ALKBH5 Suppresses Autophagy in Prostate Cancer Cells via Inhibiting m6A-Modification of TSPAN1 mRNA.

BACKGROUND: Activating autophagy promotes the invasion and progression of prostate cancer (PCa). Tetraspanin 1 (TSPAN1) has been found to promote autophagy flux and its up-regulation can enhance the migration of PCa cells. In addition, there is a binding relationship between TSPAN1 and the N6-methyladenosine (m6A) demethylase AlkB homolog 5 (ALKBH5). Therefore, we wanted to know whether ALKBH5 could affect autophagy by regulating TSPAN1 expression, and thereby participate in PCa malignant progression. METHODS: The expression of ALKBH5 and TSPAN1 in PCa was examined by quantitative real-time polymerase chain reaction (qRT-PCR), and the functional tests included cell counting kit-8 and 5-ethynyl-2'-deoxyuridine (EdU) staining assays. The expression of autophagy-related proteins was confirmed by western blot. Detection of the m6A level of TSPAN1 was performed using methylated RNA immunoprecipitation sequencing (MeRIP)-qPCR. RESULTS: ALKBH5 was significantly downregulated in PCa cells (LNCaP, DU145 and PC3 cells; p < 0.001). Overexpression of ALKBH5 inhibited cell viability and the number of EdU-positive cells (p < 0.01, p < 0.001), decreased the ratio of microtubule-associated protein light chain 3B (LC3B)-II/LC3B-I, and promoted P62 protein expression in LNCaP and DU145 cells (p < 0.001). The m6A level of TSPAN1 was high in LNCaP and DU145 cells, but was inhibited by the overexpression of ALKBH5 (p < 0.001). TSPAN1 overexpression promoted cell viability (p < 0.001), increased EdU-positive cells and the LC3B-II/LC3B-I ratio (p < 0.001, p < 0.05), reduced P62 protein expression (p < 0.05, p < 0.001), and reversed the regulation of ALKBH5 overexpression in LNCaP and DU145 cells (p < 0.01, p < 0.001). CONCLUSIONS: Promoting ALKBH5 expression may inhibit PCa autophagy by reducing the m6A level of TSPAN1.

The role of serum acylcarnitine profiling for the detection of multiple solid tumors in humans.

Metabolic reprogramming is an essential hallmark of cancer. Several studies have reported the dysregulation of acylcarnitine (ACar) metabolism in tumor cells, suggesting that changes in the blood ACar may be related to tumor growth. Accordingly, this study aimed to understand the alteration of serum ACar profiles in various solid tumors and explore the potential of differential serum ACars as diagnostic biomarkers. A series of 69 relatively abundant ACars were identified via untargeted analysis. Then, targeted metabolomics was used to describe the metabolic alterations in ACars between normal controls and patients with six types of solid tumors. The results suggested that changes in ACars correlated with their carbon chain length and saturation. The six tumor types had highly similar ACar metabolic profiles, indicating similar fatty acid oxidation (FAO) metabolic pathways. Moreover, the receiver operating curve analysis of differential ACars showed that 16 ACars (C8-C14) had high diagnostic capability towards the studied solid tumors. Specifically, the area under the curve of ACar 10:2 isomer2 and ACar 12:2 isomer2 was greater than 0.95. In conclusion, the marked decrease in the levels of medium- and long-chain ACars (C8-C18) in the six solid tumors suggests that they may have similar FAO-based metabolic pathways, which could afford a common target for cancer therapy. Additionally, 16 ACars (C8-C14) were identified as potential biomarkers for diagnosing six types of solid tumors.

Ferroptosis heterogeneity within the tumor microenvironment revealed a genetic blueprint of breast cancer.

The tumor microenvironment (TME) significantly influences disease progression through immune infiltration, while ferroptosis, a recently discovered cell death mechanism, plays a crucial role in tumor suppression. However, its role in breast cancer is not clear. In this study, we analyzed bulk RNA and single-cell RNA sequencing data from 1217 samples, including 1104 breast cancer patients and 113 controls, to identify ferroptosis-related genes (FRGs) and construct a prognostic model. Using univariate cox regression, LASSO regression, and multivariate cox regression analysis, we discovered 21 FRGs and 3 TME-related immune cell types with prognostic value. Dimensionality reduction clustering and visualization were performed using the UMAP method, while the immune infiltration process was calculated with the TIP online tool. We employed GSEA enrichment analysis, WGCNA clustering analysis, and correlation analysis to examine functional differences, and the mutation analysis of the best and worst prognosis groups was conducted using the maftools package. Our findings revealed that knocking down the expression of the hub gene SLC39A7 significantly impacted cancer cell apoptosis and combining ferroptosis and TME scores yielded high prognostic power. Epithelial cells and B cells exhibited higher ferroptosis scores, which were independently associated with immune checkpoint blockade (ICB) response and ICB gene expression. This study provides a foundation for further exploration of the relationship between ferroptosis and ICB response in breast cancer. In conclusion, we developed a prognostic model based on ferroptosis and infiltrated immune cells that effectively stratified breast cancer patients and demonstrated the role of SLC39A7 in breast cancer pathogenesis through the regulation of apoptosis.

