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This study utilized Mendelian randomization (MR) analysis and genome-wide association study (GWAS) data to investigate the association between commonly prescribed drugs and bladder cancer (BLCA) risk. Our results revealed that HMG CoA reductase (HMGCR) inhibitors, specifically simvastatin, are significantly associated with reduced BLCA risk. We further showed that simvastatin could significantly inhibit BLCA proliferation and epithelial-mesenchymal transition in animal models, with transcriptomic data identifying several pathways associated with these processes. Higher expression of HMGCR were linked with BLCA development and progression, and certain blood lipids, such as lipoprotein particles and very low density lipoprotein (VLDL) cholesterol, might influence BLCA risk. These findings suggested that HMGCR inhibitors, particularly simvastatin, could be potential treatment options or adjuvant therapies for BLCA.
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Estudo de Associação Genômica Ampla , Inibidores de Hidroximetilglutaril-CoA Redutases , Análise da Randomização Mendeliana , Sinvastatina , Neoplasias da Bexiga Urinária , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Animais , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Humanos , Sinvastatina/efeitos adversos , Transcriptoma/genética , Hidroximetilglutaril-CoA Redutases/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Polimorfismo de Nucleotídeo Único/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , CamundongosRESUMO
Tumor cells can survive when detached from the extracellular matrix (ECM) or lose cell-cell connections, a phenomenon known as anoikis-resistance (AR). AR is closely associated with tumor cell metastasis and recurrence, enabling tumor cells to disseminate, migrate, and invade after detachment. To address this issue, a novel intervention method combining intraoperative hemostasis with multifunctional nanozyme driven-enhanced chemodynamic therapy (ECDT) has been proposed, which holds the potential to weaken the AR capability of tumor cells and suppress tumor recurrence. Here, a nanocomposite containing a dendritic mesoporous nanoframework with Cu2+ was developed using an anion-assisted approach after surface PEG grafting and glucose oxidase (GOx) anchoring (DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG was further encapsulated in a thermal-sensitive hydrogel (H@DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG utilizes its high peroxidase (POD) activity to elevate intracellular ROS levels, thereby weakening the AR capability of bladder cancer cells. Additionally, through its excellent catalase (CAT) activity, DMSN-Cu@GOx/PEG converts the high level of hydrogen peroxide (H2O2) catalyzed by intracellular GOx into oxygen (O2), effectively alleviating tumor hypoxia, downregulating hypoxia-inducible factor-1α (HIF-1α) expression, inhibiting epithelial-mesenchymal transition (EMT) processes, and ultimately suppressing the migration and invasion of bladder cancer cells. Interestingly, in vivo results showed that the thermosensitive hydrogel H@DMSN-Cu@GOx/PEG could rapidly gel at body temperature, forming a gel film on wounds to eliminate residual tumor tissue after tumor resection surgery. Importantly, H@DMSN-Cu@GOx/PEG exhibited excellent hemostatic capabilities, effectively enhancing tissue coagulation during post-tumor resection surgery and mitigating the risk of cancer cell dissemination and recurrence due to surgical bleeding. Such hydrogels undoubtedly possess strong surgical application. Our developed novel nanosystem and hydrogel can inhibit the AR capability of tumor cells and prevent recurrence post-surgery. This study represents the first report of using dendritic mesoporous silica-based nanoreactors for inhibiting the AR capability of bladder cancer cells and suppressing tumor recurrence post-surgery, providing a new avenue for developing strategies to impede tumor recurrence after surgery.
