Actively extracting kidney stones combined dusting technique can improve SFR of moderate-complexity kidney stones in fURL.

PURPOSE: To evaluate the necessity and effectiveness of actively extracting kidney stones with different complexity that have been visually dusted in flexible ureteroscopic lithotripsy (fURL). METHODS: We retrospectively reviewed the medical records of patients who underwent fURL with dusting technique in established hospitals. A total of 535 cases were divided into the dusting group or the dusting plus basketing group according to the use of stone basket. Their characteristics and operative parameters were collected and analyzed. We used the R.I.R.S. scoring system to classify the complexity of kidney stones and divided these kidney stones into three subgroups, namely, mild-, moderate-, and severe-complexity group. And then, the effectiveness of stone basket in these subgroups was analyzed. RESULTS: Although using a stone basket significantly reduced re-operation rate (17.8% in dusting group versus 10.2% in dusting plus basketing group, p = 0.013), no significant difference on stone-free rate (SFR) and overall incidence of complications were noticed between groups. After we classified the complexity of kidney stones using the R.I.R.S. scoring system, we found a stone basket was helpful to improve SFR in kidney stones with moderate-complexity that had been visually dusted in fURL (73.5% in dusting group versus 87.3% in dusting plus basketing group, p = 0.002) but had limited influence on SFR in mild (93.8% in dusting group versus 92.6% in dusting plus basketing group, p = 0.783) or severe (28.5% in dusting group versus 34.0% in dusting plus basketing group, p = 0.598)-complexity kidney stones. CONCLUSION: The use of stone basket should be encouraged in moderate-complexity kidney stones which can be visually dusted in fURL.

Differential oral and gut microbial structure related to systemic metabolism in kidney stone patients.

OBJECTIVES: To investigate the role of the oral and gut microbiome related to systemic metabolism and clinical parameters in various types of kidney stone disease. PATIENTS AND METHODS: We conducted a case-control study by analyzing 16S rRNA and untargeted metabolomics profiling of 76 fecal, 68 saliva, 73 urine, and 43 serum samples from 76 participants aged 18-75 years old. The participants included 15 patients with uric acid stones, 41 patients with calcium oxalate stones, and 20 healthy controls. Correlations among microbiome, metabolism, and clinical parameters were identified through Spearman's correlation analysis. (Clinical trial No. ChiCTR2200055316). RESULTS: Patients with uric acid stones exhibited reduced richness and diversity in their microbiome, as well as altered composition in both oral and gut microbiome. Furthermore, their fecal samples showed lower relative abundances of Bacteroides and Lachnospiraceae, while their saliva samples showed higher relative abundances of Porphyromonas and Neisseria. Predicted KEGG metabolism pathways, including amino acid and fatty acid metabolisms, were significantly altered in subjects with uric acid stones. Oral, gut microbiota, and metabolism were also associated with low water intake and urine pH. The area under the curve (AUC) of the specific microbiota and metabolite prediction models was over 0.85. CONCLUSION: The structure and composition of the oral and gut microbiome in different types of kidney stone disease, the correlations between oral and gut microbiome, and the associations among oral and gut microbiota, systemic metabolism and clinical parameters imply an important role that the oral and gut microbiome may play in kidney stone disease.

Corrigendum: Systematic characterization of the clinical relevance of KPNA4 in pancreatic ductal adenocarcinoma.

[This corrects the article DOI: 10.3389/fonc.2022.834728.].

The development of prediction model on irradiation embitterment for low Cu RPV steels.

The development of prediction model on irradiation embitterment (PMIE) of reactor pressure vessel (RPV) is an important method for nuclear reactor long term operation. Based on the physical mechanism of RPV irradiation embrittlement, a preliminary model is determined and the critical threshold of Cu content of 0.072% is obtained according to this preliminary model. Then a prediction model named PMIE-2020 for low Cu RPV steels is developed. At last the residual, standard deviation and predicted values and test values distribution analysis are given. Simultaneously, a comparison between PMIE-2020 and other prediction model and irradiation data is provided. Results indicate that the predicted results of PMIE-2020 has no tendency with influence factors such as neutron fluence, flux, irradiation temperature, chemical elements Cu, P, Mn, Ni, Si. The residual standard deviation is 10.76 °C, which is lower than present prediction model. The distribution between predicted values of PMIE-2020 and test values are located the area near the 45° line. These results prove that the PMIE-2020 have high accuracy on irradiation embrittlement prediction.

