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ABSTRACTGut microbiota has demonstrated an increasingly important role in the onset and development of colorectal cancer (CRC). Nonetheless, the association between gut microbiota and KRAS mutation in CRC remains enigmatic. We conducted 16S rRNA sequencing on stool samples from 94 CRC patients and employed the linear discriminant analysis effect size algorithm to identify distinct gut microbiota between KRAS mutant and KRAS wild-type CRC patients. Transcriptome sequencing data from nine CRC patients were transformed into a matrix of immune infiltrating cells, which was then utilized to explore KRAS mutation-associated biological functions, including Gene Ontology items and Kyoto Encyclopedia of Genes and Genomes pathways. Subsequently, we analyzed the correlations among these KRAS mutation-associated gut microbiota, host immunity, and KRAS mutation-associated biological functions. At last, we developed a predictive random forest (RF) machine learning model to predict the KRAS mutation status in CRC patients, based on the gut microbiota associated with KRAS mutation. We identified a total of 26 differential gut microbiota between both groups. Intriguingly, a significant positive correlation was observed between Bifidobacterium spp. and mast cells, as well as between Bifidobacterium longum and chemokine receptor CX3CR1. Additionally, we also observed a notable negative correlation between Bifidobacterium and GOMF:proteasome binding. The RF model constructed using the KRAS mutation-associated gut microbiota demonstrated qualified efficacy in predicting the KRAS phenotype in CRC. Our study ascertained the presence of 26 KRAS mutation-associated gut microbiota in CRC and speculated that Bifidobacterium may exert an essential role in preventing CRC progression, which appeared to correlate with the upregulation of mast cells and CX3CR1 expression, as well as the downregulation of GOMF:proteasome binding. Furthermore, the RF model constructed on the basis of KRAS mutation-associated gut microbiota exhibited substantial potential in predicting KRAS mutation status in CRC patients.IMPORTANCEGut microbiota has emerged as an essential player in the onset and development of colorectal cancer (CRC). However, the relationship between gut microbiota and KRAS mutation in CRC remains elusive. Our study not only identified a total of 26 gut microbiota associated with KRAS mutation in CRC but also unveiled their significant correlations with tumor-infiltrating immune cells, immune-related genes, and biological pathways (Gene Ontology items and Kyoto Encyclopedia of Genes and Genomes pathways). We speculated that Bifidobacterium may play a crucial role in impeding CRC progression, potentially linked to the upregulation of mast cells and CX3CR1 expression, as well as the downregulation of GOMF:Proteasome binding. Furthermore, based on the KRAS mutation-associated gut microbiota, the RF model exhibited promising potential in the prediction of KRAS mutation status for CRC patients. Overall, the findings of our study offered fresh insights into microbiological research and clinical prediction of KRAS mutation status for CRC patients.

Introduction: Isobutyric acid (IBA), a short‐chain fatty acid, has been unequivocally demonstrated to exert significant influence on the progression of colorectal cancer (CRC). Nevertheless, a comprehensive understanding of its intricate regulatory mechanisms remains elusive. Methods: Employing advanced techniques such as western blot, RT‐qPCR, and flow cytometry, we systematically investigated the impact of IBA on the expression of PD‐L1 in CRC cells. Concurrently, employing RNA silencing technology and small‐molecule inhibitors, we delved into the molecular intricacies underlying the regulatory axis of IBA involving ROCK1/c‐Myc/PD‐L1. Furthermore, through flow cytometry analysis, we examined the alterations in the tumor immune microenvironment following anti‐PD‐L1 antibody therapy in a murine tumor model treated with IBA. Results: Elevated levels of IBA were found to robustly activate PD‐L1 expression in CRC cells both in vitro and in vivo, concomitantly reshaping the tumor immune microenvironment. Subsequent mechanistic investigations unveiled that IBA, through its interaction and activation of ROCK1, promotes the activation of c‐Myc, thereby enhancing the transcription of PD‐L1. Silencing of ROCK1 and application of ROCK1 inhibitors effectively reversed the regulatory effects of IBA on PD‐L1. Additionally, IBA inhibited the activity of infiltrating CD8+ T cells, resulting in diminished antitumor immunity and attenuating the sensitivity to anti‐PD‐L1 therapy. Conclusion: Our study elucidates a novel mechanism by which IBA inhibits the sensitivity of CRC to anti‐PD‐L1 antibody therapy. Emphasizing IBA and its downstream pathways as potential therapeutic targets for immune therapy resistance mechanisms, our findings provide a novel theoretical foundation for overcoming immune therapy resistance. [ABSTRACT FROM AUTHOR]

A hybrid of halloysite nanotubes decorated with titanium dioxide nanoparticles (HNTs@TiO2) was synthesized by the sol–gel method and then mixed with ultra‐high molecular polyethylene (UHMWPE) by melt compounding to enhance its wear resistance properties. The incorporation of HNTs@TiO2 increased the crystallinity as well as the hardness of UHMWPE nanocomposites, which benefited less prone to plastic deformation during the friction process. In addition, the UHMWPE/HNTs@TiO2 maintained a high ductility character with a slight decrease in tensile strength compared to pure UHMWPE. With the addition of 3 wt% HNTs@TiO2, the UHMWPE nanocomposite achieved a remarkably low friction coefficient of 0.073 and a reduced wear rate of 6.67 × 10−6 mm3/N·m. These values represented a 32.4% decrease in friction coefficient and a 43.9% decrease in wear rate compared to pure UHMWPE. The improvement in wear resistance was due to the dislodged TiO2 and HNTs had good synergistic rolling effects at the counterface. Furthermore, the wear scan morphology observation revealed that the transferred HNTs@TiO2‐based materials could help to improve the quality of the tribofilms, which alleviated the abrasive wear from the metallic counterpart. This work offers a feasible way to enhance the wear resistance of UHMWPE nanocomposite without sacrificing the high ductility for expanding its engineering applications. Highlights: TiO2‐decorated halloysite nanotubes were synthesized by the sol–gel method.The addition of HNTs@TiO2 maintained the high ductility character of UHMWPE.The UHMWPE composite with 3 wt% HNTs@TiO2 had the best wear resistance. [ABSTRACT FROM AUTHOR]

The sensitive detection of antioxidants in food is essential for the rational control of their usage and reducing potential health risks. A simple three-dimensional (3D) electrode integrated with an anti-fouling/anti-interference layer possesses great potential for the direct and sensitive electrochemical detection of antioxidants in food samples. In this work, a 3D electrochemical sensor was developed by integrating a 3D graphene electrode (3DG) with vertically ordered mesoporous silica film (VMSF), enabling highly sensitive detection of the common antioxidant, butylated hydroxyanisole (BHA), in food samples. A simple electrochemical polarization was employed to pre-activate the 3DG electrode (p3DG), enhancing its hydrophilicity. Using the p3DG as the supporting electrode, stable modification of VMSF was achieved using the electrochemical assisted self-assembly (EASA) method, without the need for any adhesive agents (VMSF/p3DG). Taking BHA in food as a model analyte, the VMSF/p3DG sensor demonstrated high sensitivity, due to the enrichment by nanochannels, towards BHA. Electrochemical detection of BHA was achieved with a linear range of 0.1 μM to 5 μM and from 5 μM to 150 μM with a low limit of detection (12 nM). Owing to the fouling resistance and anti-interference capabilities of VMSF, the constructed 3D electrochemical sensor can be directly applied for the electrochemical detection of BHA in complex food samples. [ABSTRACT FROM AUTHOR]