Integrative analyses of bulk and single-cell transcriptomics reveals the infiltration and crosstalk of cancer-associated fibroblasts as a novel predictor for prognosis and microenvironment remodeling in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.

Multi-omics data-based analysis characterizes molecular alterations of the vesicle genes in human colorectal cancer.

The role of vesicular genes in the development of colorectal cancer (CRC) is crucial. Analyzing alterations in these genes at multi-omics can aid in understanding the molecular pathways behind colorectal carcinogenesis and identifying potential treatment targets. However, studies on the overall alteration of vesicular genes in CRC are still lacking. In this study, we aimed to investigate the relationship between vesicle genetic alterations and CRC progression. To achieve this, we analyzed molecular alterations in CRC vesicle genes at eight levels, including mRNA, protein, and epigenetic levels. Additionally, we examined CRC overall survival-related genes that were obtained from a public database. Our analysis of chromatin structural variants, DNA methylation, chromatin accessibility, and proteins (including phosphorylation, ubiquitination, and malonylation), along with RNA-seq data from the TCGA database, revealed multiple levels of alterations in CRC vesicle genes in the collected tissue samples. We progressively examined the alterations of vesicle genes in mRNA and protein levels in CRC and discovered the hub genes. Further investigation identified the probable essential transcription factors. This study contributes to a thorough knowledge of the connection between vesicle gene alterations at multiple levels and the development of CRC and offers a theoretical framework for the identification of novel treatment targets.

A meta-analysis between robotic hepatectomy and conventional open hepatectomy.

Current meta-analysis was performed to compare robotic hepatectomy (RH) with conventional open hepatectomy (OH) in terms of peri-operative and postoperative outcomes. PubMed, EMBASE, and the Cochrane Library were all searched up for comparative studies between RH and OH. RevMan5.3 software and Stata 13.0 software were used for statistical analysis. Nineteen studies with 1747 patients who received RH and 23,633 patients who received OH were included. Pooled results indicated that patients who received RH were generally younger than those received OH (P < 0.00001). Moreover, RH was associated with longer operative time (P = 0.0002), less intraoperative hemorrhage (P < 0.0001), lower incidence of intraoperative transfusion (P = 0.003), lower incidence of postoperative any morbidity (P < 0.00001), postoperative major morbidity (P = 0.0001), mortalities with 90 days after surgery (P < 0.0001), and shorter length of postoperative hospital stay (P < 0.00001). Comparable total hospital costs were acquired between RH and OH groups (P = 0.46). However, even at the premise of comparable R0 rate (P = 0.86), RH was associated with smaller resected tumor size (P < 0.00001). Major hepatectomy (P = 0.02) and right posterior hepatectomy (P = 0.0003) were less frequently performed in RH group. Finally, we concluded that RH was superior to OH in terms of peri-operative and postoperative outcomes. RH could lead to less intraoperative hemorrhage, less postoperative complications and an enhanced postoperative recovery. However, major hepatectomy and right posterior hepatectomy were still less frequently performed via robotic approach. Future more powerful well-designed studies are required for further exploration.

Exosomal long non-coding RNA TRPM2-AS promotes angiogenesis in gallbladder cancer through interacting with PABPC1 to activate NOTCH1 signaling pathway.

