An oxygen vacancy-rich BiO2-x/COF heterojunction for photocatalytic degradation of diclofenac.

A BiO2-x/COF composite was successfully synthesized by simple mechanical ball milling. Compared to pure BiO2-x and COFs, the BiO2-x/COF composite (1 : 9) showed superior photocatalytic capability. Under visible light irradiation for 90 min, the photocatalytic degradation rate of DCF reached 97%. In addition, the characterization results showed that the formation of heterojunctions and the increase in oxygen vacancy concentration were the reasons for the enhancement of the photocatalytic activity. It is confirmed by free radical capture experiments that ˙O2- and h+ are the main reactive substances in the photocatalytic process. The photocatalytic degradation mechanism of the composite and the photocatalytic degradation pathway of diclofenac were deduced.

Deciphering ACE2-RBD binding affinity through peptide scanning: A molecular dynamics simulation approach.

Rapid discovery of target information for protein-protein interactions (PPIs) is significant in drug design, diagnostics, vaccine development, antibody therapy, etc. Peptide microarray is an ideal tool for revealing epitope information of PPIs. In this work, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) and the host cell receptor angiotensin-converting enzyme 2 (ACE2) were introduced as a model to study the epitope information of RBD-specific binding to ACE2 via a combination of theoretical calculations and experimental validation. Through dock and molecular dynamics simulations, it was found that among the 22 peptide fragments that consist of RBD, #14 (YNYLYRLFRKSNLKP) has the highest binding strength. Subsequently, the experiments of peptide microarray constructed based on plasmonic materials chip also confirmed the theoretical calculation data. Compared to other methods, such as phage display technology and surface plasmon resonance (SPR), this method is rapid and cost-effective, providing insights into the investigation of pathogen invasion processes and the timely development of peptide drugs and other fields.

WO3/MIL-125 (Ti) composite material for enhancing the reduction of Cr(vi) under visible light.

In wastewater containing heavy metals, Cr(vi) is a potentially toxic metal, mainly derived from production and processing processes such as textile printing, dyeing, ore mining, battery applications, metal cleaning and electroplating. WO3 is widely used in photocatalytic degradation and reduction, and its utilization rate of visible light is high. However, the rapid recombination of photogenerated electron-hole pairs of WO3 limits its use. In this work, the composite material (WxMy) of WO3 and MIL-125 (Ti) was prepared by the ball milling method, and the catalyst was used to photocatalytically reduce Cr(vi). After using W90M10 as a photocatalyst for 50 min, the reduction rate of Cr(vi) can reach 99.2%, and the reduction rate is 2.3 times that of WO3. After 5 cycles of use, the reduction rate can still reach 91.3%. It is mainly due to the formation of a II-type heterojunction between WO3 and MIL-125 (Ti), which promotes the separation of photogenerated electron-hole pairs, thus improving the efficiency of photocatalytic reduction of Cr(vi).

An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re-Epithelization and Skin Constriction for Enhancing Wound Closure.

Delayed re-epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large-scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active-shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re-epithelization and skin constriction to accelerate large-scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7-fold and ≈1.7-fold better re-epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.

Ligand-Induced Synthesis of Highly Stable NM88(DB)@COF-JLU19 Composite: Accelerating Electron Flow for Visible-Light-Efficient Degradation of Tetracycline Hydrochloride.

In recent years, the response of new porous materials to visible light and their potential applications in wastewater treatment has received extensive attention from the scientific community. Metal Organic Frameworks (MOFs) and Covalent Organic Frameworks (COFs) have been the focus of attention due to their strong visible light absorption, high specific surface area, well-regulated pore structures, and diverse topologies. In this study, a novel MOF@COF composite with a high surface area, high crystallinity, and structural stability was obtained using the covalent bond formation strategy from COF-JLU19 and NH2-MIL-88B(Fe). Under visible light irradiation, the degradation of tetracycline hydrochloride by this material reached more than 90% within 10 min and was completely degraded within 30 min, which exceeded the degradation rate of individual materials. Remarkably, the catalytic activity decreased by less than 5% even after five degradation cycles, indicating good structural stability. The excellent photocatalytic performance of the NM88(DB)@COF-JLU19 hybrids was attributed to the formation of covalent bonds, which formed a non-homogeneous interface that facilitated effective charge separation and promoted the generation of hydroxyl radicals.