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Glucose Oxidase , Hidrogéis , Hidrogéis/química , Hidrogéis/farmacologia , Animais , Humanos , Linhagem Celular Tumoral , Camundongos , Glucose Oxidase/farmacologia , Glucose Oxidase/metabolismo , Glucose Oxidase/química , Recidiva Local de Neoplasia , Camundongos Nus , Camundongos Endogâmicos BALB C , Nanocompostos/química , Nanocompostos/uso terapêutico , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Cobre/química , Cobre/farmacologia , Hemostasia/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologiaRESUMO
OBJECTIVE: In this study, we added laboratory animal ethics education into both didactic sessions and practical sessions the general surgery laboratory course, with the didactic sessions focus on teaching the fundamental principles of laboratory animal ethics, while the practical sessions emphasize the application of these principles in laboratory classes and have assessed the changes in medical students' perception of laboratory animal ethics following medical students exposure to such education. METHODS: One hundred and eighty-nine third-year medical students from Wuhan University's Second Clinical College completed a laboratory animal ethics awareness questionnaire and a laboratory animal ethics written examination before and after laboratory animal ethics education. RESULTS: After receiving laboratory animal ethics education, the percentage of students who supported euthanasia for the execution of animals and humane treatment of laboratory animals were 95.2% and 98.8%, respectively, which did not differ from the 94.9% and 96.4% observed before the education. Moreover, there was a notable increase in the proportion of students who knew about regulations related to laboratory animals (from 39.9% to 57.1%), welfare issues (from 31.9% to 50.0%), and the 3R principle (from 30.4% to 58.9%) post-education, all statistically significant at P < 0.05. Test scores also showed improvement, with students scoring (93.02 ± 11.65) after education compared to (67.83 ± 8.08) before, a statistically significant difference. CONCLUSIONS: This research helps to provide information for the good practices of laboratory animal ethics education. After receiving laboratory animal ethics education, students are better able to treat laboratory animals in a correct animal ethical manner. Laboratory animal ethics education helps improve students' knowledge of laboratory animal ethics. Students' perception towards how the laboratory animal ethics course should be delivered may vary. Still, new courses or better organized courses on laboratory animal ethics education are required in order to provide students an in-depth understanding.
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Estudantes de Medicina , Humanos , Estudantes de Medicina/psicologia , Animais , Educação de Graduação em Medicina , Masculino , Feminino , Currículo , Animais de Laboratório , Inquéritos e Questionários , Ciência dos Animais de Laboratório/educação , Ciência dos Animais de Laboratório/ética , Bem-Estar do Animal/ética , Experimentação Animal/ética , China , Avaliação Educacional , Adulto Jovem , ConscientizaçãoRESUMO
Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure-activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post-polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End-16, which demonstrates significant potential for treating bladder cancer (BLCA). End-16 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End-16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti-BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties.
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Cancer is a leading cause of death worldwide, and the identification of biomarkers and subtypes that can predict the long-term survival of cancer patients is essential for their risk stratification, treatment, and prognosis. However, there are currently no standardized tools for exploring cancer biomarkers or subtypes. In this study, we introduced Cancer Biomarker and Subtype Profiler (CBioProfiler), a web server and standalone application that includes two pipelines for analyzing cancer biomarkers and subtypes. The cancer biomarker pipeline consists of five modules for identifying and annotating cancer survival-related biomarkers using multiple survival-related machine learning algorithms. The cancer subtype pipeline includes three modules for data preprocessing, subtype identification using multiple unsupervised machine learning methods, as well as subtype evaluation and validation. CBioProfiler also includes CuratedCancerPrognosisData, a novel R package that integrates reviewed and curated gene expression and clinical data from 268 studies. These studies cover 43 common blood and solid tumors and draw upon 47,686 clinical samples. The web server is available at https://www.cbioprofiler.com/ and https://cbioprofiler.znhospital.cn/CBioProfiler/, and the standalone app and source code can be found at https://github.com/liuxiaoping2020/CBioProfiler.
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BACKGROUND: Many studies have investigated the transfer of skills between laparoscopic and robot-assisted surgery (RAS). These studies have considered time, error, and clinical outcomes in the assessment of skill transfer. However, little is known about the specific operations of the surgeon. Clutch control use is an important skill in RAS. Therefore, the present study aimed to propose a novel objective algorithm based on computer vision that can automatically evaluate a surgeon's clutch use. Additionally, the study aimed to evaluate the correlation between clutch metrics and surgical skill on different surgical robot platforms. METHODS: The robotic surgery training center of Wuhan University trained 30 laparoscopic surgeons as the study group between 2023 and 2024. Laparoscopic surgeons were trained by combining robotic simulator exercises and RAS animal experiments. During the training, video and hand movement data were collected. Hand movements identified by a skin-color model were combined with labeling information to classify clutch use. The metrics were validated on different robotic platforms (dv-Trainer, EDGE MP1000, Toumai™ MT1000, and DaVinci Xi system) and among surgeons with different surgical skill levels. RESULTS: On the robotic simulator, clutch accuracy in the expert group was significantly higher than in the study group for all tasks. No significant differences were observed in the number of clutches between the expert and study groups. In the RAS experiment, the number of clutches decreased significantly for both study and expert groups. The accuracy was maintained at a high level in the expert group but decreased rapidly in the study group. CONCLUSIONS: We proposed a new objective assessment of surgical skills, clutch use metrics, in cross-platform RAS. Additionally, we verified that the metrics significantly correlated with the surgical skill levels of the surgeons.