KMT2A maintains stemness of gastric cancer cells through regulating Wnt/ß-catenin signaling-activated transcriptional factor KLF11.

The molecular mechanisms of epigenetic regulation in gastric cancer development are not yet well established. In this study, we demonstrated that KMT2A was highly expressed in gastric cancer and associated with poor outcomes of patients and revealed that KMT2A was significantly associated with stemness and increased nuclear ß-catenin in gastric cancer. Mechanistically, KMT2A activated the translocation of ß-catenin into the nucleus of gastric cancer cells, and then, ß-catenin served as a coactivator of KLF11, which promoted the expression of specific gastric cancer stemness-related molecules, including SOX2 and FOXM1. Together, KMT2A is an important epigenetic regulator of gastric cancer stemness, which provides a novel insight to the potential application of targeting against KMT2A in treating gastric cancer.

Efficacy of emergency extracorporeal shock wave lithotripsy in the treatment of ureteral stones: a meta-analysis.

OBJECTIVE: To compare the clinical efficiency and safety of emergency extracorporeal shock wave lithotripsy (eESWL) and delayed extracorporeal shock wave lithotripsy (dESWL) in the treatment of ureteral stones. METHODS: Cochrane Library, PubMed, Google Scholar, and Web of Science were searched from January 1, 1992 to September 30, 2022, and all comparative studies involving eESWL and dESWL for ureteral calculi were included. Statistical analysis was performed using Review Manager 5.3 software. Funnel plot was used to evaluated publication bias. RESULTS: A total of 9 articles involving 976 patients diagnosed with ureteral stones were included. The results showed that the stone-free rate (SFR) after four weeks was significantly higher in the eESWL group than in the dESWL group [relative risk (RR) = 1.22, 95% confidence interval (CI): 1.13-1.32, P < 0.01]. In subgroup analysis of different stone locations, proximal ureteral calculi [RR = 1.25, 95% CI: 1.14-1.38, P < 0.01] and mid-to-distal ureteral calculi [RR = 1.18, 95% CI: 1.03-1.34, P < 0.05] all showed a higher SFR in the eESWL group. eESWL significantly shortened the stone-free time(SFT) [mean difference (MD) = -5.75, 95% CI: -9.33 to -2.17, P < 0.01]. In addition, eESWL significantly reduced auxiliary procedures [RR = 0.53, 95% CI: 0.40-0.70, P < 0.01]. No significant difference in complications was found between the two groups [RR = 0.90, 95% CI: 0.69-1.16, P > 0.05]. CONCLUSION: eESWL can significantly improve SFR, shorten SFT, and reduce auxiliary procedures.

Assessing Distinct Cognitive Workload Levels Associated with Unambiguous and Ambiguous Pronoun Resolutions in Human-Machine Interactions.

Pronoun resolution plays an important role in language comprehension. However, little is known about its recruited cognitive mechanisms. Our investigation aims to explore the cognitive mechanisms underlying various types of pronoun resolution in Chinese using an electroencephalograph (EEG). We used three convolutional neural networks (CNNs)-LeNeT-5, GoogleNet, and EffifcientNet-to discover high-level feature abstractions of the EEG spatial topologies. The output of the three models was then fused using different scales by principal component analysis (PCA) to achieve cognitive workload classification. Overall, the workload classification rate by fusing three deep networks can be achieved at 55-63% in a participant-specific manner. We provide evidence that both the behavioral indicator of reaction time and the neural indicator of cognitive workload collected during pronoun resolution vary depending on the type of the pronoun. We observed an increase in reaction time accompanied by a decrease of the theta power while participants were processing ambiguous pronoun resolution compared to unambiguous controls. We propose that ambiguous pronoun resolution involves a more time-consuming yet more flexible cognitive mechanism, consistent with the predictions of the decision-making framework from an influential pragmatic tradition. Our results extend previous research that the cognitive states of resolving ambiguous and unambiguous pronouns are differentiated, indicating that cognitive workload evaluated using the method of machine learning for analysis of EEG signals acts as a complementary indicator for studying pronoun resolution and serves as an important inspiration for human-machine interaction.

Comparison of Retzius-sparing robot-assisted laparoscopic radical prostatectomy vs standard robot-assisted radical prostatectomy: a meta-analysis.

