TUBA1C is a potential new prognostic biomarker and promotes bladder urothelial carcinoma progression by regulating the cell cycle.

BACKGROUND: TUBA1C is an α-tubulin isoform involved in mitosis, and its dysregulation has been implicated in tumor progression. There is still no clear understanding of its role in bladder urothelial carcinoma (BLCA). METHODS: This study examined the differential expression of TUBA1C and its prognostic significance in bladder cancer based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) and also assessed the correlation of TUBA1C expression level with immune cell infiltration and immune checkpoint gene expression levels and the half-inhibitory concentration (IC50) of different chemotherapeutic agents. Immunotherapy response was estimated using the Tumor Immune Dysfunction and Exclusion (TIDE) algorithm. We detected TUBA1C expression in BLCA cells using PCR and Western blotting. Functional assays, including CCK-8, colony formation, transwell, apoptosis and cell cycle assays, were also performed to assess the oncogenic role of TUBA1C in BLCA. RESULT: In three independent public cohorts, TUBA1C was significantly upregulated in bladder tumor tissues, and high TUBA1C expression in bladder cancer was associated with a poorer outcome than low expression. TUBA1C was an independent prognostic risk factor for bladder cancer, and numerous immune checkpoint genes and infiltrating immune cells were associated with TUBA1C. TIDE analysis revealed that TUBA1C showed great potential for predicting the immunotherapy response in bladder cancer patients. In addition, drug sensitivity analysis revealed that high TUBA1C expression indicated sensitivity to multiple chemotherapeutic agents. Functional assays revealed that silencing TUBA1C significantly inhibited the proliferation, migration and invasion of BLCA cells and induced apoptosis and cell cycle arrest. CONCLUSION: The overexpression of TUBA1C in bladder cancer predicts a poor prognosis and may also be a potential immunotherapeutic target. As a prognostic marker, TUBA1C influences tumor progression by regulating the cell cycle.

Pioglitazone ameliorates ischemia/reperfusion-induced acute kidney injury via oxidative stress attenuation and NLRP3 inflammasome.

Acute kidney injury (AKI) induced by renal ischemia/reperfusion injury (IRI) is a severe clinical condition. ROS accumulation, antioxidant pathways deficiency, and inflammation are involved in IRI. Pioglitazone (Pio) exerts anti-inflammatory and antioxidant effects. The aim of this study was to explore the protective effects of pioglitazone against IRI-induced AKI. Pathogen-free Sprague-Dawley (SD) rats were arbitrarily divided into four groups: Sham operation group Control (CON) group, CON + Pio group, I/R + Saline group, and I/R + Pio group. In addition, HK-2 cells were subjected to hypoxia and reoxygenation to develop an H/R model for investigation of the protective mechanism of Pio. Pretreatment with pioglitazone in the model rats reduced urea nitrogen and creatinine levels, histopathological scores, and cytotoxicity after IRI. Pioglitazone treatment significantly attenuated renal cell apoptosis, decreased cytotoxicity, increased Bcl-2 expression, and downregulated Bax expression. Besides, the levels of ROS and inflammatory factors, including NLRP3, ASC, pro-IL-1ß, pro-caspase-1, cleaved-caspase-1, TNF-α, IL-6, and IL-1ß, in I/R rats and H/R cells were normalized by the pioglitazone treatment. Pioglitazone improved IRI-induced AKI by attenuating oxidative stress and NLRP3 inflammasome activation. Therefore, pioglitazone has the potential to serve as a novel agent for renal IRI treatment and prevention.

Overexpression of DBT suppresses the aggressiveness of renal clear cell carcinoma and correlates with immune infiltration.