BACKGROUND: Abnormal angiogenesis is crucial for gallbladder cancer (GBC) tumor growth and invasion, highlighting the importance of elucidating the mechanisms underlying this process. LncRNA (long non-coding RNA) is widely involved in the malignancy of GBC. However, conclusive evidence confirming the correlation between lncRNAs and angiogenesis in GBC is lacking. METHODS: LncRNA sequencing was performed to identify the differentially expressed lncRNAs. RT-qPCR, western blot, FISH, and immunofluorescence were used to measure TRPM2-AS and NOTCH1 signaling pathway expression in vitro. Mouse xenograft and lung metastasis models were used to evaluate the biological function of TRPM2-AS during angiogenesis in vivo. EDU, transwell, and tube formation assays were used to detect the angiogenic ability of HUVECs. RIP, RAP, RNA pull-down, dual-luciferase reporter system, and mass spectrometry were used to confirm the interaction between TRPM2-AS, IGF2BP2, NUMB, and PABPC1. RESULTS: TRPM2-AS was upregulated in GBC tissues and was closely related to angiogenesis and poor prognosis in patients with GBC. The high expression level and stability of TRPM2-AS benefited from m6A modification, which is recognized by IGF2BP2. In terms of exerting pro-angiogenic effects, TRPM2-AS loaded with exosomes transported from GBC cells to HUVECs enhanced PABPC1-mediated NUMB expression inhibition, ultimately promoting the activation of the NOTCH1 signaling pathway. PABPC1 inhibited NUMB mRNA expression through interacting with AGO2 and promoted miR-31-5p and miR-146a-5p-mediated the degradation of NUMB mRNA. The NOTCH signaling pathway inhibitor DAPT inhibited GBC tumor angiogenesis, and TRPM2-AS knockdown enhanced this effect. CONCLUSIONS: TRPM2-AS is a novel and promising biomarker for GBC angiogenesis that promotes angiogenesis by facilitating the activation of the NOTCH1 signaling pathway. Targeting TRPM2-AS opens further opportunities for future GBC treatments.

PP4R1 promotes glycolysis and gallbladder cancer progression through facilitating ERK1/2 mediated PKM2 nuclear translocation.

Gallbladder cancer (GBC) is a common solid tumor of the biliary tract with a high mortality rate and limited curative benefits from surgical resection. Here, we aimed to elucidate the pathogenesis of GBC from the perspective of molecular mechanisms and determined that protein phosphatase 4 regulator subunit 1 (PP4R1) is overexpressed in GBC tissues and contributes to poor prognosis. Through a series of in vitro and in vivo experiments, we demonstrated that PP4R1 overexpression improved tumorigenesis in GBC cells. Further mechanistic exploration revealed that PP4R1 directly interacts with pyruvate kinase-M2 (PKM2), a key regulator of glycolysis. PP4R1 promotes the extracellular signal-related kinase 1 and 2 (ERK1/2)-mediated PKM2 nuclear translocation, thereby participating in the regulation of tumor glycolysis. Interestingly, we determined that PP4R1 strengthens the interaction between ERK1/2 and PKM2. Furthermore, PP4R1 enhanced the suppressive effects of the ERK inhibitor SCH772984 on GBC. In conclusion, our data showed that PP4R1 is a promising biomarker associated with GBC and confirmed that PP4R1 regulates PKM2-mediated tumor glycolysis, which provides a metabolic growth advantage to GBC cells, thereby promoting GBC tumor growth and metastasis1.

Efficacy of art therapy in enhancing mental health of clinical nurses: A meta-analysis.

INTRODUCTION: Art therapy (AT) has been widely utilized as a therapeutic approach for clinical nurses. In recent years, more and more researchers have applied art therapy to enhance clinical nurses' mental well-being. However, many studies conducted in this area have suffered from limited sample sizes and insufficient research evidence. AIM: This study aims to conduct a systematic evaluation of the efficacy of art therapy on the mental health of clinical nurses. METHODS: RCTs on art therapy for clinical nurses were searched across databases such as PubMed, Embase, etc., the results were analysed using RevMan 5.3. RESULTS: There were 19 RCTs encompassing 1338 clinical nurses involved in this analysis. The Meta-analysis revealed that art therapy exhibited a significant reduction in anxiety levels (measured by the SAS) among clinical nurses, as well as depression levels and perceived stress levels (measured by the CPSS). Furthermore, art therapy demonstrated a reduction in negative coping style and an improvement in positive coping style. DISCUSSION: Findings indicate that art therapy can reduce anxiety, depression and stress levels in clinical nurses, while also enhance positive coping styles and promote mental well-being. Therefore, the widespread implementation of art therapy in this context is highly recommended. DECLARATION: I hereby declare that my article is directly relevant to the field of mental health nursing. It highlights the critical importance of psychological well-being and supplements the evidence on The effects of art therapy on the occupational mental health of clinical nurses.

