Discovery of a Series of 4-Amide-thiophene-2-carboxyl Derivatives as Highly Potent P2Y14 Receptor Antagonists for Inflammatory Bowel Disease Treatment.

The P2Y14 receptor has been proven to be a potential target for IBD. Herein, we designed and synthesized a series of 4-amide-thiophene-2-carboxyl derivatives as novel potent P2Y14 receptor antagonists based on the scaffold hopping strategy. The optimized compound 39 (5-((5-fluoropyridin-2-yl)oxy)-4-(4-methylbenzamido)thiophene-2-carboxylic acid) exhibited subnanomolar antagonistic activity (IC50: 0.40 nM). Moreover, compound 39 demonstrated notably improved solubility, liver microsomal stability, and oral bioavailability. Fluorescent ligand binding assay confirmed that 39 has the binding ability to the P2Y14 receptor, and molecular dynamics (MD) simulations revealed the formation of a unique intramolecular hydrogen bond (IMHB) in the binding conformation. In the experimental colitis mouse model, compound 39 showed a remarkable anti-IBD effect even at low doses. Compound 39, with a potent anti-IBD effect and favorable druggability, can be a promising candidate for further research. In addition, this work lays a strong foundation for the development of P2Y14 receptor antagonists and the therapeutic strategy for IBD.

Pharmacovigilance of esketamine nasal spray: an analysis of the FDA adverse event reporting system database.

Esketamine nasal spray (ESK-NS) is a new drug for treatment-resistant depression, and we aimed to detect and characterize the adverse events (AEs) of ESK-NS using the Food and Drug Administration (FDA) adverse event reporting system (FAERS) database between 2019 Q1 and 2023 Q4. Reporting odds ratio (ROR), proportional reporting ratio (PRR), and multi-item gamma Poisson shrinker (MGPS) were performed to detect risk signals from the FAERS data to identify potential ESK-NS-AEs associations. A total of 14,606 reports on AEs with ESK-NS as the primary suspected drug were analyzed. A total of 518 preferred terms signals and 25 system organ classes mainly concentrated in psychiatric disorders (33.20%), nervous system disorders (16.67%), general disorders and administration site conditions (14.21%), and others were obtained. Notably, dissociation (n = 1,093, ROR 2,257.80, PRR 899.64, EBGM 876.86) exhibited highest occurrence rates and signal intensity. Moreover, uncommon but significantly strong AEs signals, such as hand-eye coordination impaired, feeling guilty, and feelings of worthlessness, were observed. Additionally, dissociative disorder (n = 57, ROR 510.92, PRR 506.70, EBGM 386.60) and sedation (n = 688, ROR 172.68, PRR 155.53, and EBGM 142.05) both presented strong AE signals, and the former is not recorded in the Summary of Product Characteristics (SmPC). In clinical applications, close attention should be paid to the psychiatric disorders and nervous system disorders, especially dissociation. Meanwhile, clinical professionals should be alert for the occurrence of AEs signals not mentioned in the SmPC and take preventive measures to ensure the safety of clinical use.

The Downregulation of ITGAX Exacerbates Amyloid-ß Plaque Deposition in Alzheimer's Disease by Increasing Polarization of M1 Microglia.

Background: Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Objective: Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. Methods: We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Results: Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-ß (Aß) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aß plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. Conclusions: This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction.

A two-site Kitaev chain in a two-dimensional electron gas.

Artificial Kitaev chains can be used to engineer Majorana bound states (MBSs) in superconductor-semiconductor hybrids1-4. In this work, we realize a two-site Kitaev chain in a two-dimensional electron gas by coupling two quantum dots through a region proximitized by a superconductor. We demonstrate systematic control over inter-dot couplings through in-plane rotations of the magnetic field and via electrostatic gating of the proximitized region. This allows us to tune the system to sweet spots in parameter space, where robust correlated zero-bias conductance peaks are observed in tunnelling spectroscopy. To study the extent of hybridization between localized MBSs, we probe the evolution of the energy spectrum with magnetic field and estimate the Majorana polarization, an important metric for Majorana-based qubits5,6. The implementation of a Kitaev chain on a scalable and flexible two-dimensional platform provides a realistic path towards more advanced experiments that require manipulation and readout of multiple MBSs.

Association of four metalloids in the serum and urine of individuals with major depressive disorders: a case-control study.