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Competência Clínica , Laparoscopia , Procedimentos Cirúrgicos Robóticos , Procedimentos Cirúrgicos Robóticos/educação , Humanos , Laparoscopia/educação , Laparoscopia/métodos , Animais , Treinamento por Simulação/métodos , Algoritmos , Cirurgiões/educaçãoRESUMO
This study aims to identify optimal parameters for using Thulium fiber lasers (TFL) in ureteral stone lithotripsy to ensure laser safety and maximize efficacy. Our goal is to improve the outcomes of single-use semi-rigid ureteroscopy for treating stones located in the proximal ureter. A clinically relevant thermal testing device was designed to investigate heating effects during TFL stone fragmentation. The device was utilized to identify safe power thresholds for TFL at various irrigation rates. Three other devices were used to assess varying pulse energy effects on stone fragmentation efficiency, dusting, retropulsion, and depth of tissue vaporization. Comparative experiments in fresh porcine renal units were performed to validate the efficacy and safety of optimal TFL parameters for semi-rigid ureteroscopy in proximal ureteral stone procedures. Our study found that the improved device generated a higher thermal effect. Furthermore, the safe power threshold for laser lithotripsy increased as the irrigation rate was raised. At an irrigation rate of 40 ml/min, it is safe to use an average power of less than 30 watts. Although increasing pulse energy has a progressively lower effect on fragmentation and dust removal efficiency, it did lead to a linear increase in stone displacement and tissue vaporization depth. Thermal testing showed 20 W (53.87 ± 2.67 °C) indicating potential urothelial damage. In our study of laser lithotripsy for proximal ureteral stones, the group treated with 0.3 J pulses had several advantages compared to the 0.8 J group: Fewer large fragments (> 4 mm): 0 vs. 1.67 fragments (1-2.25), p = 0.002, a lower number of collateral tissue injuries: 0.50 (0-1.25) vs. 2.67 (2-4), p = 0.011, and lower stone retropulsion grading: 0.83 (0.75-1) vs. 1.67 (1-2), p = 0.046. There was no significant difference in operating time between the groups (443.33 ± 78.30 s vs. 463.17 ± 75.15 s, p = 0.664). These findings suggest that TFL irradiation generates a greater thermal effect compared to non-irradiated stones. Furthermore, the thermal effect during laser lithotripsy is influenced by both power and irrigation flow rate. Our study suggests that using a power below 15 W with an irrigation flow rate of 20 ml/min is safe. Moreover, a pulse energy of 0.3 J appears to be optimal for achieving the best overall stone fragmentation effect.
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Litotripsia a Laser , Túlio , Cálculos Ureterais , Cálculos Ureterais/terapia , Cálculos Ureterais/cirurgia , Litotripsia a Laser/métodos , Litotripsia a Laser/instrumentação , Litotripsia a Laser/efeitos adversos , Animais , Suínos , Lasers de Estado Sólido/uso terapêutico , Ureteroscopia/métodos , Ureteroscopia/instrumentação , Ureteroscopia/efeitos adversosRESUMO
Acetyl-CoA acetyltransferase 1 (ACAT1) plays a significant role in the regulation of gene expression and tumorigenesis. However, the biological role of ACAT1 in bladder cancer (BLCA) has yet to be elucidated. This research aimed to elucidate the bioinformatics features and biological functions of ACAT1 in BLCA. Here, we demonstrate that ACAT1 is elevated in BLCA tissues and is correlated with specific clinicopathological features and an unfavorable prognosis for survival in BLCA patients. ACAT1 was identified as an independent risk factor in BLCA. Phenotypically, both in vitro and in vivo, ACAT1 knockdown suppressed BLCA cell proliferation and migration, while ACAT1 overexpression had the opposite effect. Mechanistic assays revealed that ACAT1 enhances BLCA cell proliferation and metastasis through the AKT/GSK3ß/c-Myc signaling pathway by modulating the cell cycle and EMT. Taken together, the results of our study reveal that ACAT1 is an oncogenic driver in BLCA that enhances tumor proliferation and metastasis, indicating its potential as a diagnostic and therapeutic target for this disease.