Deep Learning Based Prediction of Myopia Control Effect in Children Treated With Overnight Orthokeratology.

OBJECTIVES: To develop and validate a deep learning-based model for predicting 12-month axial length (AL) elongation using baseline factors and early corneal topographic changes in children treated with orthokeratology (Ortho-K) and to investigate the association between these factors and myopia control impact. METHODS: A total of 115 patients with Ortho-K were enrolled. Influential baseline factors that have a statistically significant correlation with 12-month AL from medical records were selected using Pearson correlation coefficients. Simultaneously, the height, area, and volume of the defocus region were directly calculated from the corneal topography. Then, the prediction model was developed by combining multiple linear regression and deep neural network and evaluated in an independent group (83 patients for developing the algorithm and 32 patients for evaluation). RESULTS: Age ( r= -0.30, P <0.001), spherical equivalent refractive (SE; r =0.20, P =0.032), and sex ( r =0.19, P =0.032) were significantly correlated with the AL elongation while pupil diameter, flat k, steep k, horizontal corneal diameter (white to white), anterior chamber depth, and cell density were not ( P >0.1). The prediction model was developed using age, SE, and corneal topographic variation, and the validation of the model demonstrated its effectiveness in predicting AL elongation. CONCLUSIONS: The AL elongation was accurately predicted by the deep learning model, which effectively incorporated both baseline factors and corneal topographic variation.

Attention-Based Deep Learning Model for Prediction of Major Adverse Cardiovascular Events in Peritoneal Dialysis Patients.

Major adverse cardiovascular events (MACE) encompass pivotal cardiovascular outcomes such as myocardial infarction, unstable angina, and cardiovascular-related mortality. Patients undergoing peritoneal dialysis (PD) exhibit specific cardiovascular risk factors during the treatment, which can escalate the likelihood of cardiovascular events. Hence, the prediction and key factor analysis of MACE have assumed paramount significance for peritoneal dialysis patients. Current pathological methodologies for prognosis prediction are not only costly but also cumbersome in effectively processing electronic health records (EHRs) data with high dimensionality, heterogeneity, and time series. Therefore in this study, we propose the CVEformer, an attention-based neural network designed to predict MACE and analyze risk factors. CVEformer leverages the self-attention mechanism to capture temporal correlations among time series variables, allowing for weighted integration of variables and estimation of the probability of MACE. CVEformer first captures the correlations among heterogeneous variables through attention scores. Then, it analyzes the correlations within the time series data to identify key risk variables and predict the probability of MACE. When trained and evaluated on data from a large cohort of peritoneal dialysis patients across multiple centers, CVEformer outperforms existing models in terms of predictive performance.

In vitro and in vivo antimicrobial effects of domiphen combined with itraconazole against Aspergillus fumigatus.