BACKGROUND: To compare the postoperative continence and clinical outcomes of Retzius-sparing robot-assisted laparoscopic radical prostatectomy (RS-RALP) with non-RS RALP for patients with prostate cancer. METHODS: We searched PUBMED, EMBASE and the Cochrane Central Register from 1999 to 2019 for studies comparing RS-RALP to non-RS RALP for the treatment of prostate cancer. We used RevMan 5.2 to pool the data. RESULTS: A total of seven studies involving 1620 patients were included in our meta-analysis. No significant difference was found in positive surgical margins (PSM), bilateral nerve-sparing, postoperative hernia, complications, blood loss, or operative time. Postoperative continence was better with RS-RALP compared with non-RS RALP (OR = 1.02, OR: 2.86, 95% CI 1.94-4.20, p < 0.05). CONCLUSIONS: RS-RALP had a better recovery of postoperative continence than non-RS RALP. The perioperative outcomes were comparable for the two methods.

[A multicenter survey of antibiotic use in very and extremely low birth weight infants in Hunan Province].

OBJECTIVE: To investigate the current status of antibiotic use for very and extremely low birth weight (VLBW/ELBW) infants in neonatal intensive care units (NICUs) of Hunan Province. METHODS: The use of antibiotics was investigated in multiple level 3 NICUs of Hunan Province for VLBW and ELBW infants born between January, 2017 and December, 2017. RESULTS: The clinical data of 1 442 VLBW/ELBW infants were collected from 24 NICUs in 2017. The median antibiotic use duration was 17 days (range: 0-86 days), accounting for 53.0% of the total length of hospital stay. The highest duration of antibiotic use was up to 91.4% of the total length of hospital stay, with the lowest at 14.6%. In 16 out of 24 NICUs, the antibiotic use duration was accounted for more than 50.0% of the hospitalization days. There were 113 cases with positive bacterial culture grown in blood or cerebrospinal fluid, making the positive rate of overall bacterial culture as 7.84%. The positive rate of bacterial culture in different NICUs was significantly different from 0% to 14.9%. The common isolated bacterial pathogens Klebsiella pneumoniae was 29 cases (25.7%); Escherichia coli 12 cases (10.6%); Staphylococcus aureus 3 cases (2.7%). The most commonly used antibiotics were third-generation of cephalosporins, accounting for 41.00% of the total antibiotics, followed by penicillins, accounting for 32.10%, and followed by carbapenems, accounting for 13.15%. The proportion of antibiotic use time was negatively correlated with birth weight Z-score and the change in weight Z-score between birth and hospital discharge (rs=-0.095, -0.151 respectively, P<0.01), positively correlated with death/withdrawal of care (rs=0.196, P<0.01). CONCLUSIONS: Antibiotics used for VLBW/ELBW infants in NICUs of Hunan Province are obviously prolonged in many NICUs. The proportion of routine use of third-generation of cephalosporins and carbapenems antibiotics is high among the NICUs.

Comparison of the retroperitoneal versus Transperitoneal laparoscopic Adrenalectomy perioperative outcomes and safety for Pheochromocytoma: a meta-analysis.

BACKGROUND: To compare the perioperative outcomes and safety of transperitoneal laparoscopic adrenalectomy with those of retroperitoneal laparoscopic adrenalectomy for patients with pheochromocytoma. METHODS: We searched PubMed, EMBASE and the Cochrane Central Register for studies from 1999 to 2019 to assess the perioperative outcomes and safety of transperitoneal laparoscopic adrenalectomy and the retroperitoneal approach for laparoscopic adrenalectomy in patients with pheochromocytoma. After data extraction and quality assessments, we used RevMan 5.2 to pool the data. RESULTS: Four retrospective studies were obtained in our meta-analysis. Patients who underwent retroperitoneal laparoscopic adrenalectomy were associated with shorter operative time (WMD: 34.91, 95% CI: 27.02 to 42.80, I2 = 15%; p < 0.01), less intraoperative blood loss (WMD: 139.32, 95% CI: 125.38 to 153.26, I2 = 0, p < 0.01), and a shorter hospital stay (WMD: 2, 95% CI: 1.18 to 2.82, I2 = 82%, p < 0.01) than patients who underwent transperitoneal laparoscopic adrenalectomy. No significant differences were found in the complication rate (OR: 1.58, 95% CI: 0.58 to 4.33, I2 = 0; p = 0.38) or in the incidence of hemodynamic crisis (OR: 0.74, 95% CI: 0.19 to 2.94, p = 0.67) between the two groups. CONCLUSION: Retroperitoneal laparoscopic adrenalectomy could achieve better perioperative outcomes than the transperitoneal approach for patients with pheochromocytoma.

A multidisciplinary clinic approach to improve physician-related diagnostic delay for patients with axial spondyloarthritis: a retrospective study.