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Single-cell chromatin accessibility sequencing (scATAC-seq) reconstructs developmental trajectory by phenotypic similarity. However, inferring the exact developmental trajectory is challenging. Previous studies showed age-associated DNA methylation (DNAm) changes in specific genomic regions, termed clock-like differential methylation loci (ClockDML). Age-associated DNAm could either result from or result in chromatin accessibility changes at ClockDML. As cells undergo mitosis, the heterogeneity of chromatin accessibility on clock-like loci is reduced, providing a measure of mitotic age. In this study, we developed a method, called EpiTrace, that counts the fraction of opened clock-like loci from scATAC-seq data to determine cell age and perform lineage tracing in various cell lineages and animal species. It shows concordance with known developmental hierarchies, correlates well with DNAm-based clocks and is complementary with mutation-based lineage tracing, RNA velocity and stemness predictions. Applying EpiTrace to scATAC-seq data reveals biological insights with clinically relevant implications, ranging from hematopoiesis, organ development, tumor biology and immunity to cortical gyrification.
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Intratumor heterogeneity (ITH) of bladder cancer (BLCA) contributes to therapy resistance and immune evasion affecting clinical prognosis. The molecular and cellular mechanisms contributing to BLCA ITH generation remain elusive. It is found that a TM4SF1-positive cancer subpopulation (TPCS) can generate ITH in BLCA, evidenced by integrative single cell atlas analysis. Extensive profiling of the epigenome and transcriptome of all stages of BLCA revealed their evolutionary trajectories. Distinct ancestor cells gave rise to low-grade noninvasive and high-grade invasive BLCA. Epigenome reprograming led to transcriptional heterogeneity in BLCA. During early oncogenesis, epithelial-to-mesenchymal transition generated TPCS. TPCS has stem-cell-like properties and exhibited transcriptional plasticity, priming the development of transcriptionally heterogeneous descendent cell lineages. Moreover, TPCS prevalence in tumor is associated with advanced stage cancer and poor prognosis. The results of this study suggested that bladder cancer interacts with its environment by acquiring a stem cell-like epigenomic landscape, which might generate ITH without additional genetic diversification.
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Análise de Célula Única , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Análise de Célula Única/métodos , Epigênese Genética/genética , Heterogeneidade Genética , Transição Epitelial-Mesenquimal/genética , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/metabolismoRESUMO
The emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) needs booster vaccination. We evaluated the long-term safety and immunogenicity of heterologous boosting with a SARS-CoV-2 messenger RNA vaccine SYS6006. A total of 1000 participants aged 18 years or more who had received two (Group A) or three (Group B) doses of SARS-CoV-2 inactivated vaccine were enrolled and vaccinated with one dose of SYS6006 which was designed based on the prototype spike protein and introduced mutation sites. Adverse events (AEs) through 30 days and serious AEs during the study were collected. Live-virus and pseudovirus neutralizing antibody (Nab), binding antibody (immunoglobulin G [IgG]) and cellular immunity were tested through 180 days. Solicited all, injection-site and systemic AEs were reported by 618 (61.8%), 498 (49.8%), and 386 (38.6%) participants, respectively. Most AEs were grade 1. The two groups had similar safety profile. No vaccination-related SAEs were reported. Robust wild-type (WT) live-virus Nab response was elicited with peak geometric mean titers (GMTs) of 3769.5 (Group A) and 5994.7 (Group B) on day 14, corresponding to 1602.5- and 290.8-fold increase versus baseline, respectively. The BA.5 live-virus Nab GMTs were 87.7 (Group A) and 93.2 (Group B) on day 14. All participants seroconverted for WT live-virus Nab. Robust pseudovirus Nab and IgG responses to wild type and BA.5 were also elicited. ELISpot assay showed robust cellular immune response, which was not obviously affected by virus variation. In conclusion, SYS6006 heterologous boosting demonstrated long-term good safety and immunogenicity in participants who had received two or three doses of SARS-CoV-2 inactivated vaccine.