In Vivo Evaluation of Corneal Biomechanics Following Cross-Linking Surgeries Using Optical Coherence Elastography in a Rabbit Model of Keratoconus.

Purpose: Validation of the feasibility of novel acoustic radiation force optical coherence elastography (ARF-OCE) for the evaluation of biomechanical enhancement of the in vivo model of keratoconus by clinical cross-linking (CXL) surgery. Methods: Twelve in vivo rabbit corneas were randomly divided into two groups. Both groups were treated with collagenase type II, and a keratoconus model was obtained. Then, the two groups were treated with CXL procedures with different irradiation energy of 15 J and 30 J (CXL-15 J and CXL-30 J, respectively). An ARF-OCE probe with an ultrasmall ultrasound transducer was used to detect the biomechanical properties of cornea. An antisymmetric Lamb wave model was combined with the frequency dispersion relationship to achieve depth-resolved elastography. Results: Compared with the phase velocity of the Lamb wave in healthy corneas (approximately 3.96 ± 0.27 m/s), the phase velocity of the Lamb wave was lower in the keratoconus region (P < 0.05), with an average value of 3.12 ± 0.12 m/s. Moreover, the corneal stiffness increased after CXL treatment (P < 0.05), and the average phase velocity of the Lamb wave was 4.3 ± 0.19 m/s and 4.54 ± 0.13 m/s after CXL-15 J and CXL-30 J treatment. Conclusions: The Young's moduli of the keratoconus regions were significantly lower than the healthy corneas. Moreover, the Young's modulus of the keratoconus regions was significantly higher after CXL-30 J treatment than after CXL-15 J treatment. We demonstrated that the ARF-OCE technique has great potential in screening keratoconus and guiding clinical CXL treatment. Translational Relevance: This work accelerates the clinical translation of OCE systems using ultrasmall ultrasound transducers and is used to guide CXL procedures.

Study on the reversal of epileptic drug resistance by tetramethylpyrazine in combination with carbamazepine through modulation of P-Glycoprotein expression in rat brain microvessel endothelial cell.

The purpose of this study was to detect the changes of P-Glycoprotein (P-GP) expression in rat brain microvessel endothelial cell line RBE4 after the action of Tetramethylpyrazine (TMP) on Carbamazepine (CBZ), so as to clarify the potential mechanism of TMP combined with CBZ against intractable epilepsy drug resistance. The RBE4 cell line was utilized for in vitro analysis. Cells were divided into control, CBZ, and CBZ-TMP group. The expression of P-GP was assessed using Western blot and reverse transcription polymerase chain reaction (RT-PCR). Intracellular concentration of CBZ was measured through high-performance liquid chromatography (HPLC). The differential expression of mRNA was evaluated by RNA sequencing. The intracellular concentration of CBZ in the CBZ-TMP group was significantly higher than that in other groups. The expression of P-GP in the CBZ group was significantly higher than that in the control group, while in the CBZ&TMP group, it was significantly lower than that in the other groups. Comparative analysis also revealed some differentially expressed genes. Compared with the CBZ group, FAM106A, SLC3A2, TENM2, etc. were upregulated most significantly in the CBZ&TMP group. ZBTB10, WDR7, STARD13, etc. were downregulated most significantly. Results suggest that TMP increases the intracellular concentration of CBZ, downregulates the expression of P-GP increased by CBZ, and modulates related cellular metabolism and signaling pathways, thus reversing the drug resistance mechanism of intractable epilepsy, providing a theoretical basis for the combination of traditional Chinese medicine and antiepileptic drugs.

Nano- and micro-plastic transport in soil and groundwater environments: Sources, behaviors, theories, and models.

With the increasing use of plastics, nano- and micro-plastic (NMP) pollution has become a hot topic in the scientific community. Ubiquitous NMPs, as emerging contaminants, are becoming a global issue owing to their persistence and potential toxicity. Compared with studies of marine and freshwater environments, investigations into the sources, transport properties, and fate of NMPs in soil and groundwater environments remain at a primary stage. Hence, the promotion of such research is critically important. Here, we integrate existing information and recent advancements to compile a comprehensive evaluation of the sources and transport properties of NMPs in soil and groundwater environments. We first provide a systematic description of the various sources and transport behaviors of NMPs. We then discuss the theories (e.g., clean-bed filtration and Derjaguin-Landau-Verwey-Overbeek theories) and models (e.g., single-site and dual-site kinetic retention and transport models) of NMP transport through saturated porous media. Finally, we outline the potential limitations of current research and suggest directions for future research. Overall, this review intends to assimilate and outline current knowledge and provide a useful reference frame to determine the sources and transport properties of NMPs in soil and groundwater environments.

