masculino , Ferroptosis/genética , Próstata , Neoplasias de la Próstata/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismoRESUMEN
BACKGROUND: Schwannomas can occur in the body where nerve sheaths are present. Genitourinary schwannomas are very rare, especially primary bladder schwannomas. They account for only 0.1% of bladder tumours. The literature reports that simple surgical resection has a good effect and prognosis. CASE PRESENTATION: A 39-year-old man had no significant improvement in symptoms due to frequent urination and urgency for 1 month following the treatment of prostatitis for 2 weeks. Ultrasound and computed tomography (CT) showed a mass in the left side wall of the bladder (size approximately 2.0 × 1.9 cm) that had clear boundaries and protruded outward from the bladder. After the extraperitoneal space was dilated with a balloon, a minimally invasive laparoscopic partial cystectomy was performed in this space to remove the tumour. The pathological diagnosis was bladder schwannoma. Immunohistochemical staining showed that it was strongly S100 protein positive. There was no recurrence after 2 years follow-up by cystoscopy and CT. CONCLUSIONS: Bladder schwannomas are clinically rare benign bladder lesions and no specific clinical manifestations. Laparoscopic partial cystectomy through the extraperitoneal space is a safe and feasible treatment option.
Asunto(s)
Laparoscopía , Neurilemoma , Neoplasias de la Vejiga Urinaria , Adulto , Cistectomía/métodos , Cistoscopía , Humanos , Laparoscopía/métodos , Masculino , Neurilemoma/diagnóstico por imagen , Neurilemoma/cirugía , Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
Background: A new form of cell death, copper-dependent cell death (termed cuproptosis), was illustrated in a recent scientific study. However, the biological function or prognostic value of cuproptosis regulators in bladder cancer (BLCA) remains unknown. Materials and Methods: Sequencing data obtained from BLCA samples in TCGA and GEO databases were preprocessed for analysis. Biological function and immune cell infiltration levels evaluated by gene set variation analysis (GSVA) were employed to calculate enrichment scores. Iteration least absolute shrinkage and selection operator (LASSO) and COX regression model were employed to select feature genes and construct a novel cuproptosis-related (CR) score signature. The genomics of drug sensitivity in cancer (GDSC) and tumor immune dysfunction and exclusion (TIDE) analysis were used to predict the chemotherapy and immunotherapy efficacy for BLCA patients. The relative expression of the genes involved in the signature was also verified by real-time quantitative PCR (qRT-PCR) in cell lines and tissues. Results: Expression abundance and the prognostic value of cuproptosis regulators proved that cuproptosis might play a vital part in the carcinogenesis of BLCA. GSVA revealed that cuproptosis regulators might be associated with metabolism and metastasis-related pathways such as TGF-ß, protein secretion, oxidative Phosphorylation, MYC targets, MTORC1, and adipogenesis pathways. CR scores could predict the prognosis and evaluate the chemotherapy and immunotherapy efficacies of BLCA. CR scores were positively correlated with EMT, MYC, MTORC1, HEDGEHOG, and E2F signaling pathways; meanwhile, they were negatively correlated with several immune cell infiltration levels such as CD8+ T cells, γδT cells, and activated dendritic cells. Several GEO datasets were used to validate the power of prognostic prediction, and a nomogram was also established for clinical use. The expressions of DDX10, RBM34, and RPL17 were significantly higher in BLCA cell lines and tissues in comparison with those in the corresponding normal controls. Conclusion: Cuproptosis might play an essential role in the progression of BLCA. CR scores could be helpful in the investigation of prognostic prediction and therapeutic efficacy and could make contributions to further studies in BLCA.
RESUMEN
Background: Some VOCs are identified as endocrine-disrupting chemicals (EDCs), interfering with the effect of sex hormones. However, no studies focused on the common spectrum of environmental VOCs exposure affecting sex hormones in the average male population. Objectives: We aimed to explore the association between VOCs and sex hormones in American adult males using multiple statistical models. Methods: The generalized linear (GLM), eXtreme Gradient Boosting (XGBoost), weighted quantile sum (WQS), Bayesian kernel machine regression (BKMR) and stratified models were used to evaluate the associations between Specific Volatile Organic Compounds and sex hormones in American adult male from NHANES 2013-2016. Results: Pearson correlation model revealed the potential co-exposure pattern among VOCs. XGBoost algorithm models and the WQS model suggested the relative importance of VOCs. BKMR models reveal that co-exposure to the VOCs was associated with increased Testosterone (TT), Estradiol (E2), SHBG and decreased TT/E2. GLM models revealed specific VOC exposure as an independent risk factor causing male sex hormones disorders. Stratified analysis identified the high-risk group on the VOCs exposures. We found Blood 2,5-Dimethylfuran in VOCs was the most significant effect on sex hormones in male. Testosterone increased by 213.594 (ng/dL) (124.552, 302.636) and estradiol increased by 7.229 (pg/mL) for each additional unit of blood 2,5-Dimethylfuran (ng/mL). Conclusion: This study is an academic illustration of the association between VOCs exposure and sex hormones, suggesting that exposure to VOCs might be associated with sex hormone metabolic disorder in American adult males.