Risk assessment of bridge construction investigated using random forest algorithm.

Bridge construction collapse is one of the most common bridge safety accidents. At present, evaluation results are often affected by the ability and experience of the assessor. Therefore, it is difficult to quickly, accurately and effectively evaluate the risk in the process of bridge construction. Moreover, key factors that can prevent accidents can hardly find from the existing bridge construction safety management and evaluation method. This paper analyzes and classifies the artificial and environmental risk factors that affect the bridge construction stage, and establishes 26 risk factors in 5 categories according to the characteristics of bridge construction and the actual situation of the project. Random forest (RF) algorithm is a non-parametric machine learning method based on decision tree, which does not need to be scored by experts in advance and avoids the influence of subjective factors. Compared with other analysis methods, random forest algorithm has the advantages of accurate and robust risk assessment results. Based on the advantages of random forest algorithm and the characteristics of bridge construction risk, this paper uses random forest algorithm to evaluate the bridge construction risk, and ranks the importance of indicators, and identify the index that has a greater influence on the risk. In order to verify the applicability and feasibility of the proposed method, a typical urban complex pedestrian bridge was taken as an example for actual engineering evaluation and verification. The results obtained are basically consistent with the actual risk assessment results of the pedestrian bridge.

Selenomethionine Promotes Milk Protein and Fat Synthesis and Proliferation of Mammary Epithelial Cells through the GPR37-mTOR-S6K1 Signaling.

Selenomethionine (SeMet) is an important nutrient, but its role in milk synthesis and the GPCR related to SeMet sensing is still largely unknown. Here, we determined the dose-dependent role of SeMet on milk protein and fat synthesis and proliferation of mammary epithelial cells (MECs), and we also uncovered the GPCR-mediating SeMet function. At 24 h postdelivery, lactating mother mice were fed a maintenance diet supplemented with 0, 5, 10, 20, 40, and 80 mg/kg SeMet, and the feeding process lasted for 18 days. The 10 mg/kg group had the best increase in milk production, weight gain of offspring mice, and mammary gland weight and acinar size, whereas a higher concentration of SeMet gradually decreased the weight gain of the offspring mice and showed toxic effects. Transcriptome sequencing was performed to find the differentially expressed genes (DEGs) between the mammary gland tissues of mother mice in the 10 mg/kg SeMet treatment group and the control group. A total of 258 DEGs were screened out, including 82 highly expressed genes including GPR37 and 176 lowly expressed genes. SeMet increased milk protein and fat synthesis in HC11 cells and cell proliferation, mTOR and S6K1 phosphorylation, and expression of GPR37 in a dose-dependent manner. GPR37 knockdown decreased milk protein and fat synthesis in HC11 cells and cell proliferation and blocked SeMet stimulation on mTOR and S6K1 phosphorylation. Taken together, our data demonstrate that SeMet can promote milk protein and fat synthesis and proliferation of MECs and functions through the GPR37-mTOR-S6K1 signaling pathway.

Analysis of risk factors for persistent PSA after radical prostatectomy: results from a high-volume center in Southeast China.