Conventional therapy for kidney renal clear cell carcinoma (KIRC) is unpromising. The tumor microenvironment (TME) is intimately linked to the invasiveness of a variety of tumor forms, including KIRC. The purpose of this research is to establish the prognostic and immune-related significance of dihydrolipoamide branched chain transacylase E2 (DBT) in individuals with KIRC. In this investigation, we discovered that DBT expression was down-regulated in a range of human malignancies, and low DBT expression in KIRC was linked to higher-level clinicopathological characteristics as well as a poor prognosis for KIRC patients. Based on the findings of univariate and multivariate Cox regression analyses, DBT might be employed as an independent prognostic factor in KIRC patients. Furthermore, we developed a nomogram to better investigate DBT's predictive usefulness. To confirm DBT expression, we examined KIRC cell lines using RT-qPCR and Western blotting. We also examined the role of DBT in KIRC using colony formation, CCK-8, EdU, transwell, and wound healing assays. We discovered that plasmid-mediated overexpression of DBT in KIRC cells slowed cell proliferation and decreased migration and invasion. Multiple enrichment analyses revealed that DBT may be involved in processes and pathways related to immunotherapy and drug metabolism. We computed the immune infiltration score and discovered that the immunological score and the ESTIMATE score were both greater in the DBT low expression group. According to the CIBERSORT algorithm, DBT seems to promote anti-cancer immune responses in KIRC by activating M1 macrophages, mast cells, and dendritic cells while inhibiting regulatory T cells. Finally, in KIRC, DBT expression was found to be highly linked to immunological checkpoints, targeted medicines, and immunotherapeutic agents. Our findings suggest that DBT is a distinct predictive biomarker for KIRC patients, playing a significant role in the TME of KIRC and serving as a reference for the selection of targeted treatment and immunotherapy.

ACSL3 is a potential prognostic biomarker for immune infiltration in clear cell renal cell carcinoma.

Objective: Long-chain acyl-coenzyme A synthases (ACSLs) catalyze the activation of fatty acid and are often dysregulated in malignancies. The purpose of this research was to figure out the ACSL3's prognostic value and mechanism in clear cell renal cell carcinoma (ccRCC). Methods: The expression of ACSL3 in ccRCC was investigated in this work using data from the GEO, TCGA, Oncomine and HPA databases. The expression differences of ACSL3 in the cell lines were further detected by qPCR and Western blot. GEPIA, MethSurv, cBioPortal, and the TIMER were used to perform survival and correlation analysis on ACSL3. GO and KEGG analyses were carried out in R using clusterProfiler and GOplot. Protein-protein interactions (PPI) are constructed from Strings website, and the results were visualized in Cytoscape software. Results: The expression level of ACSL3 was significantly reduced in ccRCC tissues, and its mRNA and protein expression were also significantly lower in both renal cancer cell lines. ACSL3 is significantly related to clinical stage, OS, DFS, DNA methylation, and immune-cell infiltration. Conclusion: Our findings demonstrated that data mining was capable of eliciting information on ACSL3 levels and its role in genetic regulatory pathways in ccRCC.

New Prognostic Gene Signature and Immune Escape Mechanisms of Bladder Cancer.

Background: The immune microenvironment profoundly affects tumor prognosis and therapy. The present study aimed to reveal potential immune escape mechanisms and construct a novel prognostic signature via systematic bioinformatic analysis of the bladder cancer (BLCA) immune microenvironment. Patients and Methods: The transcriptomic data and clinicopathological information for patients with BLCA were obtained from The Cancer Genome Atlas (TCGA). Consensus clustering analysis based on the CIBERSORT and ESTIMATE algorithms was performed with patients with BLCA, which divided them into two clusters. Subsequently, the differentially expressed genes (DEGs) in the two were subjected to univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses to identify prognostic genes, which were used to construct a prognostic model. The predictive performance of the model was verified by receiver operating characteristic (ROC) and Kaplan-Meier (K-M) analyses. In addition, we analyzed the differentially altered immune cells, mutation burden, neoantigen load, and subclonal genome fraction between the two clusters to reveal the immune escape mechanism. Results: Based on the ESTIMATE and clustering analyses, patients with BLCA were classified into two heterogeneous clusters: ImmuneScoreH and ImmuneScoreL. Univariate Cox and LASSO regression analyses identified CD96 (HR = 0.83) and IBSP (HR = 1.09), which were used to construct a prognostic gene signature with significant predictive accuracy. Regarding potential immune escape mechanisms, ImmuneScoreH and ImmuneScoreL were characterized by inactivation of innate immune cell chemotaxis. In ImmuneScoreL, a low tumor antigen load might contribute to immune escape. ImmuneScoreH featured high expression of immune checkpoint molecules. Conclusion: CD96 and IBSP were considered prognostic factors for BLCA. Innate immune inactivation and a low tumor antigen load may be associated with immune escape mechanisms in both clusters. Our research complements the exploration of the immune microenvironment in BLCA.