Duration-dependent impact of cardiometabolic diseases and multimorbidity on all-cause and cause-specific mortality: a prospective cohort study of 0.5 million participants.

BACKGROUND: The association of incident cardiometabolic multimorbidity (CMM) with mortality risk is rarely studied, and neither are the durations of cardiometabolic diseases (CMDs). Whether the association patterns of CMD durations with mortality change as individuals progress from one CMD to CMM is unclear. METHODS: Data from China Kadoorie Biobank of 512,720 participants aged 30-79 was used. CMM was defined as the simultaneous presence of two or more CMDs of interest, including diabetes, ischemic heart disease, and stroke. Cox regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the duration-dependent associations of CMDs and CMM with all-cause and cause-specific mortality. All information on exposures of interest was updated during follow-up. RESULTS: During a median follow-up of 12.1 years, 99,770 participants experienced at least one incident CMD, and 56,549 deaths were documented. Among 463,178 participants free of three CMDs at baseline, compared with no CMD during follow-up, the adjusted HRs (95% CIs) between CMM and all-cause mortality, mortality from circulatory system diseases, respiratory system diseases, cancer, and other causes were 2.93 (2.80-3.07), 5.05 (4.74-5.37), 2.72 (2.35-3.14), 1.30 (1.16-1.45), and 2.30 (2.02-2.61), respectively. All CMDs exhibited a high mortality risk in the first year of diagnosis. Subsequently, with prolonged disease duration, mortality risk increased for diabetes, decreased for IHD, and sustained at a high level for stroke. With the presence of CMM, the above association estimates inflated, but the pattern of which remained. CONCLUSION: Among Chinese adults, mortality risk increased with the number of the CMDs and changed with prolonged disease duration, the patterns of which varied among the three CMDs.

Influences of resolvin D1 and D2 on the risk of type 2 diabetes mellitus: a Chinese community-based cohort study.

Background: Although cellular and animal studies have reported that resolvin D1 (RvD1) and resolvin D2 (RvD2) are mechanisms involved in the development of type 2 diabetes mellitus (T2DM), the impact of RvD1 and RvD2 on the risk of T2DM at a population level remains unclear. Methods: We included 2755 non-diabetic adults from a community-based cohort in China and followed them for seven years. Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of RvD1 and RvD2 with T2DM probability. Time-dependent receiver operator characteristics (ROC) curve was used to evaluate the predictive performance of RvD1 and RvD2 for the risk of T2DM based on the Chinese CDC T2DM prediction model (CDRS). Results: A total of 172 incident T2DM cases were identified. Multivariate-adjusted HRs (95% CI) for T2DM across quartiles of RvD1 levels (Q1, Q2, Q3 and Q4) were 1.00, 1.64 (1.03-2.63), 1.80 (1.13-2.86) and 1.61 (1.01-2.57), respectively. Additionally, body mass index (BMI) showed a significant effect modification in the association of RvD1 with incident T2DM (P interaction = 0.026). After multivariate adjustment, the HR (95% CI) for T2DM in the fourth compared with the first quartile of RvD2 was 1.94 (95% CI: 1.24-3.03). Time-dependent ROC analysis showed that the area under time-dependent ROC curves of the "CDRS+RvD1+RvD2" model for the 3-, 5- and 7-year risk of T2DM were 0.842, 0.835 and 0.828, respectively. Conclusions: Higher RvD1 and RvD2 levels are associated with a higher risk of T2DM at the population level.

The screening of compounds regulating PD-L1 transcriptional activity in a cell functional high-throughput manner.