BACKGROUND: For localized prostate cancer, a comprehensive treatment approach centered around radical prostatectomy (RP) is often their optimal choice. Successful RP can typically reduce prostate-specific antigen (PSA) levels to below 0.1 ng/mL within 6 to 8 weeks postoperatively. However, in clinical practice, 5 to 24% of patients may have a PSA ≥ 0.1 ng/mL at 6 to 8 weeks after surgery, a phenomenon known as PSA persistence. Many studies based on data from Europe and United States have shown an association between PSA persistence and poor postoperative outcomes, further analyzing the risk factors for PSA persistence. However, relevant research based on data from China remains scarce. METHODS: Retrospective study of 1,347 prostate cancer patients who underwent RP at the First Affiliated Hospital of Zhejiang University School of Medicine from July 15, 2016, to August 31, 2022. Based on inclusion criteria, univariate and multivariate logistic regression analyses were conducted to explore the independent risk factors for persistent PSA. RESULTS: Among the 826 prostate cancer patients after RP, 124 patients experienced persistent PSA. In univariate logistic regression analysis, robot-assisted laparoscopic radical prostatectomy (RARP), preoperative PSA, high-risk group, preoperative International Society of Urological Pathology (ISUP) grades 2-5, postoperative ISUP grades 3-5, percentage of positive cores, cT3, ≥pT3b, extracapsular extension (EPE), seminal vesicle invasion (SVI), positive surgical margins (PSM) and Prostate Specific Antigen Density (PSAD) were all significantly associated with PSA persistence after RP (P < 0.05). In terms of surgical approach, RARP was considered a protective factor against postoperative PSA persistence (OR:0.53, p < 0.05). In multivariate logistic regression analysis, preoperative ISUP grade 4, percentage of positive cores and PSM were independent risk factors of PSA persistence after RP (P < 0.05). CONCLUSION: Preoperative PSA, high-risk group, preoperative ISUP grades 2-5, postoperative ISUP grades 3-5, percentage of positive cores, cT3, ≥pT3b, EPE, SVI, PSM and PSAD were independent risk factors for PSA persistence in prostate cancer patients after RP. This provides assistance for early monitoring and treatment of patients at high risk of persistent PSA in clinical practice.

Circular RNA IGF1R Promotes Cardiac Repair via Activating ß-Catenin Signaling by Interacting with DDX5 in Mice after Ischemic Insults.

The potential of circular RNAs (circRNAs) as biomarkers and therapeutic targets is becoming increasingly evident, yet their roles in cardiac regeneration and myocardial renewal remain largely unexplored. Here, we investigated the function of circIGF1R and related mechanisms in cardiac regeneration. Through analysis of circRNA sequencing data from neonatal and adult cardiomyocytes, circRNAs associated with regeneration were identified. Our data showed that circIGF1R expression was high in neonatal hearts, decreased with postnatal maturation, and up-regulated after cardiac injury. The elevation was validated in patients diagnosed with acute myocardial infarction (MI) within 1 week. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and myocardial tissue from mice after apical resection and MI, we observed that circIGF1R overexpression enhanced cardiomyocyte proliferation, reduced apoptosis, and mitigated cardiac dysfunction and fibrosis, while circIGF1R knockdown impeded endogenous cardiac renewal. Mechanistically, we identified circIGF1R binding proteins through circRNA precipitation followed by mass spectrometry. RNA pull-down Western blot and RNA immunoprecipitation demonstrated that circIGF1R directly interacted with DDX5 and augmented its protein level by suppressing ubiquitin-dependent degradation. This subsequently triggered the ß-catenin signaling pathway, leading to the transcriptional activation of cyclin D1 and c-Myc. The roles of circIGF1R and DDX5 in cardiac regeneration were further substantiated through site-directed mutagenesis and rescue experiments. In conclusion, our study highlights the pivotal role of circIGF1R in facilitating heart regeneration and repair after ischemic insults. The circIGF1R/DDX5/ß-catenin axis emerges as a novel therapeutic target for enhancing myocardial repair after MI, offering promising avenues for the development of regenerative therapies.

PRIORITI: Phase 4 study of triptorelin or active surveillance in high-risk prostate cancer.

AIM: To evaluate the efficacy and safety of triptorelin after radical prostatectomy (RP) in patients with negative lymph nodes. METHODS: PRIORITI (NCT01753297) was a prospective, open-label, randomized, controlled, phase 4 study conducted in China and Russia. Patients with high-risk (Gleason score ≥ 8 and/or pre-RP prostate-specific antigen [PSA] ≥ 20 ng/mL and/or primary tumor stage 3a) prostate adenocarcinoma without evidence of lymph node or distant metastases were randomized to receive triptorelin 11.25 mg at baseline (≤ 8 weeks after RP) and at 3 and 6 months, or active surveillance. The primary endpoint was biochemical relapse-free survival (BRFS), defined as the time from randomization to biochemical relapse (BR; increased PSA > 0.2 ng/mL). Patients were monitored every 3 months for at least 36 months; the study ended when 61 BRs were observed. RESULTS: The intention-to-treat population comprised 226 patients (mean [standard deviation] age, 65.3 [6.4] years), of whom 109 and 117 were randomized to triptorelin or surveillance, respectively. The median BRFS was not reached. The 25th percentile time to BRFS (95% confidence interval) was 39.1 (29.9-not estimated) months with triptorelin and 30.0 (18.6-42.1) months with surveillance (p = 0.16). There was evidence of a lower risk of BR with triptorelin versus surveillance but this was not statistically significant at the 5% level (p = 0.10). Chemical castration was maintained at month 9 in 93.9% of patients who had received triptorelin. Overall, triptorelin was well tolerated and had an acceptable safety profile. CONCLUSION: BRFS was observed to be longer with triptorelin than surveillance, but the difference was not statistically significant.

PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Intersection-union dual-stream cross-attention Lova-SwinUnet for skin cancer hair segmentation and image repair.

Skin cancer images have hair occlusion problems, which greatly affects the accuracy of diagnosis and classification. Current dermoscopic hair removal methods use segmentation networks to locate hairs, and then uses repair networks to perform image repair. However, it is difficult to segment hair and capture the overall structure between hairs because of the hair being thin, unclear, and similar in color to the entire image. When conducting image restoration tasks, the only available images are those obstructed by hair, and there is no corresponding ground truth (supervised data) of the same scene without hair obstruction. In addition, the texture information and structural information used in existing repair methods are often insufficient, which leads to poor results in skin cancer image repair. To address these challenges, we propose the intersection-union dual-stream cross-attention Lova-SwinUnet (IUDC-LS). Firstly, we propose the Lova-SwinUnet module, which embeds Lovasz loss function into Swin-Unet, enabling the network to better capture features of various scales, thus obtaining better hair mask segmentation results. Secondly, we design the intersection-union (IU) module, which takes the mask results obtained in the previous step for pairwise intersection or union, and then overlays the results on the skin cancer image without hair to generate the labeled training data. This turns the unsupervised image repair task into the supervised one. Finally, we propose the dual-stream cross-attention (DC) module, which makes texture information and structure information interact with each other, and then uses cross-attention to make the network pay attention to the more important texture information and structure information in the fusion process of texture information and structure information, so as to improve the effect of image repair. The experimental results show that the PSNR index and SSIM index of the proposed method are increased by 5.4875 and 0.0401 compared with the other common methods. Experimental results unequivocally demonstrate the effectiveness of our approach, which serves as a potent tool for skin cancer detection, significantly surpassing the performance of comparable methods.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm.

Aortic aneurysm is a life-threatening disease with limited interventions that is closely related to vascular smooth muscle cell (VSMC) phenotypic switching. SLC44A2, a member of the solute carrier series 44 (SLC44) family, remains undercharacterized in the context of cardiovascular diseases. Venn diagram analysis based on microarray and single-cell RNA sequencing identified SLC44A2 as a major regulator of VSMC phenotypic switching in aortic aneurysm. Screening for Slc44a2 among aortic cell lineages demonstrated its predominant location in VSMCs. Elevated levels of SLC44A2 were evident in the aorta of both patients with abdominal aortic aneurysm and angiotensin II-infused (Ang II-infused) Apoe-/- mice. In vitro, SLC44A2 silencing promoted VSMCs toward a synthetic phenotype, while SLC44A2 overexpression attenuated VSMC phenotypic switching. VSMC-specific SLC44A2-knockout mice were more susceptible to aortic aneurysm under Ang II infusion, while SLC44A2 overexpression showed protective effects. Mechanistically, SLC44A2's interaction with NRP1 and ITGB3 activates TGF-ß/SMAD signaling, thereby promoting contractile gene expression. Elevated SLC44A2 in aortic aneurysm is associated with upregulated runt-related transcription factor 1 (RUNX1). Furthermore, low-dose lenalidomide (LEN; 20 mg/kg/day) suppressed aortic aneurysm progression by enhancing SLC44A2 expression. These findings reveal that the SLC44A2-NRP1-ITGB3 complex is a major regulator of VSMC phenotypic switching and provide a potential therapeutic approach (LEN) for aortic aneurysm treatment.