Gender Differential Expression of AR/miR-21 Signaling Axis and Its Protective Effect on Renal Ischemia-Reperfusion Injury.

Objective: The aim of this study was to investigate gender differences after renal ischemia-reperfusion injury in mice and the effects of androgen receptor (AR) and microRNA-21 (miR-21) on apoptosis in renal ischemia-reperfusion injury. Methods: Renal ischemia-reperfusion injury model was induced by 45 min of bilateral renal artery ischemia and reperfusion. BALB/c mice were randomly divided into groups according to different experimental protocols. The levels of renal function were evaluated by serum creatinine and blood urea nitrogen. TUNEL staining was used to analyze the pathological changes and apoptosis levels of renal tissue, and western blotting and qPCR were used to detect the expressions of miR-21, AR, PDCD4 and caspase3. Results: After renal ischemia-reperfusion injury in mice with different genders, the levels of plasma urea nitrogen and creatinine in female and male mice increased, the histopathological score increased, and TUNEL staining in renal tissue indicated increased apoptosis. The expressions of miR-21, PDCD4, and active caspase-3 protein were up-regulated. The above trend was more pronounced in male mice, and a significant decrease in AR mRNA expression was detected. Silencing the expression of AR aggravated the decline of renal function and renal tubular injury after renal ischemia in mice. The expression of PDCD4 and active caspase-3 increased, while the level of miR-21 was correspondingly decreased. Up-regulation of miR-21 expression by pre-miR-21 could negatively regulate PDCD4, reduce the expression level of active caspase3, and yet induce AR expression accordingly. MiR-21 alleviated renal ischemia-reperfusion injury by inhibiting renal tubular epithelial cell apoptosis. The effect of antagomiR-21 was the opposite, which aggravated renal ischemia-reperfusion injury. Conclusion: There are gender differences in renal ischemia-reperfusion injury. Male mice are more susceptible to renal ischemia-reperfusion injury than female. Silencing AR expression or down-regulating the level of miR-21 can promote the expression of PDCD4 and apoptosis protein caspase3, thereby aggravating ischemia-reperfusion injury in mice. The protective effect of AR and miR-21 in renal ischemia-reperfusion injury has a certain synergy.

Identification of cuproptosis-related long noncoding RNA signature for predicting prognosis and immunotherapy response in bladder cancer.

Bladder cancer (BC) is the most common malignant tumour of the urinary system and one of the leading causes of cancer-related death. Cuproptosis is a novel form of programmed cell death, and its mechanism in tumours remains unclear. This study aimed to establish the prognostic signatures of cuproptosis-related lncRNAs and determine their clinical prognostic value. RNA sequencing data from The Cancer Genome Atlas were used to detect the expression levels of cuproptosis-related genes in BC. Cuproptosis-related lncRNAs linked to survival were identified using co-expression and univariate Cox regression. Furthermore, consensus cluster analysis divided the lncRNAs into two subtypes. Subsequently, we established a signature model consisting of seven cuproptosis-related lncRNAs (AC073534.2, AC021321.1, HYI-AS1, PPP1R26-AS1, AC010328.1, AC012568.1 and MIR4435-2Hg) using least absolute shrinkage and selection operator regression. Survival analysis based on risk score showed that the overall survival and progression-free survival of patients in the high-risk group were worse than those in the low-risk group. Multivariate Cox analysis demonstrated the independent prognostic potential of this signature model for patients with BC. Moreover, age and clinical stage were also significantly correlated with prognosis. The constructed nomogram plots revealed good predictive power for the prognosis of patients with BC and were validated using calibration plots. Additionally, enrichment analysis, Single sample gene set enrichment analysis and immune infiltration abundance analysis revealed significant differences in immune infiltration between the two risk groups, with high levels of immune cell subset infiltrations observed in the high-risk group accompanied by various immune pathway activation. Moreover, almost all the immune checkpoint genes showed high expression levels in the high-risk group. Moreover, TIDE analysis suggested that the high-risk group was more responsive to immunotherapy. Finally, eight drugs with low IC50 values were screened, which may prove to be beneficial for patients in the high-risk group.

Primitive neuroectodermal tumor of urinary bladder: A case report and literature review.