Ureteroscopic and flexible ureteroscopic lithotripsy: continuation or discontinuation of anticoagulant or antiplatelet drugs? A Chinese survey among urologists.

PURPOSE: To evaluate the management of antithrombotic drugs made by different urologists before ureteroscopic lithotripsy and flexible ureteroscopy in stone patients undergoing active anticoagulant or antiplatelet therapy. METHODS: A survey was distributed to 613 urologists in China, which included personal work information and views on the management of anticoagulants (AC) or antiplatelet (AP) drugs during the perioperative period of ureteroscopic lithotripsy (URL) and flexible ureteroscopy (fURS). RESULTS: 20.5% of urologists believed that AP drugs could be continued and 14.7% believed that AC drugs could be continued. 26.1% of the urologists who participated in more than 100 ureteroscopic lithotripsy or flexible ureteroscopy surgeries each year believed that AP drugs could be continued and 19.1% believed that AC drugs could be continued, compared with 13.6% (P < 0.01) and 9.2% (P < 0.01) of the urologists who performed less than 100 surgeries. Among the urologists with more than 20 cases undergoing active AC or AP therapy per year, 25.9% thought that AP drugs could be continued and 19.7% thought that AC drugs could be continued, compared with 17.1% (P = 0.008) and 11.5% (P = 0.005) of the urologists with less than 20 cases. CONCLUSION: The decision on the continuation of AC or AP drugs before ureteroscopic and flexible ureteroscopic lithotripsy should be individualized. The experience in URL and fURS surgeries and in dealing with patients under AC or AP therapy is the influencing factor.

Identification of molecular subtypes based on chromatin regulator and tumor microenvironment infiltration characterization in papillary renal cell carcinoma.

BACKGROUND: Papillary renal cell carcinoma (pRCC) is the second most common histological type of renal cell carcinoma. The prognosis of local pRCC is better than that of ccRCC, but the situation has changed greatly after pRCC metastasis. Chromatin regulators (CRs) are indispensable in epigenetic regulation, and their abnormal expression in tumors leads to the occurrence and development of tumor. However, the role of CRs in pRCC has not been studied yet. MATERIALS AND METHODS: 291 samples were obtained from TCGA-KIPR cohort. Unsupervised clustering analysis was utilized to divide the patients of pRCC into two subtypes. Lasso Cox regression analysis was performed to construct a CRs_score model for predicting OS. The unique characteristics of different molecular subtypes were determined by TME cell infiltration analysis, GO and KEGG analysis and drug sensitivity analysis. We also carried out drug sensitivity experiments in vitro to verify the effect of signature genes on drug sensitivity to sunitinib. RESULTS: We described the transcriptional and genetic alteration of 19 prognosis-related CRs genes in 291 cases of TCGA-KIRP cohort. We identified two distinct molecular subtypes, which have significant differences in prognosis, clinicopathological features and tumor immune microenvironment (TME). Then, four signature genes were selected by lasso regression analysis to construct a CRs_score for predicting OS, and its predictive ability for patients with pRCC was verified. A nomogram was established to improve the clinical applicability of CRs_score. We found that there was a significant difference in the proportion of immune cell infiltration between high- and low-CRs_score. In addition, CRs_score was significantly correlated with chemosensitivity. Finally, we found that SK-RC-39 cell lines were more sensitive to sunitinib after knocking down the signature gene CDCA3, PDIA4, or SUCNR1. CONCLUSIONS: Our comprehensive analysis of CRs gene in pRCC showed that CRs gene plays a potential role in TME, prognosis and drug resistance in pRCC. These findings may lay a foundation for further study of the regulatory role of CRs gene in pRCC, and provide a new method for evaluating prognosis and developing more effective targeted therapy.

Upregulation of KLF14 expression attenuates kidney fibrosis by inducing PPARα-mediated fatty acid oxidation.