Aspergillus fumigatus, a prevalent saprophytic fungus in the atmosphere, is known to rapidly induce severe invasive aspergillosis (IA) upon inhalation of its conidia by humans or animals. The mortality rate associated with IA exceeds 50%. The misuse of antifungal agents has contributed to the emergence of numerous highly pathogenic drug-resistant strains of A. fumigatus. Our study found that the combination of domiphen and itraconazole had sound synergistic antimicrobial effects against wild-type and itraconazole-resistant A. fumigatus in vivo and in vitro through MIC, FIC, plate inoculation, growth curve experiments, and Galleria mellonella infection model. Drug cytotoxicity and pharmacological tests for acute toxicity assays demonstrated that both itraconazole and domiphen showed minimal cytotoxicity and good biocompatibility. The transcriptome sequencing experiment demonstrated that domiphen exerted a suppressive effect on the expression of various genes, including those involved in drug efflux, redox regulation, and cellular membrane and cell wall remodeling. The present investigation explores the synergistic antimicrobial mechanisms of domiphen and itraconazole, encompassing three key aspects: (i) domiphen inhibited the efflux of itraconazole by reducing the expression of drug efflux-related genes, (ii) the combination has good ability to disrupt the cell membrane and cell wall, (iii) the combination also can remove biofilm more effectively. In summary, the utilization of domiphen as a synergist of itraconazole exhibited disruptive effects on the biofilm, cell wall, and cell membrane of A. fumigatus. This subsequently led to a modified distribution of itraconazole within the fungal organism, ultimately resulting in enhanced antifungal efficacy. The results of this study may provide a new therapeutic strategy for the treatment of IA caused by drug-resistant A. fumigatus.

The association between metacognition, coping style and fear of cancer recurrence among postmastectomy patients: A cross sectional study.

PURPOSE: To investigate the incidence of fear of cancer recurrence (FCR) in Chinese postmastectomy patients and explore the relationships between metacognition, coping style, and FCR on the basis of the self-regulating executive function model. METHODS: A total of 480 postmastectomy patients from two tertiary comprehensive hospitals in Xi'an were enrolled from March 2021 to November 2021. The participants completed demographic information, the Metacognitions Questionnaire-30 (MCQ-30), Positive Metacognitions and Positive Meta-Emotions Questionnaire (PMCEQ), Simplified Copying Style Questionnaire (SCSQ), and Fear of Cancer Recurrence Inventory Short Form (FCRI-SF). RESULTS: 34.2% of the respondents had scores indicating a clinical level of FCR (FCRI-SF≥13). FCR had a positive correlation with maladaptive metacognition and negative coping style (P < 0.01), while adaptive metacognition and positive coping style were negatively correlated (P < 0.01). Besides, maladaptive metacognition had both direct and indirect effects on FCR, with the indirect effect primarily mediated by negative coping style (total effect, 0.430). Adaptive metacognition had both direct and indirect effects on FCR, with the indirect effect primarily mediated by positive coping style (total effect,ï¹£0.302). CONCLUSION: FCR was a common phenomenon in postmastectomy patients and moderate in most patients. In addition, both metacognition and coping style had a direct and indirect association with the occurrence and development of FCR. Moreover, adaptive metacognition and maladaptive metacognition had different mechanisms on FCR in patients with breast cancer.

5-aminolevulinic acid photodynamic therapy using 560-1200 nm followed by 420-1200 nm broadband light in the treatment of moderate-to-severe acne.