Immune checkpoints are protein molecules expressed on the immune cell membrane, which regulate the immune system to kill tumor cells. As an essential immune checkpoint, overexpressed PD-1 on tumor cells could inhibit T-cell activation after being bonded to PD-1. Due to this inhibitory effect, T-cell proliferation and cytokine secretion are suppressed, leading to immune escape of tumor cells. Here, we established a high-throughput method based on cell function screening technology to screen drugs regulating PD-L1 expression in tumor cells at the transcriptional level. After two screening rounds, 12 compounds that enhanced PD-L1 transcription while seven weakened were sorted out among 1018 FDA-approved drugs. Finally, a tumor cell line was used to verify the upregulation of endogenous PD-L1 expression for a drug named "vorinostat," a histone deacetylation inhibitor, after the two rounds of optional selection. Therefore, our research provides another perspective for using "vorinostat" in treating tumors and offers a convenient method to detect the transcriptional expression of other intracellular proteins besides PD-L1.

Retention of trace elements in coal-fired flue gas by a novel heterogeneous agglomeration technology.

Heterogeneous agglomeration (HA) is a very potential technology for coal-fired flue gas treatment. In this paper, the distribution and migration mechanisms of trace elements (TEs) such as Se, As and Pb in CFPPs were studied on a 30,000 m3/hr pilot-scale experimental platform. The influences of HA on the removal efficiency of gaseous and particulate TEs were well analyzed. The results showed that Se, As and Pb were enriched in fly ash, and their sensitivity to particle size is quite different. The content of Se was the highest in PM1, reaching 193.04 mg/kg at the electrostatic precipitator (ESP) outlet. The average particle size of the total dust before ESP increased significantly from 21.686 to 62.612 µm after injecting the heterogeneous agglomeration adsorbent, conducive to its further removal by ESP. In addition, the concentrations of gaseous Se, As and Pb in the flue gas decreased after adsorbent spray, and accordingly, their contents in the hierarchical particles increased, indicating that the adsorbent could effectively promote the adsorption of gaseous trace elements in fly ash and reduce the possibility of their escape to the atmosphere. Total concentrations of Se, As and Pb emitted by wet flue gas desulfurization (WFGD) are 0.223, 0.668 and 0.076 µg/m3, which decreased by 59.98%, 47.69% and 90.71%, respectively. Finally, a possible HA mechanism model was proposed, where chemical adsorption, physical condensation and collision agglomeration of gaseous TEs and fine particles with adsorbent droplets occurred to form larger agglomerates.

Construction and validation of N6-methyladenosine long non-coding RNAs signature of prognostic value for early biochemical recurrence of prostate cancer.

PURPOSE: Early biochemical recurrence (eBCR) indicated a high risk for potential recurrence and metastasis in prostate cancer. The N6-methyladenosine (m6A) methylation modification played an important role in prostate cancer progression. This study aimed to develop a m6A lncRNA signature to accurately predict eBCR in prostate cancer. METHODS: Pearson correlation analysis was first conducted to explore m6A lncRNAs and univariate Cox regression analysis was further performed to identify m6A lncRNAs of prognostic roles for predicting eBCR in prostate cancer. The m6A lncRNA signature was constructed by least absolute shrinkage and selection operator analysis (LASSO) in training cohort and further validated in test cohort. Furthermore, half maximal inhibitory concentration (IC50) values were utilized to explore potential effective drugs for high-risk group in this study. RESULTS: Five hundred and thirty-eighth m6A lncRNAs were searched out through Pearson correlation analysis and 25 out of 538 m6A lncRNAs were identified to pose prediction roles for eBCR in prostate cancers. An m6A lncRNA signature including 5 lncRNAs was successfully built in training cohort. The high-risk group derived from m6A lncRNA signature could efficiently predict eBCR occurrence in both training (p < 0.001) and test cohort (p = 0.002). ROC analysis also confirmed that lncRNA signature in this study posed more accurate prediction roles for eBCR occurrence when compared with PSA, TNM stages and Gleason scores. Drug sensitivity analysis further discovered that various drugs could be potentially utilized to treat high-risk samples in this study. CONCLUSIONS: The m6A lncRNA signature in this study could be utilized to efficiently predict eBCR occurrence, various clinical characteristic and immune microenvironment for prostate cancer.

N6-methyladenosine long non-coding RNAs reveal novel tool to implicate overall survival and immune microenvironment in renal clear cell carcinoma.