Risk factor analysis and optimal cutoff value selection of PSAD for diagnosing clinically significant prostate cancer in patients with negative mpMRI: results from a high-volume center in Southeast China.

BACKGROUND: Multi-parametric magnetic resonance imaging (mpMRI) is a diagnostic tool used for screening, localizing, and staging prostate cancer. Patients with Prostate Imaging Reporting and Data System (PI-RADS) score of 1 and 2 are considered negative mpMRI, with a lower likelihood of detecting clinically significant prostate cancer (csPCa). However, relying solely on mpMRI is insufficient to completely exclude csPCa, necessitating further stratification of csPCa patients using biomarkers. METHODS: A retrospective study was conducted on mpMRI-negative patients who underwent prostate biopsy at the First Affiliated Hospital of Zhejiang University from January 2022 to June 2023. A total of 607 patients were included based on inclusion and exclusion criteria. Univariate and multivariate logistic regression analysis were performed to identify risk factors for diagnosing csPCa in patients with negative mpMRI. Receiver Operating Characteristic (ROC) curves were plotted to compare the discriminatory ability of different Prostate-Specific Antigen Density (PSAD) cutoff values for csPCa. RESULTS: Among the 607 patients with negative mpMRI, 73 patients were diagnosed with csPCa. In univariate logistic regression analysis, age, PSA, f/tPSA, prostate volume, and PSAD were all associated with diagnosing csPCa in patients with negative mpMRI (P < 0.05), with PSAD being the most accurate predictor. In multivariate logistic regression analysis, f/tPSA, age, and PSAD were independent predictors of csPCa (P < 0.05). PSAD cutoff value of 0.20 ng/ml/ml has better discriminatory ability for predicting csPCa and is a significant risk factor for csPCa in multivariate analysis. CONCLUSION: Age, f/tPSA, and PSAD are independent predictors of diagnosing csPCa in patients with negative mpMRI. It is suggested that patients with negative mpMRI and PSAD less than 0.20 ng/ml/ml could avoid prostate biopsy, as a PSAD cutoff value of 0.20 ng/ml/ml has better diagnostic performance than the traditional cutoff value of 0.15 ng/ml/ml.

Computer-aided detection of prostate cancer in early stages using multi-parameter MRI: A promising approach for early diagnosis.

BACKGROUND: Transrectal ultrasound-guided prostate biopsy is the gold standard diagnostic test for prostate cancer, but it is an invasive examination of non-targeted puncture and has a high false-negative rate. OBJECTIVE: In this study, we aimed to develop a computer-assisted prostate cancer diagnosis method based on multiparametric MRI (mpMRI) images. METHODS: We retrospectively collected 106 patients who underwent radical prostatectomy after diagnosis with prostate biopsy. mpMRI images, including T2 weighted imaging (T2WI), diffusion weighted imaging (DWI), and dynamic-contrast enhanced (DCE), and were accordingly analyzed. We extracted the region of interest (ROI) about the tumor and benign area on the three sequential MRI axial images at the same level. The ROI data of 433 mpMRI images were obtained, of which 202 were benign and 231 were malignant. Of those, 50 benign and 50 malignant images were used for training, and the 333 images were used for verification. Five main feature groups, including histogram, GLCM, GLGCM, wavelet-based multi-fractional Brownian motion features and Minkowski function features, were extracted from the mpMRI images. The selected characteristic parameters were analyzed by MATLAB software, and three analysis methods with higher accuracy were selected. RESULTS: Through prostate cancer identification based on mpMRI images, we found that the system uses 58 texture features and 3 classification algorithms, including Support Vector Machine (SVM), K-nearest Neighbor (KNN), and Ensemble Learning (EL), performed well. In the T2WI-based classification results, the SVM achieved the optimal accuracy and AUC values of 64.3% and 0.67. In the DCE-based classification results, the SVM achieved the optimal accuracy and AUC values of 72.2% and 0.77. In the DWI-based classification results, the ensemble learning achieved optimal accuracy as well as AUC values of 75.1% and 0.82. In the classification results based on all data combinations, the SVM achieved the optimal accuracy and AUC values of 66.4% and 0.73. CONCLUSION: The proposed computer-aided diagnosis system provides a good assessment of the diagnosis of the prostate cancer, which may reduce the burden of radiologists and improve the early diagnosis of prostate cancer.