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Vacinas contra COVID-19 , COVID-19 , Imunogenicidade da Vacina , Humanos , Anticorpos Neutralizantes , Anticorpos Antivirais , China , COVID-19/prevenção & controle , Imunoglobulina G , Vacinas de mRNA , Vacinas de Produtos InativadosRESUMO
Urolithiasis is closely linked to lifestyle factors. However, the causal relationship and underlying mechanisms remain unclear. This study aims to investigate the relationship between lifestyle factors and the onset of urolithiasis and explore potential blood metabolite mediators and their role in mediating this relationship. In this study, we selected single nucleotide polymorphisms (SNPs) as instrumental variables if they exhibited significant associations with our exposures in genome-wide association studies (GWAS) (p < 5.0 × 10-8). Summary data for urolithiasis came from the FinnGen database, including 8597 cases and 333,128 controls. We employed multiple MR analysis methods to assess causal links between genetically predicted lifestyle factors and urolithiasis, as well as the mediating role of blood metabolites. A series of sensitivity and pleiotropy analyses were also conducted. Our results show that cigarettes smoked per day (odds ratio [OR] = 1.159, 95% confidence interval [CI] = 1.004-1.338, p = 0.044) and alcohol intake frequency (OR = 1.286, 95% CI = 1.056-1.565, p = 0.012) were positively associated with increased risk of urolithiasis, while tea intake (OR = 0.473, 95% CI = 0.299-0.784, p = 0.001) was positively associated with reduced risk of urolithiasis. Mediation analysis identifies blood metabolites capable of mediating the causal relationship between cigarettes smoked per day, tea intake and urolithiasis. We have come to the conclusion that blood metabolites serve as potential causal mediators of urolithiasis, underscoring the importance of early lifestyle interventions and metabolite monitoring in the prevention of urolithiasis.
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Estudo de Associação Genômica Ampla , Urolitíase , Humanos , Análise da Randomização Mendeliana , Estilo de Vida , Urolitíase/etiologia , Urolitíase/genética , CháRESUMO
We used Mendelian randomization (MR) to examine the relationship between smoking, various categories of blood lipids, and bladder cancer (BLCA). Data for this study were drawn from the genome-wide association studies of the GSCAN consortium (~1.2 million participants), a subset of the UK Biobank (~120,000 participants), and the FinnGen consortium (2,072 cases and 307,082 controls). Initially, we utilized inverse variance weighted (IVW), complementary and sensitivity analyses, multivariable MR, and meta-analysis to confirm the association between blood lipids and BLCA. We then performed mediation MR to elucidate the relationship between smoking, blood lipids, and BLCA. Our analysis identified five lipids, including triglycerides in very large HDL, cholesterol in small VLDL, free cholesterol in very large HDL, total free cholesterol, and apolipoprotein B, as having strong and inverse associations with BLCA. These lipids demonstrated no heterogeneity or pleiotropy and exhibited consistent direction and magnitude across IVW, weighted median, and MR-Egger analyses. Our mediation MR further revealed that triglycerides in very large HDL and cholesterol in small VLDL could reduce the impact of smoking on BLCA, mediating -4.3% and -4.5% of the effect, respectively. In conclusion, our study identified five lipids exhibiting a robust inverse relationship with BLCA, two of which can buffer the impact of smoking on BLCA.
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OBJECTIVE: To evaluate the clinical efficacy of a novel negative pressure ureteroscopic lithotripsy (NP-URL) compared to standard ureteroscopic lithotripsy (S-URL) for treating ureteral stones. METHODS: A total of 284 patients diagnosed with ureteral stones and who underwent ureteroscopic lithotripsy between December 2020 and May 2022 at our hospital were included in the study. Among them, 146 cases underwent NP-URL and 138 cases underwent S-URL. The negative pressure device used in NP-URL consists of a 5F ureteric catheter and a tee joint. We evaluated the operative duration, stone-free rate, incidence of postoperative complications, stone retropulsion rate, and adjunct procedure rate between the two groups. RESULTS: The mean operative duration was significantly shorter in the NP-URL group compared to the S-URL group (30.17 ± 5.84 minutes vs 34.84 ± 6.62 minutes; Pï¼.05). Additionally, the NP-URL group had a lower incidence of postoperative fever (1.4% vs 8.7%; Pï¼.05), reduced stone retropulsion rate (3.4% vs 11.6%; Pï¼.05), and a statistically lower rate of adjunct procedures (5.5% vs 14.5%, Pï¼.05). The NP-URL group also demonstrated a higher primary stone-free rate (91.8% vs 81.9%; Pï¼.05). However, there was no significant difference in the final stone-free rate between the NP-URL and S-URL groups (Pï¼.05). CONCLUSION: NP-URL potentially reduces operative duration, significantly decreases the incidence of postoperative complications, and achieves better primary stone-free rates compared to S-URL.