Background: Major depressive disorder (MDD) pathogenesis may involve metalloids in a significant way. The aim of our study was to identify potential links between MDD and metalloid elements [boron (B), germanium (Ge), arsenic (As), antimony (Sb)]. Methods: A total of 72 MDD cases and 75 healthy controls (HCs) were recruited from Zhumadian Second People's Hospital in Henan Province, China. The levels of four metallic elements (B, Ge, As, and Sb) in the serum and urine were measured using inductively coupled plasma mass spectrometry (ICP-MS). Results: In comparison to the HCs, the B, As, and Sb levels were considerably lower in the MDD group (p < 0.05) in the serum; the MDD group had significantly higher (p < 0.05) and significantly lower (p < 0.001) B and Sb levels in the urine. After adjusting for potential confounders, serum B (OR = 0.120; 95% CI, 0.048, 0.300; p < 0.001) and Sb (OR = 0.133; 95% CI, 0.055, 0.322; p < 0.001) showed a negative correlation with MDD. Urine B had a negative correlation (OR = 0.393; 95% CI, 0.193, 0.801; p = 0.01) with MDD, while urine Sb had a positive correlation (OR = 3.335; 95% CI, 1.654, 6.726; p = 0.001) with MDD. Conclusion: Our current research offers insightful hints for future investigation into the function of metalloids in connection to MDD processes.

Electrocatalytic Reforming of Polylactic Acid Plastic Hydrolysate over Dynamically Formed γ-NiOOH.

Upcycling plastic waste into valuable commodity chemicals with clean energy is an appealing strategy for mitigating environmental issues. Polylactic acid (PLA), a biodegradable plastic that is produced annually in millions of tons, can be chemically recycled to valuable products instead of being degraded to carbon dioxide. Here, we demonstrate an electrochemical reforming of PLA hydrolysate to acetate and acetonate using nickel phosphide nanosheets on nickel foam (Ni2P/NF) as the catalyst. The Ni2P/NF catalyst was synthesized by electrochemical deposition and phosphide treatment and showed excellent catalytic activity and ∼100% Faraday efficiency for electroreforming PLA to acetate and acetonate in an H-cell. Moreover, a stable performance of more than 90% Faraday efficiency for value-added organics was achieved for a duration of 100 h in a flow cell at a current density of 100 mA cm-2 and a potential below 1.5 V vs. RHE. In situ characterization revealed that the catalyst underwent electrochemical reforming during the reaction to produce γ-phase NiOOH with high electrochemical activity. This work introduces a new and green solution for the treatment of waste PLA, presenting a low-cost and highly efficient strategy for electrically reforming plastics.

Design, Synthesis, and Biological Evaluation of a Novel NIK Inhibitor with Anti-Inflammatory and Hepatoprotective Effects for Sepsis Treatment.

NIK plays a crucial role in the noncanonical NF-κB signaling pathway associated with diverse inflammatory and autoimmune diseases. Our study presents compound 54, a novel NIK inhibitor, designed through a structure-based scaffold-hopping approach from the previously identified B022. Compound 54 demonstrates remarkable selectivity and potency against NIK both in vitro and in vivo, effectively suppressing pro-inflammatory cytokines and nitric oxide production. In mouse models, compound 54 protected against LPS-induced systemic sepsis, reducing AST, ALT, and AKP liver injury markers. Additionally, it also attenuates sepsis-induced lung and kidney damage. Mechanistically, compound 54 blocks the noncanonical NF-κB signaling pathway by targeting NIK, preventing p100 to p52 processing. This work reveals a novel class of NIK inhibitors with significant potential for sepsis therapy.

Targeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis.

Purinergic signaling plays a causal role in the pathogenesis of inflammatory bowel disease. Among purinoceptors, only P2Y14R is positively correlated with inflammatory score in mucosal biopsies of ulcerative colitis patients, nevertheless, the role of P2Y14R in ulcerative colitis remains unclear. Here, based on the over-expressions of P2Y14R in the intestinal epithelium of mice with experimental colitis, we find that male mice lacking P2Y14R in intestinal epithelial cells exhibit less intestinal injury induced by dextran sulfate sodium. Mechanistically, P2Y14R deletion limits the transcriptional activity of cAMP-response element binding protein through cAMP/PKA axis, which binds to the promoter of Ripk1, inhibiting necroptosis of intestinal epithelial cells. Furthermore, we design a hierarchical strategy combining virtual screening and chemical optimization to develop a P2Y14R antagonist HDL-16, which exhibits remarkable anti-colitis effects. Summarily, our study elucidates a previously unknown mechanism whereby P2Y14R participates in ulcerative colitis, providing a promising therapeutic target for inflammatory bowel disease.

Comprehensive Evolutionary Analysis of the SMXL Gene Family in Rosaceae: Further Insights into Its Origin, Expansion, Diversification, and Role in Regulating Pear Branching.