BACKGROUND: Moderate-to-severe acne vulgaris, which is a chronic inflammatory skin disease, seriously impacts millions of people. However, traditional therapies may cause severe adverse reactions that are unacceptable to many patients, thus limiting the further application of these therapies. Novel therapeutic approaches to effectively treat moderate-to-severe acne vulgaris with minimal adverse reactions are urgently needed. In this retrospective study, we investigated the efficacy and adverse reactions of photodynamic therapy (PDT) using 560-1200 nm followed by 420-1200 nm broadband light (BBL). METHODS: Twenty-four patients with moderate-to-severe acne vulgaris were included in the study and all patients expressed a strong desire for beauty. After aminolevulinic acid (ALA) gel applied, the entire face was sequentially irradiated by using BBL with a 560 nm cut-off filter (560-1200 nm), followed by BBL with a 420 nm cut-off filter (420-1200 nm). The clinical efficacy was evaluated by the proportion of patients achieving cured response and excellent response (effective rate), based on the percentage of lesions reduction (treatment rate). The fluorescent images and photographs of acne vulgaris were recorded. Pain and other common local adverse reactions during the treatment were also recorded and evaluated. RESULTS: In patients with moderate acne, the mean treatment rates were 57.74 ± 16.40 (%) and 87.40 ± 8.521 (%) at the 6th week and 12th week of treatment, respectively. In patients with severe acne, the mean treatment rates were 60.95 ± 12.06 (%) and 85.04 ± 9.115 (%) at the 6th week and 12th week of treatment, respectively. At the 6th and 12th weeks of treatment, the effective rates of patients were 20.00 % and 93.33 % in patients with moderate acne, and 0.000 % and 88.89 % in patients with severe acne, respectively. Pain scores were significantly higher in patients with severe acne compared to patients with moderate acne when receiving 560-1200 nm BBL-PDT. Additionally, patients when receiving 420-1200 nm BBL-PDT exhibited significantly higher pain scores than those when receiving 560-1200 nm BBL-PDT. The degree of erythema was more severe in patients with severe acne than in those with moderate acne. The pigmentation was observed in one patient with moderate acne and one patient with severe acne. CONCLUSION: The 560-1200 nm and 420-1200 nm BBL-PDT therapy can effectively treat moderate-to-severe acne vulgaris with tolerable adverse reactions, providing a new option for patients with higher esthetic requirements.

Relationship between myopia control and amount of corneal refractive change after orthokeratology lens treatment.

BACKGROUND: To evaluate the relationship between amount of corneal refractive change (CRC) after wearing orthokeratology (Ortho-K) lenses and axial length (AL) growth. METHODS: We retrospectively enrolled 77 patients (77 eyes) aged 8-14 years who wore Ortho-K lenses more than 12 months. We divided the patients into 2 subgroups: spherical equivalent (SE) ≤ -3.0 D and SE > -3.0 D subgroup. The sagittal and tangential curvature maps and corneal topographic data within the 8-mm diameter ring at the baseline and during follow-up visits after wearing Ortho-K lens were recorded in addition to the area, height, and volume of the CRC region. The AL data were recorded at the baseline and during follow-up visits. Multivariate linear regression was conducted to analyze associations between the area, height, and volume of the CRC region, AL elongation, and SE. RESULTS: The average change in the CRC region was 9.77 ± 0.60 D in height, 16.66 ± 3.61 mm2 in area, and 87.47 ± 8.96 D*mm2 in volume on the tangential diagram after wearing Ortho-K lenses for 3 months. The AL showed a change of 0.19 ± 0.14 mm after 1 year of Ortho-K lens wear (P < 0.05). At 1 year, AL elongation was negatively correlated with the area (P = 0.019) and volume (P < 0.001) of the CRC region. At 1 year, for every 1-mm2 increase in the area and every 1-D*mm2 increase in the volume of the CRC region, the average AL elongation decreased by 0.01 mm and 0.002 mm, respectively, in the multivariate analysis. In patients with SE ≤ -3.0 D, AL elongation was negatively correlated with the CRC-region volume (ß = -0.002, P = 0.018), and in patients with SE > -3.0 D, AL elongation was negatively correlated with the CRC-region area (ß = -0.017, P = 0.016). CONCLUSIONS: The AL elongation-control efficacy of Ortho-K lenses may be related to the area and volume of the CRC region.

The role of CD4+ T cells in tumor and chronic viral immune responses.

Immunotherapies are mainly aimed to promote a CD8+ T cell response rather than a CD4+ T cell response as cytotoxic T lymphocytes (CTLs) can directly kill target cells. Recently, CD4+ T cells have received more attention due to their diverse roles in tumors and chronic viral infections. In antitumor and antichronic viral responses, CD4+ T cells relay help signals through dendritic cells to indirectly regulate CD8+ T cell response, interact with B cells or macrophages to indirectly modulate humoral immunity or macrophage polarization, and inhibit tumor blood vessel formation. Additionally, CD4+ T cells can also exhibit direct cytotoxicity toward target cells. However, regulatory T cells exhibit immunosuppression and CD4+ T cells become exhausted, which promote tumor progression and chronic viral persistence. Finally, we also outline immunotherapies based on CD4+ T cells, including adoptive cell transfer, vaccines, and immune checkpoint blockade. Overall, this review summarizes diverse roles of CD4+ T cells in the antitumor or protumor and chronic viral responses, and also highlights the immunotherapies based on CD4+ T cells, giving a better understanding of their roles in tumors and chronic viral infections.