Cancer on motors: How kinesins drive prostate cancer progression?

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.

Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer.

R-loops are prevalent three-stranded nucleic acid structures, comprising a DNA-RNA hybrid and a displaced single-stranded DNA, that frequently form during transcription and may be attributed to genomic stability and gene expression regulation. It was recently discovered that RNA modification contributes to maintain the stability of R-loops such as N6-methyladenosine (m6A). Yet, m6A-modified R-loops in regulating gene transcription remains poorly understood. Here, we demonstrated that insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) recognize R-loops in an m6A-dependent way. Consequently, IGF2BPs overexpression leads to increased overall R-loop levels, cell migration inhibition, and cell growth retardation in prostate cancer (PCa) via precluding the binding of DNA methyltransferase 1(DNMT1) to semaphorin 3 F (SEMA3F) promoters. Moreover, the K homology (KH) domains of IGF2BPs are required for their recognition of m6A-containing R-loops and are required for tumor suppressor functions. Overexpression of SEMA3F markedly enhanced docetaxel chemosensitivity in prostate cancer via regulating Hippo pathway. Our findings point to a distinct R-loop resolution pathway mediated by IGF2BPs, emphasizing the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology.The manuscript summarizes the new role of N6-methyladenosine in epigenetic regulation, we introduce the distinct R-loop resolution mediated by IGF2BP proteins in an m6A-dependent way, which probably lead to the growth retardation and docetaxel chemotherapy resistance in prostate cancer. Moreover, our findings first emphasized the functional importance of IGF2BPs as epigenetic R-loop readers in transcriptional genetic regulation and cancer biology. In addition, our research provides a novel RBM15/IGF2BPs/DNMT1 trans-omics regulation m6A axis, indicating the new crosstalk between RNA m6A methylation and DNA methylation in prostate cancer.

Securinine inhibits the tumor growth of human bladder cancer cells by suppressing Wnt/ß-catenin signaling pathway and activating p38 and JNK signaling pathways.

Bladder cancer (BC) is the most common malignant tumor in urinary system. Although chemotherapy is one of the most important adjuvant treatments for BC, drug resistance, non-specific toxicity and severe side effects are the major obstacles to BC chemotherapy. Natural products have always been a leading resource of antitumor drug discovery, with the advantages of excellent effectiveness, low toxicity, multi-targeting potency and easy availability. In this study, we evaluated the potential anti-tumor effect of securinine (SEC), a natural alkaloid from Securinega suffruticosa, on BC cells in vitro and in vivo, and delineated the underlying mechanism. We found that SEC inhibited the proliferation, migration and invasion, induced the apoptosis of BC cells in vitro, and retarded the xenograft tumor growth of BC cell in vivo. Notably, SEC had a promising safety profile because it presented no or low toxicity on normal cells and mice. Mechanistically, SEC inactivated Wnt/ß-catenin signaling pathway while activated p38 and JNK signaling pathway. Moreover, ß-catenin overexpression, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 both mitigated the inhibitory effect of SEC on BC cells. Furthermore, we demonstrated a synergistic inhibitory effect of SEC and gemcitabine (GEM) on BC cells in vitro and in vivo. Taken together, our findings suggest that SEC may exert anti-BC cell effect at least through the activation of p38 and JNK signaling pathways, and the inhibition of Wnt/ß-catenin signaling pathway. More meaningfully, the findings indicate that GEM-induced BC cell killing can be enhanced by combining with SEC.

Hyperoside induces cell cycle arrest and suppresses tumorigenesis in bladder cancer through the interaction of EGFR-Ras and Fas signaling pathways.