Tubulointerstitial fibrosis (TIF) is essential during the development of end-stage kidney disease (ESKD) and is associated with the impairment of fatty acid oxidation (FAO). Kruppel-like factor 14 (KLF14) is an important gene in lipid metabolism, but its role in TIF remains unknown. TGF-ß-stimulated HK-2 cells and mouse unilateral ureteral obstruction (UUO) were used as renal fibrosis models. The role of KLF14 in the process of renal fibrosis was verified by gene knockout mice, genetic or pharmacological interference in animal model and cell model respectively. In the current study, we found that KLF14 expression increased after activation of the TGF-ß signaling pathway during TIF. In KLF14-/- mice, more severe fibrosis was observed after unilateral ureteral obstruction (UUO) was induced. In human HK2 cells, knockdown of KLF14 led to more severe fibrosis induced by TGF-ß1, while overexpression of KLF14 partially attenuated this process. Specifically, KLF14 deficiency decreased mitochondrial FAO activity, resulting in lipid accumulation. Thus, the energy supply to the cells was insufficient, finally resulting in TIF. We further proved that KLF14 could target peroxisome proliferator activated receptor alpha (PPARα) as a transcriptional activator. This study identified the upregulation of KLF14 expression in response to kidney stress during the process of fibrosis. Upon TIF, the activated TGF-ß signaling pathway can enhance KLF14 expression, while the upregulation of KLF14 expression can decrease the degree of TIF by improving FAO activity in tubular epithelial cells and recovering the energy supply mediated by PPARα.

MPZL1 upregulation promotes tumor metastasis and correlates with unfavorable prognosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), accounting for 85% of all lung cancer, is one of the leading causes of cancer-related death worldwide. Previously, we demonstrated that MPZL1 gene amplification promotes liver cancer metastasis through activating Src/Cortactin pathway. However, the clinical relevance and biological roles of the MPZL1 gene in lung cancer are still unknown. Here, we found that MPZL1 expression upregulates in human NSCLC, which is partly due to the copy number amplification of this gene. Next, we observed that high MPZL1 expression correlates with unfavorable prognosis of NSCLC patients. We further demonstrated that ectopic MPZL1 overexpression promotes in vitro migratory but not proliferation and colony formation abilities of both H1299 and H460 cells. Consistently, we found that MPZL1 knockdown impairs the migratory abilities of A549 and H1775 cells. Moreover, we found that MPZL1 knockdown inhibits in vivo metastatic but not tumor growth abilities of the A549 cells. Additionally, a total of 297 differentially expressed genes (DEGs) were identified by RNA sequencing in A549 cells upon MPZL1 knockdown. By integrative analysis of DEGs regulated by MPZL1 in A549 cells and human NSCLC tissues, we revealed that COL11A1 is the potential effector gene that positively regulated by MPZL1 and correlates with poor prognosis of NSCLC patients. In conclusion, our work indicates that one of the mechanisms by which MPZL1 promotes NSCLC metastasis is through upregulating the COL11A1, and MPZL1 can be used as a biomarker to predict the prognosis of NSCLC patients.

Systematic Characterization of the Clinical Relevance of KPNA4 in Pancreatic Ductal Adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with poor prognosis. Karyopherin subunit alpha 4 (KPNA4) is a nuclear transport factor and plays tumor-promoting roles in multiple cancers. However, the roles of KPNA4 in PDAC still remain unknown. This study investigated the prognostic value of KPNA4 and its potential functions in PDAC and tumor microenvironment. Methods: LinkedOmics was utilized to screen genes with survival significance in PDAC. KPNA4 expression was analyzed using multiple datasets and verified in PDAC cells and clinical samples by qRT-PCR and immunohistochemistry. Clinical correlation and survival analyses were conducted to identify the clinical significance and prognostic value of KPNA4 in PDAC patients. Subsequently, KPNA4 was knocked down in PDAC cell lines, and CCK-8, colony formation and wound healing assays were performed to test the functions of KPNA4 in vitro. Immune infiltration analysis was performed to explore the potential roles of KPNA4 in the tumor microenvironment of PDAC. Moreover, functional analyses were conducted to explore the underlying mechanism of KPNA4 in the progression of PDAC. Results: We found KPNA4 was significantly upregulated in PDAC cells and tissues. KPNA4 expression was associated with tumor progression in PDAC patients. Survival analyses further revealed that KPNA4 could act as an independent predictor of unfavorable survival for PDAC patients. KPNA4 knockdown suppressed the viability, colony formation and migration of PDAC cells. Moreover, KPNA4 was correlated with immunosuppressive cells infiltration and T cell exhaustion in the tumor microenvironment of PDAC. Finally, functional analyses indicated the association of KPNA4 with focal adhesion kinase (FAK) signaling, and KPNA4 silencing significantly decreased the expression of FAK and PD-L1. Conclusions: This study revealed that KPNA4 is an independent prognostic biomarker for PDAC and plays a tumor-promoting role by facilitating proliferation and migration of cancer cells and participating in immune infiltration, which may be mediated by FAK signaling and PD-L1 expression. These results provide a novel and potential therapeutic target for pancreatic cancer.