Green Synthesis of MOF-Mediated pH-Sensitive Nanomaterial AgNPs@ZIF-8 and Its Application in Improving the Antibacterial Performance of AgNPs.

Purpose: Herein, an emerging drug delivery system was constructed based on zeolite imidazole backbone (ZIF-8) to improve antibacterial defects of nanosilver (AgNPs), such as easily precipitated and highly cytotoxic. Methods: The homogeneous dispersion of AgNPs on ZIF-8 was confirmed by UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM. The appropriate AgNPs loading ratio on ZIF-8 was screened through the cell and antibacterial experiments based on biosafety and antibacterial performance. The optimal environment for AgNPs@ZIF-8 to exert antibacterial performance was probed in the context of bacterial communities under different acid-base conditions. The potential mechanism of AgNPs@ZIF-8 to inhibit the common clinical strains was investigated by observing the biofilm metabolic activity and the level of reactive oxygen species (ROS) in bacteria. Results: The successful piggybacking of AgNPs by ZIF-8 was confirmed using UV-Vis spectroscopy, FTIR spectroscopy, particle size analysis, zeta potential analysis, and SEM characterization methods. Based on the bacterial growth curve (0-24 hours), the antibacterial ability of AgNPs@ZIF-8 was found to be superior to AgNPs. When the mass ratio of ZIF-8 and AgNPs was 1:0.25, the selection of AgNPs@ZIF-8 was based on its superior antimicrobial efficacy and enhanced biocompatibility. Notably, under weakly acidic bacterial microenvironments (pH=6.4), AgNPs@ZIF-8 demonstrated a more satisfactory antibacterial effect. In addition, experiments on biofilms showed that concentrations of AgNPs@ZIF-8 exceeding 1×MIC resulted in more than 50% biofilm removal. The nanomedicine was found to increase ROS levels upon detecting the ROS concentration in bacteria. Conclusion: Novel nanocomposites consisting of low cytotoxicity drug carrier ZIF-8 loaded with AgNPs exhibited enhanced antimicrobial effects compared to AgNPs alone. The pH-responsive nano drug delivery system, AgNPs@ZIF-8, exhibited superior antimicrobial activity in a mildly acidic environment. Moreover, AgNPs@ZIF-8 effectively eradicated pathogenic bacterial biofilms and elevated the intracellular level of ROS.

ZFP64 Promotes Gallbladder Cancer Progression through Recruiting HDAC1 to Activate NOTCH1 Signaling Pathway.

The lack of meaningful and effective early-stage markers remains the major challenge in the diagnosis of gallbladder cancer (GBC) and a huge barrier to timely treatment. Zinc finger protein 64 (ZFP64), a member of the zinc finger protein family, is considered to be a promising predictor in multiple tumors, but its potential effect in GBC still remains unclear. Here, we identified that ZFP64 was a vital regulatory protein in GBC. We found that ZFP64 expressed higher in GBC gallbladder carcinoma tissues than in normal tissues and was positively correlated with poor prognosis. Furthermore, ZFP64 was responsible for the migration, invasion, proliferation, anti-apoptosis, and epithelial mesenchymal transition (EMT) of GBC cells in vitro and in vivo. Mechanistically, through Co-IP assay, we confirmed that ZFP64 recruits HDAC1 localized to the promoter region of NUMB for deacetylation and therefore inhibits NUMB expression. The downregulation of NUMB enhanced the activation of the Notch1 signaling pathway, which is indispensable for the GBC-promotion effect of ZFP64 on GBC. In conclusion, ZFP64 regulated GBC progression and metastasis through upregulating the Notch1 signaling pathway, and thus ZFP64 is expected to become a new focus for a GBC prognostic marker and targeted therapy.