PURPOSE: This study aimed to investigate whether N6-methyladenosine (m6A)-related long non-coding RNAs (m6ARelncRNAs) could provide novel tools to predict overall survival of renal clear cell carcinoma. METHODS: The transcriptomic data and clinical information of patients with renal clear cell carcinoma from The Cancer Genome Atlas (TCGA) were analysed. Distinct m6A modification patterns were systemically analysed via consensus clustering analysis. An m6ARelncRNA signature was constructed in the training cohort using the least absolute shrinkage and selection operator (LASSO) analysis and validated in the test cohort. Potential predictive accuracy of the signature was further assessed via Kaplan-Meier survival, univariate and multivariate Cox regression and subgroup analyses. The Tumour Immune Dysfunction and Exclusion (TIDE) algorithm was used to investigate the role of m6ARelncRNAs in guiding immunotherapy for patients with renal carcinoma. RESULTS: An m6ARelncRNA signature based on only six lncRNAs was successfully constructed. The high-risk group derived from this signature had significantly poorer overall survival in both training and test cohorts (p < 0.001). Independent prognostic analysis further revealed that m6ARelncRNA risk (p < 0.01) was an independent risk factor for survival outcomes of renal carcinoma. TIDE algorithm revealed that immunotherapy response was poorer in the high-risk group than in the low-risk group. Drug sensitivity analysis based on IC50 revealed that high-risk patients were potentially sensitive to various anti-tumour drugs, including bortezomib, cisplatin, docetaxel, etoposide and sunitinib. CONCLUSION: m6ARelncRNAs provide novel tools that can be used to predict overall survival and examine the immune microenvironment of renal clear cell carcinoma.

Ae1/Sbe1 maize-derived high amylose improves gut barrier function and ameliorates type II diabetes in high-fat diet-fed mice by increasing Akkermansia.

Type II diabetes mellitus (T2DM) has its origins in chronic inflammation due to immune dysregulation. Improving chronic inflammation can significantly reduce the probability of T2DM and the rate of disease progression. Resistance to starch 2 (RSII) high-amylose maize starch (HAMS) has been widely implicated in the improvement and regulation of T2DM. However, its exact molecular mechanisms have not been fully discovered. Here, we used CRISPR/Cas9 technology to knock out two starch-branching enzyme genes, Ae1 and Sbe1, in maize to obtain mutants containing higher levels of HAMS. In experiments in which HAMS was fed to mice on a high-fat diet (HFD), we confirmed the function of HAMS in ameliorating hyperglycemia. Mechanistically, we found that HAMS improves the gut barrier function by increasing the Akkermansia abundance in the gut. This increase led to the alleviation of chronic inflammation in mice on a HFD, resulting in improved insulin sensitivity and a decrease in blood glucose.

Ferroptosis-Related Long Noncoding RNAs Have Excellent Predictive Ability for Multiomic Characteristics of Bladder Cancer.

Background: The role of ferroptosis-related long non-coding RNAs (lncRNAs) in bladder cancer remains elusive. This study is aimed at examining the prognostic role of ferroptosis-related lncRNAs in bladder cancer. Materials and Methods: The transcriptomic matrix and clinical information of patients with bladder cancer were obtained from The Cancer Genome Atlas (TCGA) database. A ferroptosis-related lncRNA signature was developed via the least absolute shrinkage and selection operator (LASSO) analysis using data from the training cohort, and the signature was further validated using data from the test cohort. The role of AC006160.1, the most significant lncRNA in the risk signature, was examined in various cell lines including SV-HUC-1, BIU-87, HT-1376, T24, RT4, RT-112, 5637, and UMUC3. The pcDNA3.1-AC006160.1 plasmid was constructed and transfected into the bladder cancer cell lines T24 and BIU-87. In addition, cell proliferation, colony formation, transwell, and wound healing assays were performed to examine the biological function of AC006160.1 in T24 and BIU-87 cell lines. Results: Two clusters were identified through consensus clustering based on prognostic ferroptosis-related lncRNAs. A 5-lncRNA risk signature was successfully constructed using data from the training cohort and validated using data from the test cohort. The risk signature had excellent ability to predict survival outcomes, clinical stages, pathological grades, expression of immune checkpoints, and immunotherapeutic responses in bladder cancer samples. Furthermore, AC006160.1 expression was found to be lower in the cancer cell lines BIU-87, T24, RT4, RT-112, and 5637 than in the normal control cell line SV-HUC-1. Cell proliferation, colony formation, transwell migration, and wound healing assays validated that overexpression of AC006160.1 significantly inhibited the proliferation and invasion abilities of both T24 and BIU-87 cells. Drug sensitivity analysis revealed that patients with high expression of AC006160.1 were sensitive to metformin and methotrexate, and the results were further validated via in vitro drug experiments. Conclusions: Ferroptosis-related lncRNAs play a vital role in predicting the multiomic characteristics of bladder cancer. The lncRNA AC006160.1 serves as a protective factor for the development of bladder cancer.