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Litotripsia , Duração da Cirurgia , Cálculos Ureterais , Ureteroscopia , Humanos , Cálculos Ureterais/terapia , Cálculos Ureterais/cirurgia , Ureteroscopia/métodos , Masculino , Feminino , Litotripsia/métodos , Litotripsia/instrumentação , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos RetrospectivosRESUMO
OBJECTIVES: To compare the efficacy and safety of thulium fiber laser (TFL) to holmium: YAG (Ho: YAG) laser in ureteroscopic lithotripsy for urolithiasis. METHODS: PubMed, Web of Science, Embase, CENTRAL, SinoMed, CNKI database, VIP and Wanfang Database were systematically searched for all relevant clinical trials until September 2023. References were explored to identify the relevant articles. Meta-analysis was carried out for the retrieved studies using RevMan5.4.1 software, and the risk ratio, mean difference and 95% confidence interval were expressed. Statistical significance was set at p < 0.05. The main outcomes of this meta-analysis were stone-free rate (SFR), perioperative outcomes and intraoperative or postoperative complications. RESULTS: Thirteen studies, including 1394 patients, were included. According to the results of pooled analysis, TFL was associated with significantly higher stone-free rate (SFR) [0.52, 95% CI (0.32, 0.85), P = 0.009], shorter operation time [-5.47, 95% CI (-8.86, -2.08), P = 0.002], and less stone migration [0.17, 95% CI (0.06, 0.50), P = 0.001]. However, there was no significant difference in terms of the laser time, duration of hospital stay, drop of hemoglobin level, total energy, postoperative ureteral stenting, the incidence of intraoperative complications or postoperative complications between TFL and Ho: YAGs. CONCLUSION: The findings of this study demonstrated several advantages of TFL in terms of higher SFR, shorter operative time and less stone migration. TRIAL REGISTRATION: The protocol of this systematic review was listed in PROSPERO ( www.crd.york.ac.uk/PROSPERO ) (Protocol number: CRD42022362550).
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Lasers de Estado Sólido , Litotripsia a Laser , Túlio , Ureteroscopia , Humanos , Ureteroscopia/métodos , Lasers de Estado Sólido/uso terapêutico , Litotripsia a Laser/métodos , Resultado do Tratamento , Urolitíase/cirurgia , Urolitíase/terapiaRESUMO
UPP1, a crucial pyrimidine metabolism-related enzyme, catalyzes the reversible phosphorylation of uridine to uracil and ribose-1-phosphate. However, the effects of UPP1 in bladder cancer (BLCA) have not been elucidated. AKT, which is activated mainly through dual phosphorylation (Thr308 and Ser473), promotes tumorigenesis by phosphorylating downstream substrates. This study demonstrated that UPP1 promotes BLCA cell proliferation, migration, invasion, and gemcitabine resistance by activating the AKT signaling pathway in vitro and in vivo. Additionally, UPP1 promoted AKT activation by facilitating the binding of AKT to PDK1 and PDK2 and the recruitment of phosphatidylinositol 3,4,5-triphosphate to AKT. Moreover, the beneficial effects of UPP1 on BLCA tumorigenesis were mitigated upon UPP1 mutation with Arg94 or MK2206 treatment (AKT-specific inhibitor). AKT overexpression or SC79 (AKT-specific activator) treatment restored tumor malignancy and drug resistance. Thus, this study revealed that UPP1 is a crucial oncogene and a potential therapeutic target for BLCA and that UPP1 activates the AKT signaling pathway and enhances tumorigenesis and drug resistance to gemcitabine.