OBJECTIVE: To assess the diagnostic delay (DD) and physician-related DD (pDD) in patients with axial spondyloarthritis (SpA) and the potential benefits of a multidisciplinary clinic (MDC) approach. METHODS: A retrospective study was undertaken among patients with axial SpA, which aimed to analyse DD, pDD and their risk factors. The influence of pDD on disease outcomes was examined. The pDDs among consecutive SpA patients in an MDC cohort were compared with propensity score matched historical controls (1:1). RESULTS: A total of 208 patients with axial SpA formed the historical control group and 49 patients with axial SpA formed the MDC cohort after introduction of the MDC. The median DD and pDD in the historical controls were 25.5 and 10.0 months, respectively. A cut-off of pDD > 4 months was associated with more active disease and functional impairment. An initial visit to a non-rheumatologist was the most significant risk factor for pDD. Following MDC introduction, the median pDD decreased from 13 months to 1 month after adjustments were made for confounders such as sex, education level, history of smoking, human leukocyte antigen-B27 status and SpA/ankylosing spondylitis classification criteria. CONCLUSION: The MDC was a promising approach that resulted in a reduced pDD among patients with axial SpA.

Preoperative Th1/Th2 and related cytokines: Prediction value in postoperative febrile UTI after ureteroscopy in patients with ureteral calculi.

BACKGROUND: The topic of whether preoperative Th1/Th2 cells and their related factors have a predictive value for postoperative febrile urinary tract infection (UTI) in patients with ureteral calculi has not been explored. OBJECTIVES: The objective of this study was to investigate the role of preoperative Th1/Th2 cells and related cytokines in the prediction of postoperative febrile UTI after ureteroscopy in patients with ureteral calculi. MATERIAL AND METHODS: One hundred sixty patients who underwent ureteroscopic pneumatic lithotripsy in the Affiliated Hospital of Hangzhou Normal University (China) were recruited and divided into febrile UTI group (n = 78) and non-UTI group (n = 82). Flow cytometry was used to detect the proportions of Th1 and Th2 cells (Th1% and Th2%). Detection of Th1/Th2 cell-related cytokines was conducted using enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase chain reaction (qRT-PCR) was applied to measure the expression of T-bet and GATA3. RESULTS: Compared with patients in non-UTI group, those in febrile UTI group had significantly increased proportions of Th2 cells, levels of Th2 cytokines (interleukin (IL)-4, IL-10 and IL-5), and mRNA expression of Th2-associated transcription factor GATA3 (all p < 0.05). In addition, the Th1/Th2 ratio of febrile UTI group was significantly lower than that of non-UTI group (p < 0.001). Receiver operating characteristic (ROC) curve analysis showed that the accuracy rate of Th2%, Th1/Th2 ratio, and IL-4, IL-10 and IL-5 levels for the diagnosis of postoperative febrile UTI in patients with ureteral calculi was 90.63%, 85.00%, 72.50%, 87.50%, and 91.88%, respectively, and their combined diagnostic sensitivity was 97.4% with specificity as high as 100%. CONCLUSIONS: Perioperative Th2 dominance was correlated with the risk of postoperative febrile UTI after ureterscopy in patients with ureteral calculi, which can provide clinical guidance for the development of individualized treatment.

Long Non-Coding RNA Cancer Susceptibility Candidate 2a (CASC2a) Is a Marker of Early Recurrence After Radical Cystectomy in Patients with Urothelial Carcinoma of the Bladder.

BACKGROUND The aim of this study was to investigate the expression of long non-coding RNAs (lncRNA) cancer susceptibility candidate 2a (CASC2a) in patients with urothelial carcinoma of the bladder (UCB) and its predictive value in the recurrence of UCB after radical cystectomy (RC). MATERIAL AND METHODS Tumor and paired adjacent normal tissues were obtained from 112 patients with UCB who underwent RC in our hospital from March 2010 to March 2012. The expression of CASC2a was evaluated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and fluorescence in situ hybridization (FISH). RESULTS CASC2a was down-regulated in UCB tissues, and was highly negatively correlated with the pT, pN, tumor size, and lymphovascular invasion (LVI). The sensitivities of CASC2a for diagnosing UCB and its recurrence after RC were 89.30% and 81.55%, respectively, and the specificities were 71.43% and 58.21%, respectively. Patients with a high expression of CASC2a had a higher 5-year recurrence-free survival rate than those with low expression of CASC2a. Kaplan-Meier survival analysis demonstrated that the pT, pN, tumor grade, tumor size, concomitant carcinoma in situ (CIS), LVI, soft tissue surgical margin (STSM), and CASC2a expression were related to the recurrence in patients undergoing RC for UCB. Cox proportional hazard model analysis showed that CASC2 expression, pT4, lymph node metastasis, and CIS were independent risk factors. CONCLUSIONS CASC2a was down-regulated in patients with UCB, and was associated with the risk of recurrence among patients undergoing RC, indicating that lncRNAs could act as predictive biomarkers and potential therapeutic targets in bladder cancer, including CASC2a.