Hyperoside is a natural flavonol glycoside widely found in plants and has been reported to have a variety of pharmacological effects, including anticancer abilities. In this study, we demonstrated for the first time that hyperoside inhibited the proliferation of bladder cancer cells in vitro and in vivo. Moreover, hyperoside could not only induce cell cycle arrest, but also induce apoptosis of a few bladder cancer cells. Quantitative proteomics, bioinformatics analysis and Western blotting confirmed that hyperoside induced the overexpression of EGFR, Ras and Fas proteins, which affects a variety of synergistic and antagonistic downstream signaling pathways, including MAPKs and Akt, ultimately contributing to its anticancer effects in bladder cancer cells. This study reveals that hyperoside could be a promising therapeutic strategy for the prevention of bladder cancer.

S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages.

BACKGROUND: S-Nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in cardiovascular disease. Aortic aneurysm and dissection are high-risk cardiovascular diseases without an effective cure. The aim of this study was to determine the role of SNO of Septin2 in macrophages in aortic aneurysm and dissection. METHODS: Biotin-switch assay combined with liquid chromatography-tandem mass spectrometry was performed to identify the S-nitrosylated proteins in aortic tissue from both patients undergoing surgery for aortic dissection and Apoe-/- mice infused with angiotensin II. Angiotensin II-induced aortic aneurysm model and ß-aminopropionitrile-induced aortic aneurysm and dissection model were used to determine the role of SNO of Septin2 (SNO-Septin2) in aortic aneurysm and dissection development. RNA-sequencing analysis was performed to recapitulate possible changes in the transcriptome profile of SNO-Septin2 in macrophages in aortic aneurysm and dissection. Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation were used to uncover the TIAM1-RAC1 (Ras-related C3 botulinum toxin substrate 1) axis as the downstream target of SNO-Septin2. Both R-Ketorolac and NSC23766 treatments were used to inhibit the TIAM1-RAC1 axis. RESULTS: Septin2 was identified S-nitrosylated at cysteine 111 (Cys111) in both aortic tissue from patients undergoing surgery for aortic dissection and Apoe-/- mice infused with Angiotensin II. SNO-Septin2 was demonstrated driving the development of aortic aneurysm and dissection. By RNA-sequencing, SNO-Septin2 in macrophages was demonstrated to exacerbate vascular inflammation and extracellular matrix degradation in aortic aneurysm. Next, TIAM1 (T lymphoma invasion and metastasis-inducing protein 1) was identified as a SNO-Septin2 target protein. Mechanistically, compared with unmodified Septin2, SNO-Septin2 reduced its interaction with TIAM1 and activated the TIAM1-RAC1 axis and consequent nuclear factor-κB signaling pathway, resulting in stronger inflammation and extracellular matrix degradation mediated by macrophages. Consistently, both R-Ketorolac and NSC23766 treatments protected against aortic aneurysm and dissection by inhibiting the TIAM1-RAC1 axis. CONCLUSIONS: SNO-Septin2 drives aortic aneurysm and dissection through coupling the TIAM1-RAC1 axis in macrophages and activating the nuclear factor-κB signaling pathway-dependent inflammation and extracellular matrix degradation. Pharmacological blockade of RAC1 by R-Ketorolac or NSC23766 may therefore represent a potential treatment against aortic aneurysm and dissection.

Interval from transurethral resection of prostate to laparoscopic radical prostatectomy does not affect outcomes for incidental prostate cancer.

Introduction: Laparoscopic radical prostatectomy (LRP) has become a common option for the treatment of prostate cancer. The aim of our study was to examine whether LRP performed within 12 weeks of transurethral resection of the prostate (TURP) is associated with surgical difficulty or outcomes. Material and methods: A single-institutional retrospective analysis was performed on patients who underwent LRP for incidental prostate cancer after TURP between July 2009 and December 2017. The interval between TURP and LRP was determined and patients with intervals of ≤ 12 weeks were compared to those with intervals of > 12 weeks. Patient characteristics, perioperative, pathological, and postoperative functional outcomes were analyzed to determine statistically significant differences between the 2 groups. Multivariable analyses were performed to determine whether the interval between TURP and LRP was a significant independent predictor of these outcomes. Results: A total of 56 incidental prostate cancer patients detected by TURP were included in this study. No significant differences were detected in estimated blood loss, operative duration, postoperative length of stay, and rate of positive margin, Gleason score upgrading, major complications, incontinence and prostate-specific antigen (PSA) recurrence in patients with a TURP to LRP interval above and below 12 weeks. The TURP to LRP interval was not an independent predictor of outcomes during or after LRP. Conclusions: Our results showed that performing LRP within 12 weeks after TURP does not adversely influence surgical difficulty or outcomes.