HY-1C ultraviolet imager captures algae blooms floating on water surface.

Some species of algae such as cyanobacteria can vertically migrate through water during a day, which is a notable floating feature of harmful algae blooms. To date, this process has been observed and quantified using visible and near-infrared (VNIR) bands from spaceborne sensors with high temporal resolution (i.e., Geostationary Ocean Color Imager; GOCI). In this study, we conducted an in-situ measurement at Taihu Lake in China to investigate the ultraviolet (UV) reflection spectra of floating cyanobacteria blooms, and identified that they have significant UV reflection features (higher than that of background water) associated with their floating status. This has been demonstrated using spaceborne UV images at both 355 and 385 nm from the Ultraviolet Imager (UVI) onboard Haiyang-1C (HY-1C) of China. Compared with synchronous optical images from the Chinese Ocean Color and Temperature Scanner (COCTS), we found that UVI has a special ability to distinguish cyanobacteria floating on water surface. Additionally, the intensity of the UV signals obtained is positively correlated with the cyanobacterial equivalent density. Ultraviolet remote sensing, therefore, can work as a new approach for the detection of harmful algae blooms and help determine the floating status of them, which deserves further research.

Novel MDM2 Inhibitor XR-2 Exerts Potent Anti-Tumor Efficacy and Overcomes Enzalutamide Resistance in Prostate Cancer.

Background: The inactivation of tumor-suppressor p53 plays an important role in second generation anti-androgens (SGAs) drug resistance and neuroendocrine differentiation in castration-resistant prostate cancer (CRPC). The reactivation of p53 by blocking the MDM2-p53 interaction represents an attractive therapeutic remedy in cancers with wild-type or functional p53. Whether MDM2-p53 inhibitor could overcome SGAs drug resistance in CRPC is still needed further research. Here, we investigated the anti-tumor efficacy and mechanisms of a novel MDM2-p53 inhibitor XR-2 in CRPC. Methods: To investigate the functions and mechanisms of XR-2 in prostate cancer, in vitro and in vivo biofunctional assays were performed. Western blot and qRT-PCR assay were performed to detect the protein and mRNA expression levels of indicated genes. CCK8, colony formation, flow cytometry and senescence assays were performed for cell function identifications. RNA-sequencing and bioinformatics analysis were mainly used to identify the influence of XR-2 on prostate cancer cells transcriptome. Subcutaneous 22Rv1 derived xenografts mice model was used to investigate the in vivo anti-tumor activity of XR-2. In addition, the broad-spectrum anti-tumor activities in vivo of XR-2 were evaluated by different xenografts mice models. Results: XR-2 could directly bind to MDM2, potently reactivate the p53 pathway and thus induce cell cycle arrest and apoptosis in wild-type p53 CRPC cell lines. XR-2 also suppresses the AR pathway as p53 regulates AR transcription inhibition and MDM2 participates in AR degradation. As a result, XR-2 efficiently inhibited CRPC cell viability, showed a synergistic effect with enzalutamide and overcame enzalutamide resistance both in vitro and in vivo. Moreover, results illustrated that XR-2 possesses broad-spectrum anti-tumor activities in vivo with favourable safety. Conclusion: MDM2-p53 inhibitor (XR-2) possesses potently prostate cancer progresses inhibition activity both in vitro and in vivo. XR-2 shows a synergistic effect with enzalutamide and overcomes enzalutamide resistance.

Ferroptosis Mediation Patterns Reveal Novel Tool to Implicate Immunotherapy and Multi-Omics Characteristics in Bladder Cancer.