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Gencitabina , Neoplasias da Bexiga Urinária , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Carcinogênese , Proliferação de CélulasRESUMO
PRKN is a key gene involved in mitophagy in Parkinson's disease. However, recent studies have demonstrated that it also plays a role in the development and metastasis of several types of cancers, both in a mitophagy-dependent and mitophagy-independent manner. Despite this, the potential effects and underlying mechanisms of Parkin on bladder cancer (BLCA) remain unknown. Therefore, in this study, we investigated the expression of Parkin in various BLCA cohorts derived from human. Here we show that PRKN expression was low and that PRKN acts as a tumor suppressor by inhibiting the proliferation and migration of BLCA cells in a mitophagy-independent manner. We further identified Catalase as a binding partner and substrate of Parkin, which is an important antioxidant enzyme that regulates intracellular ROS levels during cancer progression. Our data showed that knockdown of CAT led to increased intracellular ROS levels, which suppressed cell proliferation and migration. Conversely, upregulation of Catalase decreased intracellular ROS levels, promoting cell growth and migration. Importantly, we found that Parkin upregulation partially restored these effects. Moreover, we discovered that USP30, a known Parkin substrate, could deubiquitinate and stabilize Catalase. Overall, our study reveals a novel function of Parkin and identifies a potential therapeutic target in BLCA.
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Proteínas Quinases , Neoplasias da Bexiga Urinária , Humanos , Catalase/genética , Proteínas Quinases/genética , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Neoplasias da Bexiga Urinária/genéticaRESUMO
A hallmark of tumor cells, including bladder cancer (BLCA) cells, is metabolic reprogramming toward aerobic glycolysis (Warburg effect). The classical oncogene MYC, which is crucial in regulating glycolysis, is amplified and activated in BLCA. However, direct targeting of the c-Myc oncoprotein, which regulates glycolytic metabolism, presents great challenges and necessitates the discovery of a more clarified regulatory mechanism to develop selective targeted therapy. In this study, a siRNA library targeting deubiquitinases identified a candidate enzyme named USP43, which may regulate glycolytic metabolism and c-Myc transcriptional activity. Further investigation using functional assays and molecular studies revealed a USP43/c-Myc positive feedback loop that contributes to the progression of BLCA. Moreover, USP43 stabilizes c-Myc by deubiquitinating c-Myc at K148 and K289 primarily through deubiquitinase activity. Additionally, upregulation of USP43 protein in BLCA increased the chance of interaction with c-Myc and interfered with FBXW7 access and degradation of c-Myc. These findings suggest that USP43 is a potential therapeutic target for indirectly targeting glycolytic metabolism and the c-Myc oncoprotein consequently enhancing the efficacy of bladder cancer treatment.
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Proteínas Proto-Oncogênicas c-myc , Neoplasias da Bexiga Urinária , Humanos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Glicólise/fisiologia , RNA Interferente Pequeno/metabolismo , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Proliferação de CélulasRESUMO
Immunotherapy is a promising mainstream approach in anti-tumor therapy. It boasts advantages such as durable responses and lower side effects. However, there are still some limitations to be addressed. Current cancer immunotherapy has shown low response rates due to inadequate immunogenicity of certain tumor cells. To address these challenges, an acid-specific nanoreactor was developed, designed to induce immunogenicity by triggering ferroptosis in tumor cells. The nanoreactor integrates glucose oxidase (GOx) with a single-atom nanoenzyme (SAE), which exhibits high peroxidase (POD)-like activity in the acidic tumor microenvironment (TME). This specific acid-sensitivity transforms endogenous hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (â¢OH). GOx enhances the POD-like SAE activity in the nanoreactor by metabolizing glucose in tumor cells, producing gluconic acid and H2O2. This nanoreactor induces high levels of oxidative stress within tumor cells through the synergistic action of SAE and GOx, leading to depletion of GSH and subsequently triggering ferroptosis. The resulting nanoreactor-induced ferroptosis leads to immunogenic cell death (ICD) and significantly recruits T lymphocyte infiltration in tumor tissues. This study was designed with the concept of triggering ferroptosis-dependent ICD mechanism in bladder cancer cells, and developed an acid-specific nanoreactor to enhance the immunotherapy efficacy for bladder cancer, which introduces a novel approach for immunotherapy of bladder cancer.