Effect of Metallic Coatings on the Wear Performance and Mechanism of 30CrMnSiNi2A Steel.

The finger lock structure of aircraft landing gear is prone to wear and failure during repeated locking and unlocking processes, which is disastrous for the service safety of the aircraft. At present, the commonly used material for finger locks in the industry is 30CrMnSiNi2A, which has a short wear life and high maintenance costs. It is crucial to develop effective methods to improve the wear resistance of 30CrMnSiNi2A finger locks. This work explores the wear resistance and wear mechanisms of different metallic coatings such as chromium, nickel, and cadmium-titanium on the surface of a 30CrMnSiNi2A substrate. The effects of load and wear time on the wear behavior are also discussed. The results indicated that the wear resistance of the chromium coating was the maximum. When the load was 80 N and 120 N, the wear mechanisms were mainly oxidation and adhesive. For greater loads, the wear mechanism of the coating after failure was mainly abrasive and oxidation, and the wear was extremely severe. When the load was 80 N, for a greater loading time, the wear mechanisms were mainly oxidation and adhesive.

Albendazole induces an anti-tumor effect and potentiates PD-L1 blockade immunotherapy.

BACKGROUND: Previously, albendazole (ABZ) has been reported as an anti-parasitic drug rather than anti-tumor drug. Our study aim to investigate whether ABZ also has a potential anti-tumor effect by shaping the tumor immune microenvironment and interrogate whether ABZ could synergize with the PD-L1 blockade. METHODS: C57BL/6 mice (C57) were intravenously injected with B16F10-luciferase (B16-luc) cells to establish a lung metastatic melanoma model and subcutaneously inoculated with B16-luc cells to establish a subcutaneous tumor model. The tumor volume and tumor metastasis loci of the mice were measured by a vernier caliper and in vivo imaging. RNA sequencing was performed to analyze the different genes and pathways of immune cells in the tumors. Flow cytometry and immunofluorescence were used to analyze the different subsets of tumor-infiltrating immune cells. RESULTS: The results suggested that ABZ significantly inhibited lung melanoma metastasis with decreased fluorescence intensity and nodule score and mediated the regression of subcutaneous melanoma in mice with decreased tumor volume. Moreover, RNA sequencing results showed that ABZ regulated the gene expression levels and pathways of immune cells in the tumor microenvironment (TME). Meanwhile, flow cytometry and immunofluorescence showed that the number and percentage of CD8+ T cells, CD4+ T cells, and TH1 cells were enhanced in tumors after ABZ treatment. Furthermore, the combination of ABZ and anti-PD-L1 treatment significantly potentiated anti-tumor efficacy in both lung metastasis and subcutaneous melanoma models and mediated an increase in the percentage of CD8+ T cells, CD4+ T cells, and TH1 cells as compared to the control group. CONCLUSION: ABZ inhibits melanoma growth and metastasis. Moreover, ABZ synergized with PD-L1 blockade mediates tumor regression.

Artificial mixed microbial system for polycyclic aromatic hydrocarbons degradation.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants with major risks to human health. Biological degradation is environmentally friendly and the most appealing remediation method for a wide range of persistent pollutants. Meanwhile, due to the large microbial strain collection and multiple metabolic pathways, PAH degradation via an artificial mixed microbial system (MMS) has emerged and is regarded as a promising bioremediation approach. The artificial MMS construction by simplifying the community structure, clarifying the labor division, and streamlining the metabolic flux has shown tremendous efficiency. This review describes the construction principles, influencing factors, and enhancement strategies of artificial MMS for PAH degradation. In addition, we identify the challenges and future opportunities for the development of MMS toward new or upgraded high-performance applications.