Background: The regulatory role of ferroptosis in malignant tumours has been recently demonstrated. However, the potential roles of ferroptosis mediation patterns in bladder cancer remain elusive. Materials and Methods: The ferroptosis mediation patterns of 889 bladder cancer samples were comprehensively evaluated based on ferroptosis-related genes. The underlying correlations between these mediation patterns and multi-omic characteristics of bladder cancer were systematically analysed. The ferroptosis mediation patterns of individual samples were quantified by ferropscore using the principal component analysis algorithm. The typical ferroptosis-related genes with prognostic roles were further randomly validated using immunohistochemical staining, real-time polymerase chain reaction and western blotting. Results: Three different ferroptosis mediation patterns were identified. The abundance of infiltration of 23 immune cells was different among the three mediation patterns. The quantification of ferroptosis mediation patterns in individual samples served as a promising tool for predicting patient survival outcomes; immune cell infiltration abundance; tumour mutation burden; oncogenic mutation status and tumour grade, stage and molecular subtypes. Low ferropscore combined with high tumour mutation burden was associated with the best survival prognosis. Expressions of PD-L1 (p < 0.001), PD-1 (p = 0.002) and CTLA-4 (p = 0.003) were all significantly upregulated in the high ferropscore group. Low ferropscores also predicted good immunotherapy response for anti-CTLA4 strategy. The mRNA and protein levels of FADS2, a typical ferroptosis-related gene used in the study, were higher in bladder cancer cell lines than in controlled SV-HUC-1 cells. In addition, immunohistochemical staining revealed significantly higher expression levels of FADS2 in human bladder cancer tumour tissues than in normal tissues. Conclusion: This study identified three distinct ferroptosis mediation patterns in bladder cancer. Quantification of ferroptosis mediation patterns in individual samples may help to improve the understanding of multiomic characteristics and guide future immunotherapy responses to bladder cancer.

Predictive role of ferroptosis-related long non-coding RNAs in bladder cancer and their association with immune microenvironment and immunotherapy response.

BACKGROUND: We have previously reported that ferroptosis has an important role in bladder cancer development. In this study, we aimed to further explore the possible predictive ability of ferroptosis-related long non-coding RNAs (lncRNAs) in bladder cancer and their relation with immune microenvironment and immunotherapy response. MATERIALS AND METHODS: The ferroptosis-related lncRNAs were identified by Pearson's correlation analysis. The predictive lncRNA signature was developed by univariate and multivariate regression analyses. Only the main effects of independent variables in multivariate analysis were included in this signature. The TCGA dataset was defined as the training cohort and GEO was the validation cohort in this study. All samples were grouped into a high- or low-risk group depending on risk signature. The prognostic role of lncRNA signature was explored through survival analysis and receiver operating characteristic curve (ROC) analysis in both TCGA and GEO cohorts. Additionally, the independent prognostic ability of the lncRNA signature was confirmed by multivariate independent analysis. Furthermore, the relationship between lncRNAs and immune microenvironment as well as immunotherapy response in bladder cancers was studied. RESULTS: The Kaplan-Meier curves identified significantly poorer overall survival outcomes for high-risk groups in both TCGA (p < 0.001) and GEO (p < 0.001) cohorts. The area under the curve (AUC) during ROC analysis of 1, 3, and 5 years was 0.781 ± 0.046, 0.784 ± 0.027, and 0.817 ± 0.025, respectively, in the TCGA cohort and 0.665 ± 0.177, 0.719 ± 0.068, and 0.791 ± 0.055, respectively, in the GEO cohort. The multivariate independent analysis in TCGA cohort identified age (p = 0.003), stage (p < 0.001), and signature risk score (p < 0.001) as independent risk factors for overall survival. Furthermore, this study demonstrated a significant difference in infiltration levels of various immune cells between high- and low-risk groups. The high risk group tended to have a lower expression of proteins including PD1 (p < 0.01), PD-L1 (p < 0.01), CTLA-4 (p < 0.05), etc. corresponding to various immune checkpoints. Additionally, the immunotherapy trial confirmed that the high-risk group tended to have a poorer treatment response than the low-risk group (p < 0.001). CONCLUSIONS: The ferroptosis-related lncRNAs exhibited a good predictive capacity for overall survival in bladder cancer. Additionally, they could be utilized to reveal tumour-immune microenvironment and immunotherapy responses.