Ferroptosis-related gene CHAC1 is a valid indicator for the poor prognosis of kidney renal clear cell carcinoma.

To evaluate the validity of CHAC1 for predicting the prognosis of kidney renal clear cell carcinoma (KIRC) and to explore its therapeutic potential for KIRC, we conducted several bioinformatic analyses using the sequencing data and clinical information derived from online databases. We found CHAC1 is down-regulated in KIRC samples when compared with normal samples but up-regulated in KIRC samples with relatively higher malignancy and later stages. Univariate cox analysis and multivariate cox regression analysis were conducted and the results revealed up-regulated CHAC1 is an independent risk factor for poor prognosis of KIRC. Further, the nomogram model based on the result of multivariate cox regression analysis was constructed and effectively predicted patients' 1-year, 3-year and 5-year survival respectively. The correlation analyses showed CHAC1 is associated with the immune pathway markers of memory B cell, natural killer cell and type1 T helper cell as well as the checkpoint genes like ADORA2A, CD200, CD44, CD70, HHLA2, NRP1, PDCD1LG2 and TNFRSF18. Furthermore, experiments in vitro indicated CHAC1 could induce cell death in KIRC cell lines but had limited influence on cell migration and cell invasion. In conclusion, CHAC1 is found a valid indicator for poor prognosis of kidney renal clear cell carcinoma.

Acyl-CoA Thioesterase 8 and 11 as Novel Biomarkers for Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is essentially a metabolic disorder characterized by reprogramming of several metabolic pathways. Acyl-coenzyme A thioesterases (ACOTs) are critical enzymes involved in fatty acid metabolism; however, the roles of ACOTs in ccRCC remain unclear. This study explored ACOTs expressions and their diagnostic and prognostic values in ccRCC. METHODS: Three online ccRCC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were utilized to measure the expressions of ACOTs in paired normal and tumor tissues. Receiver operating characteristic (ROC) curves were depicted to assess the diagnostic values of ACOTs in ccRCC. Quantitative real-time PCR and immunohistochemical analysis were performed to validate the ACOT11 expression in ccRCC cell lines and clinical samples. Survival curves and Cox regression analysis were used to evaluate the predictive values of ACOTs in clinical outcome of ccRCC patients. Functional enrichment analyses and correlation analysis were carried out to predict the potential roles of ACOT8 in tumorigenesis and progression of ccRCC. RESULTS: ACOT1/2/8/11/13 were found to be significantly downregulated in ccRCC samples. In particular, ACOT11 was decreased in almost every matched normal-tumor pair, and had extremely high diagnostic value as shown by ROC curve analysis (AUC = 0.964). The expression of ACOT11 was further verified in ccRCC cell lines and clinical samples at mRNA and protein levels. Furthermore, clinical correlation analysis and survival analysis indicated that ACOT8 was correlated with disease progression and was an independent predictor of unfavorable outcome in ccRCC. Moreover, functional analyses suggested potential roles of ACOT8 in the regulation of oxidative phosphorylation (OXPHOS), and correlation analysis revealed an association between ACOT8 and ferroptosis-related genes in ccRCC. CONCLUSION: Our study revealed that ACOT11 and ACOT8 are promising biomarkers for diagnosis and prognosis of ccRCC, respectively, and ACOT8 may affect ccRCC development and progression through the regulation of OXPHOS and ferroptosis. These findings may provide new strategies for precise diagnosis and personalized therapy of ccRCC.