Identification and verification of a novel anoikis-related gene signature with prognostic significance in clear cell renal cell carcinoma.

PURPOSE: Clear cell renal cell carcinomas (ccRCCs) are the most common form of renal cancer in the world. The loss of extracellular matrix (ECM) stimulates cell apoptosis, known as anoikis. A resistance to anoikis in cancer cells is believed to contribute to tumor malignancy, particularly metastasis; however, the potential influence of anoikis on the prognosis of ccRCC patients is not fully understood. METHODS: In this study, anoikis-related genes (ARGs) with discrepant expression were selected from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The anoikis-related gene signature (ARS) was built using a combination of the univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses. ARS was also evaluated for their prognostic value. We explored the tumor microenvironment and enrichment pathways between different clusters of ccRCC. We also examined differences in clinical characteristics, immune cell infiltration and drug sensitivity between the high- and low-risk sets. In addition, we utilized three external databases and quantitative real-time polymerase chain reaction (qRT-PCR) to validate the expression and prognosis of ARGs. RESULTS: Eight ARGs (PLAUR, HMCN1, CDKN2A, BID, GLI2, PLG, PRKCQ and IRF6) were identified as anoikis-related prognostic factors. According to Kaplan-Meier (KM) analysis, ccRCC patients with high-risk ARGs have a worse prognosis. The risk score was found to be a significant independent prognostic indicator. According to tumor microenvironment (TME) scores, stromal score, immune score, and estimated score of the high-risk group were superior to those of the low-risk group. There were significant differences between the two groups regarding the amount of infiltrated immune cells, immune checkpoint expression as well as drug sensitivity. A nomogram was constructed using ccRCC clinical features and risk scores. The signature and the nomogram both performed well in predicting overall survival (OS) for ccRCC patients. According to a decision curve analysis (DCA), clinical treatment options for patients with ccRCC could be improved using this model. CONCLUSION: The results of validation from external databases and qRT-PCR were basically agreement with findings in TCGA and GEO databases. The ARS serving as biomarkers may provide an important reference for individual therapy of ccRCC patients.

JAG1 enhances angiogenesis in triple-negative breast cancer through promoting the secretion of exosomal lncRNA MALAT1.

Despite significant improvements in five-year survival rates due to early diagnosis and combination therapy, triple-negative breast cancer (TNBC) treatment remains a major challenge. Finding new and effective targets for diagnosis and drug therapy is urgent for TNBC patients. Jagged-1 (JAG1), one of the canonical ligands of the Notch signaling pathway, is involved in vascular budding and is a poor prognostic factor of TNBC. In this study, combined with quantitative real-time PCR, database analysis, animal experiments, and other means, JAG1 was confirmed to be related to the poor prognosis of TNBC patients. JAG1 was highly expressed in MDA-MB-231 Bone (231B) cells, with stronger invasion and metastasis ability than MDA-MB-231 (231) cells. Treatment of human vascular endothelial cells (HUVEC) with TNBC conditioned medium showed that TNBC JAG1 promoted the angiogenesis of HUVEC. Next, we detected the exosomes extracted from TNBC conditioned medium and found that JAG1 promoted the exosome secretion from 231 cells via ALIX-RAB11A/RAB35. In addition, we also found that the exosomes from JAG1 overexpressed TNBC cells contained more long non-coding RNA (lncRNA) MALAT1, and MALAT1 promoted angiogenesis of HUVEC by targeting miR-140-5p. Finally, the angiogenesis-promoting effect of JAG1 in TNBC was further investigated by matrix gel assay. In conclusion, we reveal that JAG1 has a pro-invasion effect on TNBC and is involved in microenvironment angiogenesis by promoting exosome secretion and the MALAT1-miR-140-5p-JAG1/VEGFA pathway.