SMXL genes constitute a conserved gene family that is ubiquitous in angiosperms and involved in regulating various plant processes, including branching, leaf elongation, and anthocyanin biosynthesis, but little is known about their molecular functions in pear branching. Here, we performed genome-wide identification and investigation of the SMXL genes in 16 angiosperms and analyzed their phylogenetics, structural features, conserved motifs, and expression patterns. In total, 121 SMXLs genes were identified and were classified into four groups. The number of non-redundant SMXL genes in each species varied from 3 (Amborella trichopoda Baill.) to 18 (Glycine max Merr.) and revealed clear gene expansion events over evolutionary history. All the SMXL genes showed conserved structures, containing no more than two introns. Three-dimensional protein structure prediction revealed distinct structures between but similar structures within groups. A quantitative real-time PCR analysis revealed different expressions of 10 SMXL genes from pear branching induced by fruit-thinning treatment. Overall, our study provides a comprehensive investigation of SMXL genes in the Rosaceae family, especially pear. The results offer a reference for understanding the evolutionary history of SMXL genes and provide excellent candidates for studying fruit tree branching regulation, and in facilitating pear pruning and planting strategies.

Nodakenin Ameliorates Ovariectomy-Induced Bone Loss by Regulating Gut Microbiota.

Disordered gut microbiota (GM) structure and function may contribute to osteoporosis (OP). Nodakenin has been shown to ameliorate osteoporosis; however, its anti-osteoporotic mechanism is unknown. This study aimed to further reveal the mechanism of the anti-osteoporotic action of nodakenin from the perspective of the microbiome and metabolome. An osteoporosis model was induced in mice through ovariectomy (OVX), with bone mass and microstructure assessed using µCT. Subsequently, ELISA and histologic examination were used to detect biochemical indicators of bone conversion and intestinal morphology. Using metabolomics and 16S rRNA sequencing, it was possible to determine the composition and abundance of the gut microbiota in feces. The results revealed that nodakenin treatment improved the bone microstructure and serum levels of bone turnover markers, and increased the intestinal mucosal integrity. 16S rRNA sequencing analysis revealed that nodakenin treatment decreased the relative abundance of Firmicutes and Patescibacteria, as well as the F/B ratio, and elevated the relative abundance of Bacteroidetes in OVX mice. In addition, nodakenin enhanced the relative abundance of Muribaculaceae and Allobaculum, among others, at the genus level. Moreover, metabolomics analysis revealed that nodakenin treatment significantly altered the changes in 113 metabolites, including calcitriol. A correlation analysis revealed substantial associations between various gut microbiota taxa and both the osteoporosis phenotype and metabolites. In summary, nodakenin treatment alleviated OVX-induced osteoporosis by modulating the gut microbiota and intestinal barrier.

Retracted: Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Tian-Wei Zhang, Li Xing, Jun-Long Tang, Jing-Xiao Lu, Chun-Xiao Liu. Marchantin M Induces Apoptosis of Prostate Cancer Cells Through Endoplasmic Reticulum Stress. Med Sci Monit, 2015; 21: 3570-3576. DOI: 10.12659/MSM.894476.

Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma.

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8+ T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8+ T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC.

SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.

Treatment patterns and healthcare resource utilization in patients with metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer in China: a real-world observational study.

AIM: This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China. METHODS: A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes. RESULTS: In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer-related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer-related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50-1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50-818.50]). LIMITATIONS: EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden. CONCLUSIONS: A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer-related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.

Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cß/store-operated calcium entry/calreticulin/scavenger receptor A pathways.

BACKGROUND AND AIMS: Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. METHODS: The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. RESULTS: The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cß/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. CONCLUSIONS: Macrophage P2Y6R regulates phospholipase Cß/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

Bicarbonate ringer's solution could improve the intraoperative acid-base equilibrium and reduce hepatocellular enzyme levels after deceased donor liver transplantation: a randomized controlled study.

BACKGROUND: Bicarbonate Ringer's (BR) solution is a direct liver and kidney metabolism-independent HCO3- buffering system. We hypothesized that BR solution would be more effective in improving acid-base equilibrium and more conducive to better liver function than Acetate Ringer's (AR) solution in conventional orthotopic liver transplantation (OLT) patients. METHODS: Sixty-nine adult patients underwent OLT. Patients in the bicarbonate and acetate groups received BR solution or AR solution as infused crystalloids and graft washing solution, respectively. The primary outcome was the effect on pH and base excess (BE) levels. The secondary outcome measures were the incidence and volume of intraoperative 5% sodium bicarbonate infusion and laboratory indicates of liver and kidney function. RESULTS: The pH and absolute BE values changed significantly during the anhepatic phase and immediately after transplanted liver reperfusion in the bicarbonate group compared with the acetate group (all P < 0.05). The incidence and volume of 5% sodium bicarbonate infusion were lower in the bicarbonate group than in the acetate group (all P < 0.05). The aspartate transaminase (AST) level at 7 postoperative days and the creatine level at 30 postoperative days were significantly higher in the acetate group than in the bicarbonate group (all P < 0.05). CONCLUSION: Compared with AR solution, BR solution was associated with improved intraoperative acid-base balance and potentially protected early postoperative liver graft function and reduced late-postoperative renal injury.