Oral Chinese Herbal Medicine plus usual care for diabetic kidney disease: study protocol for a randomized, double-blind, placebo-controlled pilot trial.

Background: Diabetic kidney disease (DKD) has become the leading cause of kidney failure, causing a significant socioeconomic burden worldwide. The usual care for DKD fails to achieve satisfactory effects in delaying the persistent loss of renal function. A Chinese herbal medicine, Tangshen Qushi Formula (TQF), showed preliminary clinical benefits with a sound safety profile for people with stage 2-4 DKD. We present the protocol of an ongoing clinical trial investigating the feasibility, efficacy, and safety of TQF compared to placebo in delaying the progressive decline of renal function for people with stage 2-4 DKD. Methods: A mixed methods research design will be used in this study. A randomized, double-blind, placebo-controlled pilot trial will evaluate the feasibility, efficacy, and safety of TQF compared to placebo on kidney function for people with stage 2-4 DKD. An embedded semi-structured interview will explore the acceptability of TQF granules and trial procedures from the participant's perspective. Sixty eligible participants with stage 2-4 DKD will be randomly allocated to the treatment group (TQF plus usual care) or the control group (TQF placebo plus usual care) at a 1:1 ratio for 48-week treatment and 12-week follow-up. Participants will be assessed every 12 weeks. The feasibility will be assessed as the primary outcome. The changes in the estimated glomerular filtration rate, urinary protein/albumin, renal function, glycemic and lipid markers, renal composite endpoint events, and dampness syndrome of Chinese medicine will be assessed as the efficacy outcomes. Safety outcomes such as liver function, serum potassium, and adverse events will also be evaluated. The data and safety monitoring board will be responsible for the participants' benefits, the data's credibility, and the results' validity. The intent-to-treat and per-protocol analysis will be performed as the primary statistical strategy. Discussion: Conducting a rigorously designed pilot trial will be a significant step toward establishing the feasibility and acceptability of TQF and trial design. The study will also provide critical information for future full-scale trial design to further generate new evidence supporting clinical practice for people with stage 2-4 DKD. Trial registration number: https://www.chictr.org.cn/, identifier ChiCTR2200062786.

Methionine Promotes Milk Synthesis through the BRCC36-BRG1-mTOR Signaling Axis in Mammary Epithelial Cells.

Methionine (Met) functions as a key stimulator on the mTOR signaling pathway and milk synthesis, but the molecular mechanism remains incompletely understood. We investigated the regulatory roles of BRCC36 in Met-stimulated milk lipid and protein synthesis, cell proliferation, and the mTOR signaling pathway. Knockdown of BRCC36 promoted milk lipid and protein synthesis in HC11 cells as well as cell proliferation by increasing the levels of mTOR gene transcription and protein phosphorylation. Conversely, the gene activation of BRCC36 had opposite effects. Furthermore, BRCC36 gene activation completely blocked Met stimulation on the BRG1 protein level and mTOR mRNA level and protein phosphorylation. BRCC36 bound to BRG1, and BRCC36 and BRG1 bound to the same region on the mTOR promoter. BRCC36 inhibited the BRG1 protein level and the binding of BRG1 to the mTOR promoter. Met decreased the BRCC36 protein level, and this effect was significantly attenuated by MG132 but not affected by cycloheximide or chloroquine. We further showed that Met increased BRCC36 ubiquitination degradation. Our findings reveal that Met promotes milk lipid and protein synthesis in MECs through the BRCC36-BRG1-mTOR signaling axis.