RATIONALE: Primitive neuroectodermal tumor (PNET) of the urinary bladder is a highly aggressive tumor with high local recurrence and distant metastasis rates in cases of incomplete excision. We report a case of a young female patient, in whom early laparoscopic radical cystectomy combined with standard lymph node dissection and a modified vincristine, doxorubicin hydrochloride, and cyclophosphamide (VAC) chemotherapy regimen was controversial. Because PNET of the urinary bladder is a rare malignancy, the standard treatment regimen has not yet been established. It is not clear whether surgery combined with postoperative chemotherapy for PNET patients may be superior to surgery alone on long term survival. PATIENT CONCERNS: The patient was a 45-year-old Chinese woman who complained of lower urinary tract symptoms, including urgency, frequency, and difficulty in urination, for 2 months. DIAGNOSES: PNET. INTERVENTIONS: The patient underwent laparoscopic radical cystectomy and standard lymph node dissection, combined with modified VAC chemotherapy regimens. OUTCOMES: After undergoing radical surgery in 2018, the patient completed 6 courses of adjuvant chemotherapy. Abdominal and thorax computed tomography scanning was performed 3, 6, 9, and 12 months after the surgery was completely free of tumor. The patient is still alive with no signs of recurrent disease 2 years after diagnosis. LESSONS: Radical surgery and standard lymphadenectomy combined with adjuvant chemotherapy may be essential to improve the prognosis of PNET of the urinary bladder.

Impact of neoadjuvant chemotherapy on survival prognosis and pathological downstaging in patients presenting with high-risk upper tract urothelial carcinoma: A protocol for systematic review and meta analysis.

PURPOSE: Controversy remains with using neoadjuvant chemotherapy (NAC) in patients with upper tract urothelial carcinoma (UTUC). Thus, we conducted a systematic review and meta-analysis of the peer-reviewed literature to assess the role of NAC in high-risk UTUC patients. METHODS: PubMed, EMBASE, and the Cochrane Library were the main sources of relevant studies. The search terms included: "Upper urothelial carcinoma"; "UTUC"; "Urinary tract cancer"; and "Transitional cell carcinoma" combined with "Neoadjuvant chemotherapy" and "adjuvant chemotherapy". We studied the relationship of UTUC and NAC. Overall survival, recurrent-free survival, cancer-specific survival and pathological response rate in patients treated with/without NAC before radical surgery were evaluated. RESULTS: Five trials were selected, and included 532 participants. Each of the included studies was retrospective. The combined analysis showed that when compared to controls, the pooled hazard ratios of overall survival, recurrence-free survival and cancer-specific survival were 0.47 (95% confidence interval [CI], 0.34-0.64; P < .00001); 0.50 (95% CI, 0.37-0.66; P < .00001); and 0.37 (95% CI, 0.25-0.54; P < .00001), respectively. It indicates the beneficial effects of NAC for the prognosis of survival in UTUC. Additionally, NAC was significantly associated with T-stage down-grading (T3/4 to ≤T2; OR=7.58 [4.66, 12.33]; P < .0001) and pathological lymph node status (N+ to N0; OR = 6.24 [2.57,15.15]; P < .00001). CONCLUSIONS: NAC treatment before radical nephron-ureterectomy significantly improves survival prognosis in patients with high-risk upper tract urothelial carcinoma. However, considerable prospective and randomized studies are needed to confirm this perspective.

Chinese Herbal Medicine for Dysfunctional Uterine Bleeding: a Meta-analysis.

We conducted a systematic review to evaluate the efficacy and safety of Chinese herbal medicine (CHM) for dysfunctional uterine bleeding (DUB) by performing a meta-analysis. Randomized controlled trials (RCTs) or quasi-RCTs comparing CHM vs no treatment, placebo, conventional western medicine (CWM), or general non-specific surgical treatment for DUB were identified by electronic and manual searches. Trials of CHM treatments with CWM treatments were compared with CWM treatments alone. Jadad scale and allocation concealment were used to assess the quality of included studies. Four RCTs or quasi-RCTs involving 525 patients were included. The methodological quality was poor in all trials except one trial. No serious adverse events were reported in the included studies. With the lack of trials comparing CHM with no treatment or placebo, it is impossible to accurately evaluate the efficacy of CHM. However, CHM in these studies seem to show an encouraging comparative effectiveness with CWM. More RCTs with a higher quality are required.