Nodakenin alleviates ovariectomy-induced osteoporosis by modulating osteoblastogenesis and osteoclastogenesis.

Osteoporosis, a systemic bone disease defined by decreased bone mass and deterioration of bone microarchitecture, is becoming a global concern. Nodakenin (NK) is a furanocoumarin-like compound isolated from the traditional Chinese medicine Radix Angelicae biseratae (RAB). NK has been reported to have various pharmacological activities, but osteoporosis has not been reported to be affected by NK. In this study, we used network pharmacology, molecular docking and molecular dynamics simulation techniques to identify potential targets and pathways of NK in osteoporosis. We found that NK treatment significantly promoted osteogenic differentiation of BMSCs while activating the PI3K/AKT/mTOR signalling pathway by measuring alkaline phosphatase activity and the expression of various osteogenic markers. In contrast, LY294002, an inhibitor of PI3K, reversed these changes and inhibited the osteogenic differentiation-enabling effect of NK. Meanwhile, prevent the Akt and NFκB signalling pathways by down-regulating c-Src and TRAF6 thereby effectively inhibiting RANKL-induced osteoclastogenesis. In addition, oral administration of NK to mice significantly elevated bone mass and ameliorated ovariectomized (OVX)-mediated bone microarchitectural disorders. In conclusion, these data suggest that NK attenuates OVX-induced bone loss by enhancing osteogenesis and inhibiting osteoclastogenesis.

LncRNA IGFBP4-1 promotes tumor development by activating Janus kinase-signal transducer and activator of transcription pathway in bladder urothelial carcinoma: retraction.

[This retracts the article DOI: 10.7150/ijbs.46986.].

Development and experimental validation of a folate metabolism-related gene signature to predict the prognosis and immunotherapeutic sensitivity in bladder cancer.

Folate metabolism is critical for the maintenance of genomic stability due to its regulatory ability to methylation, nucleotide metabolism, and reduction capabilities in cancer cells. However, the prognostic value of folate metabolism-related genes has not been clarified, especially in bladder cancer (BLCA). 91 folate metabolism-related genes were retrieved from the public database. TCGA-BLCA cohort, obtained from the Cancer Genome Atlas, was selected for training, while GSE13507, GSE31684, and GSE32894, downloaded from the Gene Expression Omnibus, and 35 BLCA samples collected from the local hospital were used for external validation. Through genomic difference detection, protein-protein interaction network analysis, LASSO regression, and Cox regression, a three-gene signature, including ATIC, INS, and MTHFD1L, was constructed. The signature was a reliable prognosis predictor across multiple independent cohorts (pooled hazard ratio = 2.79, 95% confidence interval = 1.79-4.33). The signature was associated with the BLCA malignant degree, which was validated in the local clinical samples (P < 0.01) and multiple cell lines (all P < 0.05). Additionally, the TIDE algorithm, GSE111636 cohort, and IMvigor210 cohort indicated that the signature was a promising tool to evaluate the immunotherapeutic response. Collectively, a folate metabolism-related gene signature was constructed to predict the prognosis and immunotherapeutic sensitivity in BLCA, which was verified in multiple large-scale cohorts, clinical samples, and cellular experiments, providing novel insights into the biological mechanisms.

Endovascular repair of thoracic aortic disease with isolated left vertebral artery and unfavorable proximal landing zone using fenestrated castor stent-graft.

Objective: The main purpose of this study was to evaluate the safety and efficacy of Castor single-branched stent-graft combined with fenestrated technique in treatment of thoracic aortic disease (TAD) with unfavorable proximal landing area (PLZ) and isolated left vertebral artery (ILVA). Methods: From January 2018 to March 2022, 8 patients with TAD (6 patients with type B aortic dissections, 1 patient with type B intramural hematomas, and 1 patient with thoracic aortic aneurysm) underwent thoracic endovascular aortic repair with fenestrated Castor stent-graft due to the existence of ILVA and unfavorable PLZ. Demographic characteristics, surgical details, postoperative complications, follow-up and postoperative CTA imaging results were collected and analyzed. Results: The primary technical success rate was 100%. The mean operation time was 115 min (range, 70-180 min). All the left subclavian arteries (LSAs) and ILVAs of the eight patients were revascularized by fenestrated Castor stent-grafts. During the follow-up period, no deaths and complications were observed. No internal leakage, aortic rupture, retrograde type A dissection were found on computed tomography angiography. All of the LSAs and ILVAs maintained patency without stenosis. Conclusion: Castor single-branched stent-graft implantation combined with fenestration technique may be safe and feasible for TAD patients with ILVA and unfavorable PLZ.